WO2023235545A2 - Dosage and administration of fusion polypeptides for treatment of myasthenia gravis - Google Patents

Dosage and administration of fusion polypeptides for treatment of myasthenia gravis Download PDF

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Publication number
WO2023235545A2
WO2023235545A2 PCT/US2023/024252 US2023024252W WO2023235545A2 WO 2023235545 A2 WO2023235545 A2 WO 2023235545A2 US 2023024252 W US2023024252 W US 2023024252W WO 2023235545 A2 WO2023235545 A2 WO 2023235545A2
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study
administered
weeks
subject
dose
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PCT/US2023/024252
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French (fr)
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Stephan ORTIZ
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Alexion Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific

Definitions

  • the complement system acts in conjunction with other immunological systems of the body to defend against intrusion of cellular and viral pathogens.
  • complement proteins There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors.
  • the plasma proteins make up about 10% of the globulins in vertebrate serum.
  • Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events.
  • the resulting complement cascade leads to the production of products with opsonic, immunoregulatory and lytic functions.
  • MG Myasthenia Gravis
  • NMJ neuromuscular junction
  • auto-Abs auto-antibodies
  • proteins involved in signaling at the NMJ include the nicotine acetylcholine receptors (AChRs) or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering.
  • AChRs nicotine acetylcholine receptors
  • MuSK muscle-specific tyrosine kinase
  • MG may cause life-threatening respiratory failure, referred to as myasthenic crisis.
  • myasthenic crisis MG has a prevalence of 14-20 per 100,000 in the U.S., affecting roughly 60,000 Americans. It affects males and females in equal ratio, although the incidence in females peaks in the 3rd decade as compared to males in whom the peak age at onset is in the 6th or 7th decade. About 15% to 20% of subjects experience a myasthenic crisis during the course of their disease, 75% within 2 years of diagnosis, requiring hospitalization and ventilatory support. Mortality from MG is approximately 4%, mostly due to respiratory failure.
  • MG myasthenia gravis is clinically characterized by weakness and fatigability of voluntary skeletal muscles.
  • MG may initially present with ocular muscle weakness affecting eye and eyelid movement, referred to as ocular MG (oMG).
  • oMG ocular MG
  • Bulbar weakness refers to muscles controlled by nerves originating from the bulb-like part of the brainstem and manifests as difficulty in talking, chewing, swallowing and control of the head.
  • gMG Generalized myasthenia gravis
  • oMG ocular myasthenia gravis
  • gMG a rare disorder, having an estimated prevalence between 145 to 278 per million. Patients with gMG suffer from a devastating inflammatory neuromuscular disorder with limited therapeutic options.
  • MG While there is no cure for MG, there are therapies that reduce muscle weakness and improve neuromuscular function.
  • Current available treatments for myasthenia gravis aim to modulate neuromuscular transmission, inhibit the production or effects of pathogenic antibodies, or inhibit inflammatory cytokines.
  • ISTs immunosuppressive therapies
  • AZA azathioprine
  • MMF mycophenolate mofetil
  • these therapies may not be optimal for all patients, and there is a cohort of subjects who do not respond adequately to ISTs, or cannot tolerate ISTs, and those who require repeated treatments with plasma exchange (PE) and/or intravenous immunoglobulin (I Vlg) to maintain clinical stability.
  • PE plasma exchange
  • I Vlg intravenous immunoglobulin
  • patients with gMG experience unrelenting inflammation, tissue destruction, and consequent severe morbidities including profound muscle weakness, impaired mobility, shortness of breath, pulmonary failure, extreme fatigue, risk for aspiration, and markedly impaired ADLs. These patients are typically diagnosed in the prime of their adult lives, with a median age of onset ranging from 36 to 60 years. As a result of the morbidities associated with gMG, many patients cannot work or have diminished work capacity, experience difficultly caring for themselves and others, and require assistance speaking, eating, ambulating, breathing and performing ADLs.
  • Uncontrolled terminal complement activation has been implicated in animal models of experimental autoimmune gMG as well as in other forms of autoimmune neuropathy in humans.
  • Auto-Abs recognize targeted neural or muscle tissues, including the AChR, leading to uncontrolled terminal complement activation at the neural or muscle surface.
  • the disclosure provides a method of treating myasthenia gravis (MG) in a human subject in need thereof, including administering to the human subject a therapeutically effective dose of a fusion protein including an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the engineered polypeptide that specifically binds to human complement component C5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 5, 6, and 7, respectively, and wherein the engineered polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2, and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 1 , 2,
  • the polypeptide that specifically binds to human serum albumin includes a VHH domain. In some embodiments, the polypeptide that specifically binds to human serum albumin includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 4. In some embodiments, the polypeptide that specifically binds to human serum albumin includes an amino acid sequence of SEQ ID NO: 4.
  • the polypeptide that specifically binds to human complement component C5 includes a VHH domain. In some embodiments, the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 8. In some embodiments, the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence of SEQ ID NO: 8. In some embodiments, the peptide linker includes the amino acid sequence of SEQ ID NO:10.
  • the fusion protein includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 9. In some embodiments, the fusion protein includes an amino acid sequence of SEQ ID NO: 9.
  • the C-terminal residue of the polypeptide that specifically binds to human serum albumin is fused via the linker to the N-terminal residue of the polypeptide that specifically binds to human complement component C5.
  • the subject is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR).
  • the MG is generalized myasthenia gravis (gMG).
  • the subject has been diagnosed with MG, e.g., anti-AChR positive gMG, for at least 3 months.
  • the subject is 18 years old or older in age.
  • the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification of between II and IV.
  • the patient has a Myasthenia Gravis Activities of Daily Living (MG-ADL) score greater than or equal to 5.
  • the subject is being administered one or more additional pharmaceutical compositions.
  • the pharmaceutical composition is an acetylcholinesterase inhibitor, an immunosuppressive therapy (1ST), or immunoglobulins.
  • 1ST is selected from the group consisting of a corticosteroid, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).
  • the subject has not been administered a B cell-depleting therapy in the prior 6 months.
  • the B cell-depleting therapy is rituximab or ocrelizumab.
  • the subject has not been administered an FcRn inhibitor within 5 half-lives of the FcRn before administration of the fusion protein.
  • the subject has not been administered a complement inhibitor within 5 half-lives of the complement inhibitor before administration of the fusion protein.
  • the subject weighs at least 40 kg.
  • the subject has a body mass index of > 18.5 kg/m 2 and ⁇ 40 kg/m 2 (e.gr, between 18.5 kg/m 2 and 39.5 kg/m 2 , 20 kg/m 2 and 35 kg/m 2 , 25 kg/m 2 and 30 kg/m 2 , 25 kg/m 2 and 39.5 kg/m 2 , and 18.5 kg/m 2 and 35 kg/m 2 .
  • the therapeutically effective dose is based on the weight of the subject.
  • the fusion protein is administered to a patient weighing ⁇ 80 kg once on Day 1 of the administration cycle at a loading dose of 600 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 300 mg. In some embodiments, fusion protein is administered at a dose of 300 mg every week after the administration cycle for up to two years. In some embodiments, the fusion protein is administered to a patient weighing > 80 kg once on Day 1 of the administration cycle at a loading dose of 900 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 600 mg. In some embodiments, fusion protein is administered at a dose of 600 mg every week after the administration cycle for up to two years
  • the fusion protein is administered to the subject subcutaneously. In some embodiments, the fusion protein is administered to the subject using a pre-filled syringe. In some embodiments, the pre-filled syringe includes a passive needle safety device. In some embodiments, the fusion protein is administered to the subject using an autoinjector.
  • the treatment results in the patient experiencing a change from baseline in MG-ADL score. In some embodiments, the treatment results in the patient experiencing a change from baseline in MG-ADL score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in the MG-ADL score after 26 weeks. In some embodiments, the reduction is at least 3.0 points. In some embodiments, the reduction is at least 4.0 points.
  • the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis (QMG) score. In some embodiments, the treatment results in the patient experiencing a change from baseline in QMG score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in QMG score after 26 weeks. In some embodiments, the reduction is at least 2.0 points. In some embodiments, the reduction is at least 5.0 points. In some embodiments, the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis composite (MGC) score. In some embodiments, the treatment results in the patient experiencing a change from baseline in MGC score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in MGC score after 26 weeks.
  • QMG quantitative Myasthenia Gravis
  • the treatment results in subject experiencing a change from baseline in serum free or total C5 concentration. In some embodiments, the treatment results in the patient experiencing a change from baseline in MG Quality of Life 15 (MG-QoL15r) score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in EQ-5D-5L score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in SF-36 score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in Neuro-QoL Fatigue (Quality of Life in Neurological Disorders Fatigue Short Form) score after 26 weeks. In some embodiments, the treatment results in the patient experiencing an MG-ADL score of 1 or less after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change in MGFA postintervention status after 26 weeks.
  • MG-QoL15r MG Quality of Life 15
  • the treatment results in the patient experiencing a reduction in incidence of clinical deteriorations after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in incidence of hospitalizations after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in incidence of requiring rescue therapy after 26 weeks. In some embodiments, the treatment results in a change in concentration of one or more inflammation biomarkers. In some embodiments, the one or more inflammation biomarkers includes MMP-10 or IL-6. In some embodiments, the treatment results in a change in concentration of complement proteins or complement pathway regulators. In some embodiments, the treatment effect is maintained through week 26 after initiation of treatment. In some embodiments, the treatment effect is maintained through week 96 after initiation of treatment.
  • the disclosure provides a method of treating gMG in a human subject in need thereof, including administering to the human subject a therapeutically effective dose of a fusion protein including an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the polypeptide that specifically binds to human complement component C5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 5, 6 and 7, respectively, and wherein the polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 1 , 2 and 3, respectively, wherein the subject is positive for
  • FIG. 1 is a schematic drawing showing the study design for administration of the fusion polypeptide having the amino acid sequence of SEQ ID NO: 9.
  • FIG. 2A -FIG. 2C are tables showing the schedule of test and measurements that are performed over the course of the randomized controlled period.
  • AChR Ab acetylcholine receptor antibody
  • ADA antidrug antibody
  • ADE adverse device effect
  • AE adverse event
  • B Baseline sample
  • C Clinic Visit
  • C5 complement component 5
  • C-SSRS Columbia- Suicide Severity Rating Scale
  • D day
  • ECG electrocardiogram
  • eCRF electronic case report form
  • EQ-5D-5L Euro Quality of Life-5 Dimensions-5 Levels
  • ET Early Termination
  • FSH follicle- stimulating hormone
  • HIV human immunodeficiency virus
  • MG myasthenia gravis
  • MG-ADL Myasthenia Gravis Activities of Daily Living
  • MGC Myasthenia Gravis Composite
  • MGFA Myasthenia Gravis Foundation of America
  • MGFA-PIS Myasthenia Gravis Foundation of America Post-Intervention Status
  • MGFA My
  • PK/PD pharmacokinetic(s)/pharmacodynamic(s);
  • FIG. 3A-FIG. 3D are tables showing the schedule of tests and measurements over the course of the open label extension.
  • FIG. 5 shows a diagram of an exemplary pre-filled syringe with a safety device.
  • antibody as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chain version thereof.
  • An “antibody” refers, in one preferred embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyterminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • a “heavy chain antibody” refers to an antibody that consists of two heavy chains and lacks the two light chains found in conventional antibodies.
  • Camelids members of the biological family Camelidae, the only currently living family in the suborder Tylopoda; extant camelids include dromedary camels, Bactrian camels, wild or feral camels, llamas, alpacas, vicunas and guanacos
  • camelids are the only mammals with single chain VHH antibodies.
  • About 50% of the antibodies in camelids are heavy chain antibodies with the other 50% being of the ordinary or conventional mammalian heavy/light chain antibody type.
  • VHH domain refers to variable domains present in naturally occurring heavy chain antibodies to distinguish them from the heavy chain variable domains that are present in conventional four chain antibodies (referred to herein as “VH domains”) and from the light chain variable domains that present in conventional four chain antibodies (referred to herein as “VL domains”).
  • VHH domains have a number of unique structural characteristics and functional properties that make isolated VHH domains (as well as sdAbs, which are based on VHH domains and share these structural characteristics and functional properties with the naturally occurring VHH domains) and proteins containing the VHH domains highly advantageous for use as functional antigen binding domains or proteins.
  • VHH domains which bind to an antigen without the presence of a VL, and sdAbs can function as a single, relatively small, functional antigen binding structural unit, domain or protein. The small size of these molecules distinguishes VHH domains from the VH and VL domains of conventional four-chain antibodies.
  • VHH domains and sdAbs as single antigen-binding proteins or as antigen-binding domains (e.g., as part of a larger protein or polypeptide) offers a number of significant advantages over the use of conventional VH and VL domains, as well as scFv or conventional antibody fragments (such as Fab or F(ab')2 fragments). Only a single domain is required to bind an antigen with high affinity and with high selectivity, for example, so that there is no need to have two separate domains present, nor to assure that these two domains are present in a particular spatial conformation and configuration (e.g., through the use of specific linkers, as with an scFv).
  • VHH domains and sdAbs can also be expressed from a single gene and require no post-translational folding or modifications. VHH domains and sdAbs can easily be engineered into multivalent and multi-specific formats. VHH domains and sdAbs are also highly soluble and do not have a tendency to aggregate (Ward, E. et al., Nature, 341 :544-6, 1989), and they are highly stable to heat, pH, proteases and other denaturing agents or conditions (Ewert, S. et al., Biochemistry, 41 :3628-36, 2002). VHH domains and sdAbs are relatively easy and cheap to prepare, even on a scale required for production.
  • VHH domains, sdAbs, and polypeptides containing VHH domains or sdAbs can be produced using microbial fermentation using methods known in the art and do not require the use of mammalian expression systems, as with, for example, conventional antibody fragments.
  • VHH domains and sdAbs are relatively small (approximately 15 kDa, or 10 times smaller than a conventional IgG) compared to conventional four-chain antibodies and antigen-binding fragments thereof, and therefore show higher penetration into tissues (including but not limited to solid tumors and other dense tissues) than conventional four-chain antibodies and antigen-binding fragments thereof.
  • VHH domains and sdAbs can show so-called "cavity-binding" properties (due to, for example, their extended CDR3 loop) and can access targets and epitopes not accessible to conventional four-chain antibodies and antigen-binding fragments thereof. It has been shown, for example, that VHH domains and sdAbs can inhibit enzymes (WO 97/49805; Transue, T. et al., Proteins, 32:515-22, 1998; Lauwereys, M. et al., EMBO J., 17:3512-20, 1998).
  • single-domain antibody is an antibody or fragment thereof consisting of a single monomeric variable antibody domain. It is not limited to a specific biological source or to a specific method of preparation.
  • a sdAb can be obtained, for example, by (1) isolating the VHH domain of a naturally occurring heavy chain antibody; (2) expressing a nucleotide sequence encoding a naturally occurring VHH domain; (3) "humanization” of a naturally occurring VHH domain or by expression of a nucleic acid encoding such humanized VHH domain; (4) “camelization” of a naturally occurring VH domain from any animal species, in particular a species of mammal, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) "camelization” of a "domain antibody” (“Dab”) or by expression of a nucleic acid encoding such a camelized VH domain; (6) using synthetic or semi-s
  • the fusion polypeptides or fusion proteins described herein can comprise, for example, amino acid sequences of naturally occurring VHH domains that have been "humanized,” e.g., by replacing one or more amino acid residues in the amino acid sequence of the naturally occurring VHH sequence by one or more of the amino acid residues that occur at the corresponding positions in a VH domain from a human being.
  • the fusion polypeptides or fusion proteins described herein can comprise, for example, amino acid sequences of naturally occurring VH domains that have been "camelized," i.e., by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain with one or more of the amino acid residues that occur at the corresponding positions in a VHH domain of, for example, a camelid antibody.
  • This can be performed in a manner known in the art.
  • camelization may preferentially occur at amino acid positions that are present at the VH-VL interface and at the so-called “Camelidae hallmark residues" (WO 94/04678).
  • the VH domain or sequence that is used as a parental sequence or starting material for generating or designing the camelized sequence can be, for example, a VH sequence from a mammal, and in certain embodiments, the VH sequence of a human. It should be noted, however, that such camelized sequences can be obtained in any suitable manner known in the art and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring parental VH domain.
  • Both “humanization” and “camelization” can be performed by providing a nucleotide sequence that encodes a naturally occurring VHH domain or VH domain, respectively, and then changing, in a manner known to those skilled in the art, one or more codons in the nucleotide sequence such that the new nucleotide sequence encodes a humanized or camelized sequence, respectively.
  • a nucleotide sequence encoding a desired humanized or camelized sequence can be designed and synthesized de novo using techniques for nucleic acid synthesis known in the art, after which the nucleotide sequence thus obtained can be expressed in a manner known in the art.
  • antigen or "antigen target,” as used herein, refer to a molecule or a portion of a molecule that is capable of being bound to by an antibody, one or more Ig binding domain, or other immunological binding moiety, including, for example, the engineered polypeptides or fusion polypeptides disclosed herein.
  • An antigen is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen.
  • An antigen may have one or more epitopes.
  • antibody fragment refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen.
  • fragments are, for example between about 8 and about 1500 amino acids in length, suitably between about 8 and about 745 amino acids in length, suitably about 8 to about 300, for example about 8 to about 200 amino acids, or about 10 to about 50 or 100 amino acids in length. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • binding fragments encompassed within the term “antigen-binding fragment” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V_, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341 :544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs, which may optionally be joined by a synthetic linker.
  • a Fab fragment a monovalent fragment consisting of the V_, VH, CL and CH
  • the two domains of the Fv fragment, VL and H are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (sFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” of an antibody.
  • Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
  • binding domain refers to the portion of a protein or antibody that comprises the amino acid residues that interact with an antigen. Binding domains include, but are not limited to, antibodies (e.g., full length antibodies), as well as antigen-binding portions thereof. The binding domain confers on the binding agent its specificity and affinity for the antigen. The term also covers any protein having a binding domain that is homologous or largely homologous to an immunoglobulin-binding domain.
  • the phrase “clinical deterioration” refers to patients who experience an MG Crisis, which is defined as weakness from MG that is severe enough to necessitate intubation or to delay extubation following surgery, where the respiratory failure is due to weakness of respiratory muscles, severe bulbar (oropharyngeal) muscle weakness accompanies the respiratory muscle weakness, or is the predominant feature in a patient; or when there is significant symptomatic worsening to a score of 3 or a 2-point worsening from baseline on any one of the individual MG- Activities of Daily Living (MG-ADL) items other than double vision or eyelid droop; or administration of rescue therapy is provided to a patient whose, in the opinion of the investigator or investigator- designated physician, health would be in jeopardy, if rescue therapy were not given (e.g., emergent situations).
  • MG-ADL MG- Activities of Daily Living
  • epitopes refers to a site on an antigen to which an immunoglobulin or antibody specifically binds.
  • Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents.
  • An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 amino acids in a unique spatial conformation.
  • epitope mapping Methods for determining what epitopes are bound by a given antibody (/.e., epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, wherein overlapping or contiguous peptides from the antigen are tested for reactivity with the given antibody.
  • Methods of determining spatial conformation of epitopes include techniques in the art and those described herein, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G. E. Morris, Ed. (1996)).
  • bispecific refers to a fusion polypeptide of the disclosure that is capable of binding two antigens.
  • an “effective amount” refers to an amount of an agent that provides the desired biological, therapeutic and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying and/or alleviation of one or more of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system.
  • an “effective amount” is the amount of fusion polypeptide or fragment thereof clinically proven to alleviate at least one symptom of MG.
  • An effective amount can be administered in one or more administrations.
  • effective treatment refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder.
  • a beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method.
  • Effective treatment may refer to alleviation of at least one symptom of MG.
  • fused to refers to a polypeptide made by combining more than one sequence, typically by cloning one sequence, e.g., a coding sequence, into an expression vector in frame with one or more second coding sequence(s) such that the two (or more) coding sequences are transcribed and translated into a single continuous polypeptide.
  • parts of a polypeptide can be "fused to” each other by means of chemical reaction, or other means known in the art for making custom polypeptides.
  • induction and “induction phase” are used interchangeably and refer to the first phase of treatment in the clinical trial.
  • the terms “loading dose” refers to the initial dose administered to the patient.
  • the loading dose is 500-1000 mg of the fusion polypeptide.
  • the loading dose is 600-900 mg, 700-900 mg, or 600-800 mg of the fusion polypeptide.
  • the loading dose is 800-1000 mg, 600-700 mg, or 700-1000 mg of the fusion polypeptide.
  • the loading dose is about 600 mg, about 700 mg, about 800, or about 900 mg of the fusion polypeptide. Loading doses may be titered based on body weight.
  • patients with a body weight greater than or equal to 40 kg, but less than 80 kg is administered 200-700 mg, 300-600 mg, about 600 mg or 300 mg of the fusion polypeptide. In some embodiments, patients with a body weight greater than or equal to 80 kg, are administered 500-1000 mg, 600-900 mg, about 600 mg, or 900 mg of the fusion polypeptide.
  • the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment in the clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs.
  • the maintenance phase of the fusion polypeptide dosing can last for between 1 week and the life of the subject. According to other embodiments, the maintenance phase lasts for 26-52, 26- 78, 26-96, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more.
  • the maintenance phase lasts for greater than 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 78, 96, 104, 130, 156, or 182 weeks. According to other embodiments, the maintenance phase lasts for greater than 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or more years. In certain embodiments, the maintenance phase lasts for the remainder of the subject's life.
  • the terms “maintenance dose” or “maintenance phase” refers to a dose administered to the patient after the loading dose.
  • the loading dose is 200- 700 mg of the fusion polypeptide.
  • the maintenance dose is 300-700 mg, 400-600 mg or 300-700 mg of the fusion polypeptide.
  • the maintenance dose is 200-600 mg, 200-500 mg, or 400-700 mg of the fusion polypeptide.
  • the maintenance dose is about 300 mg, about 200 mg, or about 400 mg of the fusion polypeptide.
  • the maintenance dose is 600 mg, 500 mg, or 700 mg of the fusion polypeptide. Maintenance doses may be titered based on body weight.
  • patients with a body weight greater than or equal to 40 kg, but less than 80 kg is administered 200-400 mg, 300-400 mg, about 300 mg, or 200 mg of the fusion polypeptide. In some embodiments, patients with a body weight greater than or equal to 80 kg is administered 500-700 mg, 600-700 mg, about 600 mg, or 700 mg of the fusion polypeptide.
  • the phrase “requires chronic plasma exchange” to maintain clinical stability refers to the use of plasma exchange therapy on a patient on a regular basis for the management of muscle weakness at least every 3 months over the last 12 months.
  • peptide linker refers to one or more amino acid residues inserted or included between the engineered polypeptides of the fusion polypeptide(s).
  • the peptide linker can be, for example, inserted or included at the transition between the engineered polypeptides of the fusion polypeptide at the sequence level.
  • composition refers to a compound or composition capable of inducing a desired therapeutic effect when administered to a patient.
  • pharmaceutically acceptable carrier refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of the engineered polypeptides or fusion polypeptides ofthe disclosure.
  • An antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or the engineered polypeptides or fusion polypeptides disclosed herein, are said to "specifically" bind an antigen when the molecule preferentially recognizes its antigen target in a complex mixture of proteins and/or macromolecules.
  • the term "specifically binds,” as used herein, refers to the ability of an antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or an engineered polypeptide or fusion polypeptide of the disclosure, to bind to an antigen containing an epitope with an KD of at least about 10’ 6 M,10' 7 M, 10’ 8 M, 10' 9 M, 10' 1 ° M, 10' 11 M, 10' 12 M, or more, and/or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen.
  • the term “subject” or “patient” is a human patient (e.g., a patient having myasthenia gravis (MG)). As used herein, the term “subject” and “patient” are interchangeable.
  • treatment or “treat,” as used herein, refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having the disorder as well as those at risk of having the disorder orthose in which the disorder is to be prevented.
  • treatment effect refers to a reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis (QMG) score, Myasthenia Gravis (MG) Quality of Life Questionnaire (MGQOL15R) score, Neuro-QOL-Fatigue score, or another score that assesses the severity of MG, relative to baseline priorto initiation of a treatment.
  • the reduction may be 1 point or greater.
  • the disclosure provides methods of treating myasthenia gravis (MG) in subjects in need thereof by administering a fusion polypeptide comprising an engineered polypeptide that specifically binds human complement component C5 fused to a polypeptide that specifically binds to human serum albumin by way of a peptide linker.
  • MG myasthenia gravis
  • the fusion polypeptide includes an engineered polypeptide that specifically binds human serum albumin, having the sequence of SEQ ID NO: 4, fused to a polypeptide that specifically binds to human complement component 5, having the amino acid sequence of SEQ ID NO: 8.
  • fusion polypeptides that comprise engineered polypeptides that specifically bind albumin and complement component C5, wherein the engineered polypeptides are fused directly or are linked via one or more suitable linkers or spacers.
  • the peptide linker can be, for example, inserted or included at the transition between the engineered polypeptides of the fusion polypeptide at the sequence level.
  • the identity and sequence of amino acid residues in the linker may vary depending on the desired secondary structure. For example, glycine, serine and alanine are useful for linkers having maximum flexibility.
  • any amino acid residue can be considered as a linker in combination with one or more other amino acid residues, which may be the same as or different from the first amino acid residue, to construct larger peptide linkers as necessary depending on the desired properties.
  • the linker is GGGGAGGGGAGGGGS (SEQ ID NO:10).
  • One of skill in the art can select a linker, for example, to reduce or eliminate post-translational modification, e.g., glycosylation, e.g., xylosylation.
  • the C-terminal residue of the albumin-binding domain of the fusion polypeptide can be fused either directly or via a peptide to the N-terminal residue of the complement component C5 binding domain.
  • the polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2 and CDR3, wherein CDR1 has an amino acid sequence of GRPVSNYA (SEQ ID NO: 1), CDR2 has an amino acid sequence of INWQKTAT (SEQ ID NO: 2) and CDR3 has an amino acid sequence of AAVFRVVAPKTQYDYDY (SEQ ID NO: 3).
  • the polypeptide that specifically binds to human complement component 5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, wherein CDR1 has an amino acid sequence of GRAHSDYAMA (SEQ ID NO: 5), CDR2 has an amino acid sequence of GIGWSGGDTLYADSVRG (SEQ ID NO: 6) and CDR3 has an amino acid sequence of AARQGQYIYSSMRSDSYDY (SEQ ID NO: 7).
  • the polypeptide that specifically binds to human serum albumin includes an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to the VHH sequence:
  • the polypeptide that specifically binds to human serum albumin has an amino acid sequence of SEQ ID NO: 4.
  • the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to the VHH sequence:
  • the polypeptide that specifically binds to human complement component C5 has an amino acid sequence of SEQ ID NO: 8.
  • a fusion polypeptide comprises a complement component C5 binding comprising an amino acid sequences of SEQ ID NO: 8 or a fragment thereof; and the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence of SEQ ID NO: 4 or a fragment thereof.
  • the fusion polypeptide may have an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to:
  • the fusion polypeptide has an amino acid sequence of SEQ ID NO: 9.
  • the C-terminus of the sequence that specifically binds human serum albumin (SEQ ID NO:4) is fused to a GGGGAGGGGAGGGGS (SEQ ID NO:10) linker, which is fused to the N-terminus of the polypeptide that specifically binds human complement component C5 (SEQ ID NO:8).
  • the fusion polypeptides disclosed herein can be made by expressing in a host cell at least one nucleic acid molecule comprising a nucleotide sequence encoding the fusion polypeptide.
  • Host cells can be mammalian, plant or microbial in origin.
  • yeast host cells e.g., Pichia pastoris, Saccharomyces cerevisiae, and/or plant host cells can be used.
  • the polypeptide has been studied in a Phase 1 , randomized, double-blind, placebo- controlled, single and multiple ascending dose study involving 97 healthy subjects (EudraCT 2018- 004500-19, NCT04920370).
  • Single doses of the polypeptide ranged from 30 mg to 1700 mg SC, included 1700 mg SC combined with a recombinant human hyaluronidase, and intravenous (IV) administration of 300 mg. Multiple doses ranged from 100 to 300 mg SC Q1 W for 3 doses, and 600 mg SC Q1W following an initial (loading) dose of 900 mg, for a total of 8 doses. While a detailed analysis of the data from this Phase 1 study is still pending, preliminary findings indicate a favorable safety and tolerability profile. All adverse events (AEs)were of mild or moderate severity, and no serious adverse events (SAEs) were observed.
  • AEs adverse events
  • SAEs serious adverse events
  • the purpose of the pivotal Phase 3 study described in this protocol is to test the safety and efficacy of the polypeptide(s) described herein, administered through SC injection using a pre-filled syringe with safety device (PFS-SD), for the treatment of adults with AChR+ gMG.
  • PFS-SD pre-filled syringe with safety device
  • MG e.g., generalized MG (gMG), e.g., gMG when the patient is anti-AChR antibody positive
  • a fusion polypeptide comprising an engineered polypeptide that specifically binds human complement component C5 fused to a polypeptide that specifically binds to human serum albumin by way of a peptide linker according to a particular clinical dosage regimen (/.e., at a particular dose amount and according to a specific dosing schedule).
  • MG includes gMG.
  • gMG is characterized as including subjects or patients positive for auto-antibodies binding to AChR who continue to show marked generalized weakness or bulbar signs and symptoms of MG while receiving current standard of care for MG such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability.
  • the fusion polypeptide is administered once on Day 1 of the administration cycle, once on Day 8 of the administration cycle, and every week thereafter. In some embodiments, the fusion polypeptide is administered every week after the administration cycle for an extension period up to two years (e.g., at a dose of 300 mg or 600 mg). In some embodiments, the fusion polypeptide is administered every week after the administration cycle for an extension period for the life of the subject (e.g., at a dose of 300 mg or 600 mg).
  • the fusion polypeptide is administered for one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In another embodiment, the treatment is continued for the lifetime of the human patient.
  • the dose of the fusion polypeptide is based on the weight of the patient.
  • the fusion polypeptide is administered to a patient weighing ⁇ 80 kg on Day 1 of the administration cycle in an amount of between 500 mg and 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing ⁇ 80 kg on Day 1 of the administration cycle in an amount of 600 mg.
  • 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg is administered to a patient weighing ⁇ 80 kg on
  • the fusion polypeptide is administered to a patient weighing ⁇ 80 kg on Day 8 of the administration cycle at a maintenance does of between 200 mg and 400 mg (e.g., 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing ⁇ 80 kg on Day 8 of the administration cycle at a maintenance does of 600 mg.
  • the fusion polypeptide is administered to a patient weighing > 80 kg on Day 1 of the administration cycle in an amount of between 800 mg and 1000 mg (e.g., 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 1 of the administration cycle in an amount of 900 mg.
  • 800 mg and 1000 mg e.g., 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg.
  • the fusion polypeptide is administered to a patient weighing > 80 kg on Day 8 of the administration cycle at a maintenance does of between 500 mg and 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 8 of the administration cycle at a maintenance does of 600 mg.
  • 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg is administered to a patient weighing > 80 kg
  • the fusion polypeptide is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily. In another embodiment, the fusion polypeptide is administered twice daily. In another embodiment, the fusion polypeptide is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the fusion polypeptide is administered at a loading dose on Day 1 , followed by a different maintenance dose on Day 8 and every week thereafter.
  • the fusion polypeptide is administered using a pre-filled syringe.
  • the fusion polypeptide is administered using an autoinjector device.
  • the autoinjector device may include a single vial system, such as a pen injector device for solution delivery.
  • Such devices are commercially available from manufacturers such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D®Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, DosePro®, Medi-Ject®, e.g., as made or developed by Becton Dickinson (Franklin Lakes, NJ), Ypsomed (Burgdorf, Switzerland, www.ypsomed.com; Bioject, Portland, OR.; National Medical Products, Weston Medical (Peterborough, UK), Medi-Ject Corp (Minneapolis, MN), and Zogenix, Inc, Emeryville, CA.
  • manufacturers such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D®P
  • Recognized devices comprising a dual vial system include those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery of the reconstituted solution such as the HumatroPen®.
  • the autoinjector is a YpsoMate 2.25 or YpsoMate 2.25 Pro (Ypsomed) disposable injection device.
  • the patients treated according to the methods described herein have been vaccinated against meningococcal infections within three years prior to, or at the time of, initiating study drug.
  • patients who initiate treatment less than two weeks after receiving a meningococcal vaccine receive treatment with appropriate prophylactic antibiotics until two weeks after vaccination.
  • patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.
  • treatment of MG includes the amelioration or improvement of one or more symptoms associated with MG.
  • Symptoms associated with MG include muscle weakness and fatigability. Muscles primarily affected by MG include muscles that control eye and eyelid movement, facial expressions, chewing, talking, swallowing, breathing, neck movements, and limb movements.
  • treatment of MG includes the improvement of a clinical marker for MG progression.
  • markers include MG-ADL scores, QMG score for disease severity, MGC, NIF, forced vital capacity, MGFA post-intervention status, and other quality of life measurements.
  • MG-ADL is the primary score for measuring improvement of MG.
  • the MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living (ADL) in MG subjects (Table 1).
  • the 8 items of the MG- ADL were derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG.
  • each response is graded 0 (normal) to 3 (most severe).
  • the range of total MG-ADL score is 0-24.
  • a clinically meaningful improvement in a patient's MG-ADL in one embodiment is, for example, a 3 point or greater reduction in score after 26 weeks of treatment.
  • the current QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe (Table 2).
  • the range of total QMG score is 0-39.
  • the QMG scoring system is an objective evaluation of therapy for MG and is based on quantitative testing of sentinel muscle groups.
  • the MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG (Benatar, M. et al., Muscle Nerve, 45:909-17, 2012).
  • a clinically meaningful improvement in a patient’s QMG in one embodiment is, for example, a 5 point or greater reduction in score after 26 weeks of treatment.
  • the MGC is a validated assessment tool for measuring clinical status of subjects with MG (16).
  • the MGC assesses 10 important functional areas most frequently affected by MG and the scales are weighted for clinical significance that incorporates subject-reported outcomes (Table 3; Burns, T. et al., Muscle Nerve, 54:1015-22, 2016).
  • MGC is administered at Screening, Day 1 , Weeks 1-4, 8, 12, 16, 20, and 26 or ET (Visits 1-6, 8, 10, 12, 14, and 17 or ET).
  • a clinically meaningful improvement in a patient’s MGC in one embodiment is, for example, a 3 point or greater reduction in score after 26 weeks of treatment.
  • MG composite scale The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) is a health-related
  • the MG-QOL15r was designed to provide information about patients’ perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily.
  • the MG- QOL15r is completed by the patient. Higher scores indicate greater extent of and dissatisfaction with MG-related dysfunction.
  • a clinically meaningful improvement in a patient's MG-QOL 15 is a decrease in score after 26 weeks of treatment.
  • the Euro Quality of Life-5L (EQ-5D-5L) is a self-assessed, health-related QoL questionnaire.
  • the EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive scale system and the EQ visual analogue scale (EQ VAS).
  • the scale measures QoL on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
  • Each level is rated on a scale that describes the degree of problems in that area (e.g., I have no problems walking about, slight problems, moderate problems, severe problems, or unable to walk).
  • the patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions.
  • This decision results in a 1 -digit number that expresses the level selected for that dimension.
  • the digits for the five dimensions can be combined into a 5- digit number that describes the patient’s health state.
  • a clinically meaningful improvement in a patient’s EQ 5D is reflected as a decrease in scores in each category after 26 weeks of treatment.
  • This tool also has an overall health scale (EQ VAS) where the rater selects a number between 1 - 100 to describe the condition of their health, 100 being the best imaginable.
  • the EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints are labeled ‘The best health you can imagine’ and ‘The worst health you can imagine.’
  • the VAS can be used as a quantitative measure of health outcome that reflect the patient’s own judgement.
  • EQ-5D-5L approach is reliable, average test-retest reliability using interclass coefficients with mean of 0.78 and 0.73 (Brooks, R., Health Policy, 37:53-72, 1996; Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).
  • FVC Forced Vital Capacity
  • NIF Los of upper airway integrity
  • the MG clinical state is assessed using the MGFA Post-Intervention Status (MGFA-PIS). Change in status categories of Improved, Unchanged, Worse, Exacerbation and Died of MG as well as the Minimal Manifestation (MM) can be assessed (Table 6).
  • Patients administered the fusion polypeptide may show a reduced MG-ADL.
  • the subjects have an initial MG-ADL score of greater than or equal to 5 points.
  • the subjects have an initial MG-ADL score greater than 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22 or 23 points.
  • the MG-ADL score of the subject is reduced to less than 5 points.
  • the MG-ADL score is reduced at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, or at least 24 points after treatment with fusion polypeptide.
  • the MG-ADL score of the patient is reduced by at least 2 points after a course of treatment with the fusion polypeptide.
  • the MG-ADL of the patient is reduced by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 points after a course of treatment with the fusion polypeptide.
  • the course of treatment with fusion polypeptide lasts for 26 weeks. According to some embodiments, the course of treatment lasts for 26-52, 26-78, 26-96, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more. In some embodiments, the course of treatment lasts for greater than 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43,
  • the course of treatment lasts for greater than 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
  • the course of treatment lasts for the remainder of the subject’s life.
  • one or more symptoms or scores associated with MG improves during the course of treatment and is maintained at the improved level throughout treatment.
  • MG-ADL can improve, for example, after 26 weeks of treatment with the fusion polypeptide and then remain at the improved level for the duration of the treatment, which is 96 weeks of treatment with the fusion polypeptide.
  • the first sign of improvement occurs by 26 weeks of treatment with the fusion polypeptide. According to some embodiments, the first sign of improvement occurs between weeks 1-26, 26-52, 52-78, 26-96, 78-104, 104-130, 130-156, 156-182, or 182-208 of treatment with the fusion polypeptide.
  • the first sign of improvement occurs at week 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 78, 96, 104, 130, 156 or 182.
  • MG includes refractory gMG.
  • refractory gMG is characterized as including subjects or patients positive for auto-antibodies binding to AChR who continue to show marked generalized weakness or bulbar signs and symptoms of MG while receiving current standard of care for myasthenia gravis such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability.
  • refractory gMG is characterized as including subjects or patients who continue to show marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving current standard of care for MG such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability.
  • the subject is 18 years old or older in age.
  • the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification of between II and IV.
  • MGFA Myasthenia Gravis Foundation of America
  • the subject is being administered one or more additional pharmaceutical compositions.
  • the pharmaceutical composition is an acetylcholinesterase inhibitor, an 1ST, or immunoglobulins.
  • 1ST is selected from the group consisting of a corticosteroid, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).
  • the subject has not been administered a B cell-depleting therapy in the prior 6 months.
  • the B cell-depleting therapy is rituximab or ocrelizumab.
  • the subject has not been administered an FcRn inhibitor within 5 half-lives of the FcRn before administration of the fusion polypeptide.
  • kits that include a pharmaceutical composition containing a fusion polypeptide described herein, such as the fusion polypeptide having the amino acid sequence of SEQ ID NO: 9, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods.
  • the kits can also optionally include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse or patient) to administer the composition contained therein to administer the composition to a patient having MG.
  • the kit also can include a syringe.
  • Kits can optionally include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the fusion polypeptide for a single administration in accordance with the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits.
  • a kit may provide one or more pre-filled syringes containing an amount of the fusion polypeptide.
  • a kit may include one or more autoinjectors containing an amount of the fusion polypeptide.
  • Example 1 A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel, Multicenter Study to Evaluate the Safety and Efficacy of a C5-binding polypeptide in Adults with gMG
  • Table 7 Mapping Objectives and Estimands and/or Endpoints Table 7: Mapping Objectives and Estimands and/or Endpoints Table 7: Mapping Objectives and Estimands and/or Endpoints Table 7: Mapping Objectives and Estimands and/or Endpoints
  • AChR+ anti-acetylcholine receptor antibody-positive
  • ADA antidrug antibody
  • ADE adverse device effect
  • AE adverse event
  • C5 complement component 5;
  • ECG electrocardiogram
  • EQ-5D-5L Euro Quality of Life- 5 Dimensions-5 Levels
  • gMG generalized myasthenia gravis
  • IL-6 interleukin-6
  • MG-ADL Myasthenia Gravis-Activities of Daily Living
  • MGC Myasthenia Gravis Composite
  • MGFA-PIS Myasthenia Gravis Foundation of America Post-Intervention Status
  • MG-QoL15r revised 15-item Myasthenia Gravis Quality of Life scale
  • MM minimal manifestation
  • MMP-10 matrix metalloproteinase-10
  • MSE Minimal Symptom Expression
  • Neuro-QoL Fatigue Quality of Life in Neurological Disorders Fatigue (Short Form)
  • PD pharmacodynamic(s)
  • PFS-SD prefilled syringe with safety device;
  • PK pharmacokinetic(s);
  • QMG Quantitative Myasthenia Gravis score for disease severity;
  • QoL quality of life;
  • SADE serious adverse device effect;
  • SAE serious adverse event;
  • SF-36 Short Form Health Survey (36 question version).
  • the estimand corresponding to the primary objective is defined as follows:
  • the study compares the fusion polypeptide described herein with placebo in adults with AChR+ gMG.
  • the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the MG-ADL total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention.
  • the difference between treatment groups in the mean change from Baseline in the MG-ADL total score at Week 26 is assessed.
  • the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the Quantitative Myasthenia Gravis score for disease severity (QMG) total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention.
  • QMG Quantitative Myasthenia Gravis score for disease severity
  • the other secondary objectives assess the efficacy of the fusion polypeptide described herein compared with placebo in the treatment of gMG based on the level of improvement in the QMG total score, the level of improvement in the MG-ADL total score, and the change in the Myasthenia Gravis Composite (MGC) total score.
  • MMC Myasthenia Gravis Composite
  • the estimands corresponding to these secondary objectives are defined as follows:
  • the question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the QMG total score at Week 26 by > 5 points from Baseline regardless ofwhether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention.
  • the odds ratio of a reduction by > 5 points from Baseline in the QMG total score at Week 26 (the fusion polypeptide described herein compared to placebo) is calculated.
  • the question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the MG-ADL total score at Week 26 by > 3 points from Baseline regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention.
  • the odds ratio of a reduction by > 3 points from Baseline in the MG-ADL total score at Week 26 is calculated.
  • the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the MGC total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention.
  • the difference between treatment groups in the mean change from Baseline in the MGC total score at Week 26 is assessed.
  • Described herein is a Phase-3, randomized, double-blind, placebo-controlled, parallel, multicenter study to evaluate the safety and efficacy of the fusion polypeptide described herein in adults with generalized myasthenia gravis (gMG).
  • the study is conducted in North and South America, Europe, Asia, and the Pacific region.
  • Approximately 200 eligible participants are stratified by geographical region and body weight ( ⁇ 80 kg and > 80 kg) at Baseline and randomized 1 :1 to treatment with the fusion polypeptide described herein or placebo, both administered through weekly subcutaneous (SC) injection by using a PFS-SD.
  • Randomization of participants with an MG-ADL total score ⁇ 7 and participants receiving concomitant periodic (chronic) intravenous (IVIg) or SC immunoglobulin (SCIg) treatment are restricted as specified in Section 4.1 .2.
  • the study comprises 3 periods: Screening ( ⁇ 4 weeks), Randomized Control Trial (RCT) (26 weeks), and Open Label Extension (OLE) (96 weeks) (FIG. 1). Consenting participants are screened for study eligibility up to 4 weeks prior to Day 1 . Participants with confirmed gMG and a positive serological test for AChR antibodies are included if the severity of their disease is classified as between II and IV according to clinical criteria established by the Myasthenia Gravis Foundation of America (MGFA) (Jaretzki et al., Neurology, 55:16-23, 2000), and if their MG-ADL total score is > 5.
  • MGFA Classes II to IV comprise a broad participant population, excluding only participants with solely ocular symptoms or signs (Class I) and participants requiring intubation (Class V).
  • Participants who satisfy all eligibility criteria are randomized into the RCT Period and receive a weight-based loading dose of the fusion polypeptide described herein or placebo on Day 1 , followed by weight based maintenance treatment with the fusion polypeptide described herein or placebo on Week 1 (Day 8) and once a week (Q1 ) thereafter for a total of 26 weeks.
  • Doses in the RCT Period are based on participant body weight at Randomization.
  • participants and, if applicable, their caregivers are trained in administering the study intervention by designated study site personnel. Once training is complete and certified, participants may self-administerthe treatment at home unless the scheduled dose falls on the same day as an upcoming Clinic Visit. In this case, participants are asked to administer the study intervention at the clinic under supervision of the clinic staff to monitor their injection skills. Participants make every effort to maintain the weekly dosing intervals. However, deviations of ⁇ 1 day are acceptable if they cannot be avoided.
  • Participants who complete the 26-week RCT Period continue the study through the 96-week OLE Period (FIG. 1), or until the product is registered or approved (in accordance with countryspecific regulations), or until the fusion polypeptide described herein can be provided via a sponsor post-trial access program (as allowed by local laws and regulations), whichever occurs first. Participants transition to open-label treatment with the fusion polypeptide described herein following completion of the Day 183 assessments. To maintain the blinding of participants for their treatment allocation in the previous RCT Period, the first dose upon entry to the OLE Period on Day 183 is administered by study site personnel. Participants who were in the placebo group during the RCT Period receive a blinded weight-based loading dose of the fusion polypeptide described herein.
  • Participants who were in the fusion polypeptide group during the RCT Period receive a weight-based maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose. Participants resume the weekly self administered maintenance doses the following week (Day 190). Doses in the OLE Period are based on participant body weight at Day 183 and are reassessed approximately every 6 months as specified in the Schedule of Activities (SoA).
  • SoA Schedule of Activities
  • Final study assessments are performed in an EoS Visit at Week 122, 3 weeks after the last dose of the study intervention at Week 119. If a participant withdraws from the study or completes the study prior to Week 122 of the OLE Period, the participant is encouraged to return for an Early Termination (ET) Visit 3 weeks after the last dose of the study intervention is administered.
  • EERT Early Termination
  • the overall study duration for an individual participant is approximately 126 weeks (from Screening Visit through EoS Visit).
  • Participants treated with AChE inhibitors or immunosuppressive therapy (1ST) including corticosteroids at the time of the Screening Visit may continue taking their therapy throughout the RCT and OLE periods.
  • the dosage of AChE inhibitor or ISTs must not be changed, discontinued, or new AChE inhibitor or 1ST added, unless deemed medically necessary by the Investigator.
  • ISTs that are not permitted are listed in Section 6.5.2.
  • therapy with AChE inhibitor or ISTs can be changed at the discretion of the Investigator.
  • rescue therapy is allowed when a participant’s health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences a Clinical Deterioration as defined in Section 4.2.1 .
  • Rescue therapy may consist of plasmapheresis (PP), plasma exchange (PE), IVIg, SCIg, or short-term use of high-dose corticosteroids (Section 6.5.3).
  • the therapy used in the individual participant is, within these boundaries, be determined at the discretion of the Investigator.
  • Clinical Evaluators must be properly trained and certified in administering MG-ADL and other relevant disease assessments (Section 4.2.2).
  • Clinical Evaluators may be a neurologist (including a neurology resident in training) or other qualified study team member assigned by the Investigator. Section 4.2.2 describes responsibilities for clinical evaluations and study assessments in greater detail.
  • the participant After obtaining informed consent, the participant is screened over a period of up to 4 weeks ( ⁇ 28 days) for study eligibility through a review of demographic data, medical history, physical examination, and laboratory tests.
  • Medical history covers date of the diagnosis of MG, initial clinical presentation (ocular or gMG), time to the manifestation of gMG (if the initial clinical presentation was limited to ocular symptoms or signs), maximum MGFA Classification and requirement of ventilatory support since diagnosis, dates of gMG exacerbations or crises, diagnosis of thymoma or thymic carcinoma, thymectomy if applicable, and any hospitalizations related to MG in the 2 years prior to Screening. Medical treatment and physical therapy related to MG over the 2 years prior to Screening is also be recorded. Additional information about such treatment in earlier years should be documented, if available.
  • Participants are be vaccinated against Neisseria meningitidis (N meningitidis) during screening or at the time of treatment initiation as a prophylaxis against meningococcal infection. Vaccination is not required if participants have been vaccinated against N meningitidis including serogroups A, C, W135, Y (and where available, serogroup B), within 3 years prior to randomization, and vaccination against these serogroups is documented or confirmed by the treating physician. Participants who initiate study intervention ⁇ 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination (see Section 6.5.4).
  • Randomization is carried out using a centralized interactive response technology (IRT) application.
  • the randomization is stratified by geographical region and body weight ( ⁇ 80 kg and > 80 kg), as specified in the statistical analysis plan (SAP). Randomization of participants with an MG-ADL total score ⁇ 7 and participants receiving concomitant periodic (chronic) IVIg or SCIg administrations is limited to approximately 10% each.
  • the fusion polypeptide described herein and placebo is administered through SC injection.
  • Study intervention consists of a loading dose followed by weekly maintenance doses (Table 2). Both loading and maintenance doses are based on the participant’s body weight ( ⁇ 80 kg or > 80 kg) as determined at Randomization. Assessments ofthe disease status, safety and outcome measures of efficacy, and other procedures are performed at regular visits specified in the SoA in FIG. 2A-FIG.2C.
  • rescue therapy is allowed when a participant’s health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences Clinical Deterioration, including a crisis related to gMG, as defined in Section 4.2.1 .
  • Management of a Clinical Deterioration always includes treatment directed at the precipitating condition, e.g., an infection, if applicable.
  • the Investigator or designee determines whether the participant meets the definition of Clinical Deterioration and intervene accordingly.
  • Rescue therapy may consist of PP, PE, IVIg, SCIg, or high-dose corticosteroids. Supplemental dosing of the study intervention is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details).
  • a weight-based blinded dose is administered on Day 183 by designated study site personnel who are not permitted to participate in any safety or efficacy assessments (see Section 0 on Blinding). Participants who were in the placebo group during the RCT Period receive a weight-based loading dose of the fusion polypeptide described herein to ensure rapid and complete C5 inhibition before the next scheduled maintenance dose. Participants who were in the fusion polypeptide group during the RCT Period receive a weight-based maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose. Weekly open-label maintenance doses resume the following week (Day 190).
  • the OLE Period for each participant begins when the participant receives their study intervention on Day 183 and continues, for 96 weeks, or until the fusion polypeptide described herein is registered or approved (in accordance with country-specific regulations), or until the fusion polypeptide described herein can be provided via a sponsor post-trial access program (as allowed by local laws and regulations), whichever occurs first.
  • Data for scheduled assessments are collected via remote interaction, which may include one or a combination of the following methods: digital device, phone, or virtual meeting with the study site staff via video conferencing platform.
  • the method of interaction must comply with local and institutional requirements of data privacy and regulation.
  • the Investigator collects as many of the scheduled assessments as possible remotely instead, to avoid missing data.
  • the information collected remotely comprises the MG-ADL, concomitant medication including physical and other non-pharmaceutical therapy, and the hospitalization status of the participant.
  • Clinical Deterioration is defined as any of the following:
  • Clinical Deterioration Visit the Investigator or the Investigator’s designee performs clinical and laboratory assessments as specified in the SoAs. Additional assessments may be performed, and additional evaluation visits may be scheduled at the discretion of the Investigator or designee.
  • the Investigator or designee determines whether the criteria of a Clinical Deterioration are met and intervene accordingly.
  • Rescue therapy may consist of PP, PE, I Vlg or SCIg, or high-dose corticosteroids. Supplemental dosing is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details and Figure 5).
  • the appropriate intervention for the individual participant is, within these boundaries, chosen at the discretion of the Investigator. Current treatment guidance should be considered. Management of a Clinical Deterioration always includes treatment directed at the precipitating condition, for example, an infection, if applicable. Following the intervention, treatment should return to the standard of care administered before the Clinical Deterioration.
  • Information related to a Clinical Deterioration is collected from the signing of the informed consent form (ICF) until the EoS or ET Visit and must be documented in the eCRF.
  • the collected information must include the administration of rescue therapy, if applicable, a description of the chosen therapy, and if applicable, supplemental dosing of the study intervention.
  • Clinical Evaluators may be a neurologist or other qualified study team member assigned by the Investigator, as specified in Table 8. Clinical Evaluators are study staff that have been trained and certified in administering the MG-ADL profile and other relevant assessments related to disease severity as specified in Table 8. Only Clinical Evaluators may administer these assessments. Clinical Evaluator training and certification for this study may take place either at an Investigator Meeting or through an online training program.
  • MG assessments should be performed in the morning and at approximately the same time of day and preferably by the same evaluator for each participant.
  • the MG-ADL profile should always be performed first, followed by the QMG, MGC, then other assessments of the disease status.
  • Table 8 Responsibility forthe Clinical Evaluation of gMG a Can be an appropriately qualified senior neurology resident in training.
  • b Neurologist or appropriately qualified other study team member e.g., senior neurology resident in training, physician assistant, or nurse practitioner.
  • Vital capacity which is part of the QMG assessment, may also be measured by a qualified physical therapist.
  • gMG generalized myasthenia gravis
  • MG-ADL Myasthenia Gravis Activities of Daily Living
  • MGC Myasthenia Gravis Composite
  • MGFA Myasthenia Gravis Foundation of America
  • MGFA-PIS MGFA Post-Intervention Status
  • QMG Quantitative Myasthenia Gravis score for disease severity
  • the goal of this study is to assess the safety and efficacy of the fusion polypeptide described herein compared with placebo in the treatment of adults with gMG based on the ability of participants to perform activities of daily living, and participants’ muscle strength.
  • Primary and key secondary objectives reflect this goal:
  • the MG-ADL profile is a valid and sensitive instrument to assess the impact of gMG and measure treatment-associated changes in disease severity.
  • a decrease in the MG-ADL by 2 points compared to Baseline is considered an indicator of clinical improvement (Muppidi et al., Muscle Nerve, 44:727-731 , 2011).
  • Length of the RCT Period and determination of primary and secondary endpoints at Week 26 are designed to demonstrate durable changes in symptoms and signs, which is critical in a chronic disease such as gMG.
  • the study includes adults (> 18 years old) with gMG corresponding to MGFA Classification Grades II, III, or IV to evaluate the therapeutic potential of the fusion polypeptide described herein in a broad participant population with mild, moderate, or severe disease, respectively. If successful, the fusion polypeptide described herein provides these participants with a treatment option that they can administer themselves, at home, at convenient weekly dosing intervals.
  • a weight-based dosage regimen was selected based on modeling and dosing simulations using clinical PK, PD and antidrug antibody (ADA) data from a first-in-human Phase 1 study of the fusion polypeptide described herein.
  • the dosage regimen for the fusion polypeptide described herein in this Phase 3 study leverages prior experience in treating complement-mediated diseases (including gMG) with the C5 inhibitors eculizumab and ravulizumab.
  • complement-mediated diseases including gMG
  • C5 inhibitors eculizumab and ravulizumab Using PK/PD data from healthy participants in the healthy volunteer study (HV-101), a population PK/PD model was developed and used to generate dosing simulations to determine the dosage regimen predicted to achieve rapid and complete terminal complement inhibition (Table 12).
  • Targeting sustained terminal complement inhibition in patients with gMG has shown favorable benefit/risk profiles following therapeutic dosing with eculizumab and ravulizumab. Based on the totality of PK, PD, ADA, safety, and efficacy data obtained during the development of eculizumab and ravulizumab and approved treatment with eculizumab, the proposed dosage regimen based on body weight is expected to be beneficial in treating participants with gMG.
  • Delayed doses defined as doses administered > 1 day later than scheduled, is administered as soon as possible and not later than the next scheduled dose. Replacement of missed doses is determined on an individual basis.
  • Supplemental dosing is required if PP or PE is used as rescue therapy on non-dosing days. If PP or PE falls on the same day as a scheduled administration of the study intervention, no supplemental dosing is required, but the scheduled dose of the study intervention is administered within 60 minutes after the completion of the PP or PE, if feasible. If PP or PE is performed in the interval between 2 scheduled doses of the study intervention, supplemental administration of the study intervention within 4 hours after the PP or PE session is recommended, if feasible (see Section 6.5.3.1 for details).
  • participant groups who are in the placebo group during the RCT Period receive a blinded weight-based loading dose of the fusion polypeptide described herein at the start of the OLE Period on Day 183.
  • Participants who are in the fusion polypeptide group during the RCT Period receive a blinded maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose.
  • Weekly open-label maintenance doses resume the following week (Day 190).
  • a participant is considered to have completed the study if they complete all scheduled study visits in the RCT Period and the OLE Period. If the study is terminated early or the study intervention becomes registered or approved in accordance with country-specific regulations, a participant is also considered to have completed the study if they complete all scheduled study visits in the applicable periods of the study, including the EoS Visit, until study termination.
  • the end of the study is defined as the date of the last visit of the last participant in the study, or the last scheduled procedure shown in the SoAs for the last participant in the study.
  • Protocol waivers or exemptions Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
  • Test results may be collected from existing participant records or obtained during Screening, unless otherwise specified: a. Positive response in an AChE inhibitor test, for example, the edrophonium chloride test, or b. Abnormal neuromuscular transmission demonstrated by repetitive nerve stimulation or single fiber electromyography, or c. Previous improvement of symptoms or signs related to MG by treatment with an oral AChE inhibitor, as confirmed by the treating physician
  • a participant has recently discontinued any of the above medications, a period of time equal to the stable dose requirement listed above forthat medication (e.g., > 2 months for azathioprine or > 4 weeks for corticosteroids) must have passed prior to the first day of the Screening Period. a Intermittent use of an AChE inhibitor is not permitted during the study. b A maximum dose of 20 mg/day prednisone or equivalent is recommended. Investigators should notify the Medical Monitor if they intend to maintain a higher corticosteroid dosage during the RCT Period. c Requirement of a stable dose does not apply to IVIg or SCIg administered as rescue therapy, e.g., for a myasthenic crisis
  • AChE acetylcholine esterase
  • IVIg intravenous immunoglobulin
  • RCT Randomized Controlled Treatment
  • SCIg subcutaneous immunoglobulin
  • Participants must weigh > 40 kg, with a body mass index > 18.5 kg/m 2 and ⁇ 40 kg/m 2
  • Medical conditions e.g., cardiac, pulmonary, renal, oncologic, neurological or psychiatric disorder
  • risk factor that, in the opinion of the Investigator or the Medical Monitor, might interfere with participation in the study, pose any added risk to the participant, or confound the assessment of safety or efficacy of the study intervention
  • Participants with a history of treated benign thymoma are eligible if they meet all of the following conditions: d. Histopathological or equivalent records confirming the diagnosis of benign thymoma e. Treatment completed > 12 months prior to the Screening Visit f. No known recurrence within the 12 months prior to the Screening Visit g. No radiological indication of recurrence in a CT or MRI scan, including administration of IV contrast, performed within 6 months of Randomization on Day 1 h. If adequate records confirming the diagnosis of benign thymoma are not available, the participant must satisfy the eligibility criteria for thymic malignancy or carcinoma stated above.
  • Complement inhibitor received within ⁇ 5 half-lives before Randomization on Day 1 .
  • Participants receiving prior treatment with a complement inhibitor > 5 half-lives before Randomization on Day 1 may be enrolled but must have tolerated such treatment well, without side effects that, in the opinion of the Investigator or the Medical Monitor, might interfere with participation in the study, pose any added risk to the participant, or confound the assessment of safety or efficacy of the study intervention.
  • FcRn Human neonatal Fc receptor (FcRn) inhibitor: received within ⁇ 5 half-lives before Randomization on Day 1 . Participants receiving prior treatment with an FcRn inhibitor > 5 half-lives before Randomization on Day 1 may be enrolled but the total immunoglobulin G (IgG) level must be above the lower limit of normal (LLN) before these participants can be randomized.
  • IgG immunoglobulin G
  • Rituximab, ocrelizumab or other B cell-depleting therapy received or scheduled within ⁇ 6 months (180 days) before Randomization on Day 1.
  • HIV human immunodeficiency virus
  • hepatitis B positive hepatitis B surface antigen [HBsAg] or positive core antibody [anti-HBc]
  • anti-HBs negative surface antibody
  • HCV antibody positive hepatitis C virus infection
  • SVR sustained virologic response
  • Screen failures are defined as enrolled participants who consent to participate in the clinical study but are subsequently not randomly assigned to study intervention.
  • a minimal set of screen failure information is required to ensure transparent reporting, meet the publishing requirements for Consolidated Standards of Reporting Trials and respond to queries from regulatory authorities.
  • Minimal information includes demographic data about the participant, screen failure details (e.g., failed eligibility criteria), and AEs, and any related concomitant medication, during the Screening Period.
  • Laboratory tests with results outside of the reference range at Screening may be repeated at the Investigator’s discretion for the purpose of further determining eligibility.
  • Individuals who do not meet the criteria for participation in this study (screen failure) for any other reason that is expected to resolve or has resolved may be rescreened after consultation of the Medical Monitor. Participants who are rescreened outside of the Screening window are required to sign a new ICF (Section 10.1.3).
  • Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
  • study intervention refers to the combination product consisting of a PFS-SD containing the fusion polypeptide described herein or placebo.
  • the PFS-SD is a single-use, disposable device to deliver the fusion polypeptide described herein or placebo subcutaneously.
  • the prefilled glass syringe is equipped with the accessory safety device to prevent needlestick injuries and improve its ergonomic use.
  • the safety device is designed to automatically retract the needle into the syringe after the injection is administered. Details regarding the study intervention are presented in Table 10.
  • IMP investigational medicinal product
  • LD loading dose
  • MD maintenance dose
  • OLE Open-label Extension
  • PFS-SD prefilled syringe with safety device
  • Q1 W once every week
  • ROT Randomized Controlled Treatment
  • SC subcutaneous
  • w/v weight per volume
  • the PFS-SD combination product is a single-use, disposable device comprised of the fusion polypeptide or placebo formulation (2 mL) in a prefilled syringe with a needle safety device (BD UltraSafe PlusTM Passive).
  • the PFS-SD is designed to enable the SC administration of the fusion polypeptide or placebo and provide an automated safety mechanism to reduce the risk of accidental needlestick injuries by retracting the needle into the syringe after the injection is given. Participants and, if applicable, their caregivers will be trained in the use of the PFS-SD so that they can inject themselves during the study.
  • the PFS-SD constitutes a container closure system that is the sum of packaging components that together contain and protect fusion polypeptide or placebo (Figure 5). Main parts of the device constituent are provided in Table 11 . Table 11 : Device Constituent Parts for the PFS-SD
  • the PFS-SD are distributed with IFU.
  • the study intervention must be administered as specified in the IFU.
  • the PFS-SD is packaged in a carton with an insert that holds the device in place within the carton.
  • Each PFS-SD has a single panel label attached that contains a unique identifying kit number and other minimum required information such as Sponsor’s name, product description, protocol number, lot number to allow for traceability of the device.
  • Secondary packaging (carton) is labeled either with single-panel or booklet label that includes investigational biologic cautionary statement and a “For Clinical Trial Use only” statement, as needed, as well as other required information. 6.1 .3.
  • the dosage regimen for the study intervention in the RCT Period is based on the participant’s body weight at Randomization on Day 1 (Table 12).
  • Table 12 Weight-Based Dosing During the RCT Period a One PFS-SD contains 300 mg fusion polypeptide or placebo.
  • PFS-SD prefilled syringe with safety device
  • Q1W once per week
  • the maintenance dose may be adjusted at the beginning of the OLE Period and approximately every 6 months thereafter if the weight group ( ⁇ 80 kg or > 80 kg) of the participant changes. Adjustments of the maintenance dose, if applicable, do not require administration of an additional loading dose.
  • the first doses of study intervention on Day 1 (Baseline) and Day 8 (Week 1) shall only be administered by trained and certified study site personnel specifically designated to the administration of the study intervention and the training of participants and caregivers in the administration of the study intervention (see Section 6.3.2).
  • participants and if applicable, caregivers are trained on how to administer study intervention under supervision of the designated study site personnel.
  • participants After completion of the training and if certified by the training personnel, participants receive kits containing the study intervention and accessories, so that they can selfadminister the study intervention at home.
  • participants may request additional training in the administration of the study intervention by the designated personnel at the study site; these retraining visits are not considered Clinic Visits. Participants shall make every effort to maintain the weekly dosing intervals. However, deviations of ⁇ 1 day are acceptable if they cannot be avoided.
  • Participants must document each study intervention administration in the eDiary (Section 6.4).
  • participant should self-administer the treatment at home unless the scheduled dose falls on the same day as an upcoming Clinic Visit. On such days, participants are asked to administer the study intervention at the clinic under supervision of the designated clinic staff to monitor their injection skills. If an upcoming Clinic Visit falls outside of the ⁇ 1 day window for the administration of the study intervention, participants shall administer study intervention at home to maintain regular weekly dosing intervals. In this situation, no planned PK/PD or ADA assessments need to be performed at the Clinic Visit.
  • Injection sites include the abdomen and the anterior thigh. A caregiver administering the study intervention may also choose the backside of the participant’s upper arm for injection. Injection sites should be rotated such that the participant receives the study intervention at a different anatomical site in consecutive weeks. Participants and caregivers must follow the IFU.
  • the IFU describes the injection technique, including the activation of the safety device when the plunger of the PFS-SD is fully depressed. Retraction of the needle is a safety feature forthe prevention of needlesticks injuries after the injection.
  • the participant In the event of a PFS-SD malfunction in which no dose or only a partial dose is delivered, the participant should use a new PFS-SD to ensure the required dose is administered and record the event in the eDiary (refer to Section 10.5). Participants should report the malfunctioning or deficient device as specified in the IFU irrespective of the need to use a new PFS-SD. Malfunctioning or deficient devices need to be returned to the study site at the next Clinic Visit (see Section 8.5.5 and refer to the Pharmacy Manual for further reporting requirements of device malfunctions and deficiencies).
  • a product complaint is defined as any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, usability, safety, effectiveness, or performance of a product or clinical study material and/or its packaging components after it is has been released for distribution to an end user that affects the performance of such product or material.
  • Participants are randomized on Day 1 after the Investigator has verified that they are eligible. Participants are stratified by geographical region (e.g., North America, Europe) and weight group ( ⁇ 80 kg or > 80 kg) as specified in the SAP, and randomized 1 :1 to the fusion polypeptide described herein or placebo using a centralized IRT.
  • geographical region e.g., North America, Europe
  • weight group ⁇ 80 kg or > 80 kg
  • PFS-SDs containing the fusion polypeptide described herein or placebo are provided in identical study intervention kits and with identical labels for all participants in the RCT Period. Yellow transparent tape covers the PFS-SDs to conceal a color difference between the fusion polypeptide described herein and placebo. Because the viscosity of the fusion polypeptide described herein also differs from the placebo formulation, a moderately different injection force is required for its administration. To maintain the blind despite this difference in viscosity, study sites are required to designate an independent staff member who can:
  • These designated staff members can be a nurse, study coordinator, or subinvestigator trained to administer the study intervention. They remain blinded to the participant’s assigned study intervention and are not permitted to communicate observations related to the injection force required to administer the intervention to the study participant, a caregiver, other site personnel, sponsor staff or designees, or any other personnel associated with the conduct of the study. They must not have any other role in the study and, specifically, are not permitted to participate in any safety or efficacy assessments.
  • Intervention start and stop dates including dates of intervention delays or dose changes is also recorded in the eCRF.
  • Medications including vitamins and herbal preparations
  • procedures including therapeutic interventions such as surgery or physical therapy
  • eCRF Information about previously prescribed medications or administered procedures as it relates to the eligibility criteria (Section 5.1 and Section 5.2) must also be documented in the eCRF.
  • MG-specific medication or therapy e.g., thymectomy, ISTs including corticosteroids and rescue therapy
  • Additional information about such medication or therapy in earlier years should be documented, if available.
  • history of meningococcal vaccination must be collected for the 3 years prior to first dose of study intervention.
  • the Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy. 6.5.1 . Allowed Medicine and Therapy
  • the dose must be withheld for at least 8 hours prior to the MGC and QMG assessments. Treatment with the AChE inhibitor can resume once QMG and MGC assessments are complete.
  • Rescue therapy including PP/PE, IVIg, SCIg, or short-term use of high-dose corticosteroid is allowed when a participant's health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences a Clinical Deterioration (as defined in Section 4.2.1).
  • the appropriate intervention for the individual participant is chosen, within these boundaries, at the discretion of the Investigator. Current treatment guidance should be considered. Participants who require rescue medication may continue the study. However, the Investigator should notify sponsor or its designee within 24 hours of the initiation of rescue therapy. Following the intervention, treatment should return to the standard of care administered before the Clinical Deterioration. Additional PK/PD/ADA blood samples should be collected before and after receiving rescue therapy. Supplemental dosing of the study intervention is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details).
  • Supplemental dosing of study intervention is required if PP/PE rescue therapy is performed on days that do not coincide with administration of the study intervention; if PP/PE is performed on a dosing day, no supplemental study intervention is required but the PP/PE session must occur prior to administration of the study intervention.
  • a supplemental dose of 1 PFS-SD should be administered, if feasible, within 4 hours following every second PP/PE session for participants with a body weight ⁇ 80 kg, or following each PP/PE session for participants with a body weight > 80 kg (Table 13).
  • Table 13 Weight-Based Supplemental Dose Following PP/PE a
  • One PFS-SD contains 300 mg fusion polypeptide or placebo.
  • PE plasma exchange
  • PFS-SD prefilled syringe with safety device
  • a supplemental dose equivalent to 300 mg fusion polypeptide or placebo (1 PFS-SD) should be administered prior to or with the next weekly maintenance dose of the study intervention.
  • Participants should be vaccinated or revaccinated against other pathogens according to national vaccination guidelines or local standard of care.
  • the dosage regimen of the study intervention is based on the participant’s body weight.
  • the weight at Randomization is determined the doses administered in the RCT Period.
  • the dosage regimen is adjusted at the beginning of the OLE Period and approximately every 6 months thereafter if the weight group ( ⁇ 80 kg or > 80 kg) of the participant changes. Adjustments of the maintenance dose, if applicable, do not require administration of an additional loading dose.
  • the Investigator notifies the Medical Monitor as soon as possible of any discontinuation or consideration to discontinue the study intervention. If a participant permanently discontinues treatment, the Investigator attempts to follow participants up for safety and perform, if the participant agrees, assessments specified for the ET Visit (see SoA). If an ET Visit cannot be arranged, the Investigator attempts to follow up by phone 3 weeks after the last dose of study intervention has been administered. Time and scope ofthe communication is recorded in the eCRF.
  • an ET Visit should be conducted, as shown in the SoA. Refer to the SoA for data to be collected at the time of study discontinuation and follow-up, and for any further evaluations that need to be completed. Once an ET Visit has been completed, the participant is permanently discontinued from both the study intervention and the study.
  • participant withdraws consent for disclosure of future information
  • sponsor may retain and continue to use any data collected before such a withdrawal of consent.
  • a participant is considered lost to follow-up if the participant repeatedly fails to return for scheduled visits and cannot be contacted by the study site.
  • the site must attempt to contact the participant to reschedule the missed visit as soon as possible, counsel the participant on the importance of maintaining the assigned visit schedule, and ascertain whether or not the participant wishes to and should continue in the study.
  • Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and obtained before signing of the ICF may be utilized for screening or baseline purposes provided the procedures meet the protocol-specified criteria and were performed within the time frame defined in the SoA.
  • the MG-ADL Profile is a questionnaire that focuses on activities of daily living that are likely to be impaired by gMG.
  • the 8 items of the MG-ADL assess disability secondary to ocular (2 items), oropharyngeal (3 items), respiratory (1 item), and extremity (2 items) functions. Each response is graded 0 (normal) to 3 (most severe).
  • the MG-ADL total score ranges from 0 to 24, with higher scores indicating greater impairment.
  • the recall period for the MG-ADL Profile is the preceding 7 days or time past since the last visit, if the visit interval is shorter than 7 days.
  • the MG-ADL Profile must be administered by a properly trained Clinical Evaluator.
  • the MG-ADL should be performed in the morning and at approximately the same time of the day throughout the study. For consistency, the same evaluator should administer the questionnaire throughout the study. It is anticipated that the form takes ⁇ 10 minutes to complete. If multiple efficacy assessments are scheduled, the MG-ADL must be performed first, followed in this order, by QMG, MGC and the remaining tests.
  • the QMG total score provides a quantitative evaluation of function in sentinel muscle groups.
  • the QMG total score consists of 13 items: ocular (and facial) (3 items), oropharyngeal (2 items), extremity (and head lift) (7 items), and respiratory (1 item) functions. Strength in each of the muscle groups is graded 0 to 3, with 3 indicating severe impairment.
  • the QMG total score ranges from 0 to 39.
  • the MGFA recommends that the QMG total score be used as one outcome measure in prospective interventional studies in MG (Benatar ef al., Muscle Nerve, 2012;45:909-917, 2012).
  • the QMG total score must be administered by a neurologist or an appropriately qualified other study team member, e.g., senior neurology resident in training, physician assistant, or nurse practitioner.
  • the QMG should be performed in the morning and at approximately the same time of the day throughout the study. Vital capacity may be measured by a qualified physical therapist. For consistency, the same evaluator should administer the assessment throughout the study. If a participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the assessment. The time from the last dose to the QMG assessment should be documented and kept similar between visits. If multiple efficacy assessments are scheduled, the QMG is required to be performed after the MG-ADL, before the MGC and other remaining tests.
  • the MGC combines participant-reported and Investigator-reported test items to assess the clinical status of MG by measuring both symptoms and objective signs of the disease.
  • the MGC assesses 10 functional areas commonly affected by MG. Grading scales are weighted for clinical significance (see, e.g., Burns et al. Neurology 74:1434-1440, 2010).
  • the MGC total score ranges from 0 to 50., 2010).
  • the MGC total score ranges from 0 to 50.
  • the MGC must be administered by a neurologist or appropriately qualified other study team member, e.g., senior neurology resident in training, physician assistant, or nurse practitioner.
  • the MGC should be performed in the morning and at approximately the same time of the day throughout the study. For consistency, the same evaluator should administer the assessment throughout the study. If a participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the assessment. The time from the last dose to the MGC assessment should be documented and kept similar between visits. If multiple efficacy assessments are scheduled, the MGC is required to be performed after MG-ADL and QMG, but before any other tests.
  • the revised 15-item Myasthenia Gravis Quality of Life scale evaluates the quality of life (QoL) as it relates specifically to participants with MG.
  • the MG-QoL15r is designed to provide information about participants’ perception of impairment and disability and determine the degree to which disease manifestations are tolerated (Burns et al., Muscle Nerve, 54:1015-1022, 2016).
  • the MG-QoL15r is completed by the participant. Higher scores indicate greater MG-related dysfunction and dissatisfaction with the current disease status.
  • Neuro-QoL Fatigue The Quality of Life in Neurological Disorders Fatigue (Neuro-QoL Fatigue) scale is one of the Quality of Life in Neurological Disorders (Neuro-QoL) measures developed through a research initiative in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS). It is a brief survey, completed by the participant (Celia Measuring Quality of Life in Neurological Disorders; Final Report of the Neuro-QOL Study September 2010. 2010). Higher scores indicate greater fatigue and greater impact of MG on activities of daily life.
  • the Euro Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) is a self-assessed, standardized instrument to measure the health-related quality of life that has been used in a wide range of health conditions.
  • the EQ-5D-5L describes mobility, self-care, usual activities, pain and discomfort, and anxiety and depression by using 5 response levels ranging from “no problems” to inability to perform activities or “extreme problems.”
  • the Short Form Health Survey (36 question version) (SF-36) is a 36-item self-report of health-related quality of life (Stewart et al., Med. Care, 26:724-735, 1988; Ware et al., Med. Care, 30:473-483, 1992). It contains 8 subscales measuring different domains including physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health.
  • the 2 summary scores are the physical component summary and the mental component summary.
  • MSE Minimal Symptom Expression
  • MGFA-PIS MGFA PostIntervention Status
  • PIS Post- Intervention Status
  • MM Minimal Manifestation
  • the PIS including achievement of MM must be determined by a neurologist or an appropriately qualified neurology resident in training skilled in the evaluation of participants with MG. For consistency, the same evaluator should administer the assessment throughout the study.
  • the experience of participants or, if applicable, their caregivers with the use of the PFS-SD is evaluated using a 4-item questionnaire.
  • the questionnaire assesses the overall confidence, convenience and comfort of users with the SC injection of the study intervention.
  • the instrument also collects information on whether participants would recommend this route of self-administration to another patient. Each item is answered on a 5-point Likert scale.
  • a complete physical examination includes, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems.
  • An abbreviated physical examination is performed, if necessary, based on the participant’s health status and the clinical judgment of the Investigator.
  • a symptom-based neurologic examination should be performed if the participant has any complaints or clinical findings attributable to the nervous system. If neurological findings are revealed, a full neurologic examination should follow immediately and be repeated at future assessments as needed based on the clinical judgement of the Investigator.
  • a full neurologic examination comprises mental status, cranial nerve examination, motor examination, reflex status, sensory examination, and examination of coordination and gait.
  • Body temperature degrees Celsius [°C]
  • respiratory rate pulse rate (beats/minute)
  • pulse oximetry oxygen saturation
  • systolic and diastolic blood pressure mmHg
  • Vital signs (to be taken before blood collection for laboratory tests) consist of a single pulse check and a single blood pressure measurement.
  • Pulse and blood pressure measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Ideally, the same arm for each participant should be used for measurements.
  • Pulse and blood pressure should be assessed with the participant in a supine or seated position, and by using an automated device. Manual measurements of pulse and blood pressure should only be used if an automated device is not available.
  • a single 12-lead electrocardiogram is conducted as outlined in the SoA to obtain heart rate, PR interval (time from the onset of the P wave to the start of the QRS complex), combination of the Q wave, R wave, and S wave (QRS) interval, interval between the start of the Q wave and the end of the T wave (QT), and corrected QT interval (QTc).
  • the QT interval is corrected for heart rate using Fridericia’s formula.
  • Participants must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
  • the Investigator is responsible for reviewing the ECG to assess whether the ECG is within normal limits and determine the clinical significance of the results.
  • Results are recorded on the eCRF. Clinically significant findings should be recorded on the AE form.
  • Clinically significant abnormal laboratory findings are those that are not associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the participant’s condition. 2. All laboratory tests with abnormal values and considered clinically significant by the Investigator during the study or within 3 weeks after the last dose of study intervention should be repeated until the values return to normal or Baseline or are no longer considered clinically significant by the Investigator or Medical Monitor.
  • Urine samples are analyzed for the parameters listed in Section 0. A microscopic examination of urine samples is performed if the results of the macroscopic analysis are abnormal.
  • Follicle-stimulating hormone may be obtained to confirm postmenopausal status in female participants who are considered postmenopausal.
  • a high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT).
  • HRT hormone replacement therapy
  • Information related to hospitalization defined as admissions to a healthcare facility (hospital, rehabilitation center, or hospice), is collected irrespective of the relation to MG. Dates of admission, discharge, reason for hospitalization, relationship to MG, and other relevant information is recorded on the eCRF.
  • the NINDS in collaboration with regulatory agencies has developed a set of data to be collected in clinical studies of a neurological indication.
  • Participants receiving study intervention should be monitored and observed closely for suicidal ideation and behavior, or any other unusual changes in behavior, especially at the beginning and end of the course of intervention, or at the time of dose changes. Discontinuation of the study intervention should be considered in participants who experience signs of suicidal ideation or behavior.
  • Families and caregivers of participants being treated with study intervention should be alerted about the need to monitor participants for the emergence of unusual changes in behavior, including the emergence of suicidal ideation or behavior, and the need to report such symptoms immediately to the study Investigator.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • the C-SSRS is performed by the Investigator or an appropriately trained designee at visits specified in the SoA to ensure that participants who are experiencing suicidal thoughts or behavior are recognized and adequately managed, or referred for further evaluation. Additional C-SSRS assessments are permitted as needed.
  • Injection site reactions may occur with any agent administered SC. Monitoring for injection site reactions is part of the routine safety assessments for this study. Injection-site reactions may include erythema, pruritus (itch), pain and bruising at the site of the administration of the study intervention. These reactions are typically observed during or shortly after an injection but may occur with a delay of up to 2 or 3 days. Injection site reactions should not be recorded as AEs unless they are judged by the Investigator to be clinically significant.
  • Systemic injection-related reactions may be mediated by immune or nonimmune mechanisms and occur generally during the administration of a drug or biological treatment, or within hours after the administration.
  • Immune-mediated reactions may include allergic reactions, e.g., fever, chills, flushing, alterations in heart rate and blood pressure, dyspnea, generalized skin rash or anaphylaxis.
  • Nonimmune-mediated reactions may produce less specific symptoms, e.g., headache, dizziness, nausea, vomiting or diarrhea. Monitoring for these reactions is part of routine safety assessments for this study.
  • a serum or urine pregnancy test is administered in all participants of childbearing potential.
  • a negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1 are required for eligibility to enter the study.
  • Pregnancy data from participants of childbearing potential and pregnant partners of participants is collected from the first dose of study intervention and at the time points specified in the SoA. Any female participant who becomes pregnant while participating in the study discontinues study intervention or be withdrawn from the study. If a pregnancy is reported, the Investigator must inform sponsor within 24 hours of awareness of the pregnancy and follow the procedures outlined. 8.3.10. Patient Safety Card
  • the Patient Safety Card is provided to increase participant awareness of the risk of meningococcal infection, promote quick recognition and disclosure of any potential signs or symptoms of such an infection during the study, and to inform participants about actions that must be taken if they are experiencing these symptoms or signs.
  • the Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and remain responsible for following up AEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study intervention (Section 7).
  • AEs and SAEs are collected from the signing of the ICF at the time points specified in the SoA.
  • Investigators are not obligated to actively seek AE or SAE data after conclusion of the study participation. However, if Investigators learn of any SAE, including a death, at any time after a participant has been discharged from the study, and they consider the event to be reasonably related to the study intervention or study participation, the Investigator must promptly notify sponsor.
  • Regulatory Reporting Requirements for SAEs a. Prompt notification of an SAE by the Investigator to sponsor is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met. b. Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. Sponsor complies with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators. c. Sponsor is required to submit individual SUSAR reports (defined in Section 10.3.2) in the format of MedWatch 3500 or Council for International Organizations of Medical Sciences (CIOMS) I Form to health authorities and Investigators as required. Forms submitted to Investigators are blinded to treatment assignment.
  • COMS Council for International Organizations of Medical Sciences
  • the Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an ADE or SADE and remain responsible for following up ADEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study intervention (see Section 7). Procedures for recording, evaluating, follow-up, and reporting ADEs and SADEs are outlined in Section 10.4.
  • Prompt notification of an SADE by the Investigator to sponsor is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met.
  • Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation.
  • Sponsor complies with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators.
  • an Investigator safety report describing an SADE or other specific safety information e.g., summary or listing of SADEs
  • the Investigator is responsible for ensuring that all device deficiencies that occur after signing of the ICF through 30 days after the last dose of study intervention or at the end of the study, whichever is later, are reported.
  • the Investigator may be required to follow-up participants, including those who discontinue study intervention, and perform or arrange for the conduct of supplemental investigations as medically indicated or requested by sponsor to elucidate the nature and causality of a device deficiency as fully as possible.
  • any blinded dose of the study intervention that is greater than the dose specified in the protocol is considered a suspected overdose.
  • replacement doses that compensate for incomplete or missing delivery of the study intervention e.g., following a user error or malfunction of the PFS-SD, or supplemental doses that are administered as required after PP/PE (Section 6.5.3.1), do not constitute an overdose.
  • Overdoses are medication errors that are not considered AEs or ADEs unless there is an untoward medical occurrence resulting from the overdose.
  • Sponsor recommends general symptom- oriented measures after an overdose with the fusion polypeptide described herein. Specific treatment, e.g., related to the mechanism of action, is not required.
  • Samples collected for analyses of the fusion polypeptide serum concentration may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.
  • Samples collected for PD analyses may also be used for research purposes or to evaluate safety or efficacy aspects during or after the study.
  • Samples are collected for analyses that may include, but are not limited to, evaluation of complement components, functional assays, anti-AChR antibody functional assays, markers of inflammation, and other nongenetic exploratory biomarkers in adults with gMG.
  • Serum samples for ADA analysis are collected according to the SoA. All efforts are made to obtain the immunogenicity samples at the specified nominal time relative to dosing. ADA samples collected out-of-window are recorded as a protocol deviation.
  • ADA variables include ADA response category incidence and titer over the duration of the study as follows. ADA response category definitions and titer thresholds are provided in the SAP.
  • a review of demographic parameters, including age, sex, race, and ethnicity is performed at Screening, if allowed per country specific regulations, and documented in the eCRF.
  • the Investigator notifies the IRB/IEC of deviations from the study protocol or GCP as defined by Clinical Trial Regulation EU No 536/2014 as a serious breach or as required by IRB/IEC procedures.
  • the Investigator is responsible for the following:
  • the Investigator or designee explains the nature of the study (including but not limited to the objectives, potential benefits and risks, inconveniences, and the participant’s rights and responsibilities) to the participant or his/her legally authorized representative, defined according to local and country regulations where the study is taking place, and answer all questions regarding the study.
  • Participants must be informed that their participation is voluntary. Participants or their legally authorized representative is required to sign a statement of informed consent or a certified translation, if applicable, that meets the requirements of 21 CFR 50, local regulations, European Union (EU) General Data Protection Regulation (GDPR), ICH GCP guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.
  • EU European Union
  • GDPR General Data Protection Regulation
  • ICH GCP guidelines Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.
  • HIPAA Health Insurance Portability and Accountability Act
  • the participant’s medical record must include a statement that signed (written or electronic) informed consent was obtained before any screening procedures were performed with a participant, and the date the written consent was obtained.
  • the authorized person obtaining the informed consent must also sign the ICF(s). Participants must be reconsented to the most current version of the ICF(s) during their participation in the study, as applicable.
  • a copy of the signed (written or electronic) informed consent documentation (j.e., a complete set of participant information sheets and fully executed signature pages) must be provided to the participant or the participant’s legally authorized representative, as applicable. This document may require translation into the local language.
  • Original signed (written or electronic) consent forms must remain in each participant’s study file and must be available for verification at any time.
  • the study start date is the date on which the first participant is consented.
  • Study sites are closed after the study is completed or following the decision to close or terminate the study.
  • a study site is considered closed when all participants have completed the EoS or ET Visit, all data have been collected and entered into the electronic data capture (EDC) system, all required documents and study supplies have been collected and reconciled, and a study-site closure visit has been performed.
  • EDC electronic data capture
  • the Investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination.
  • Reasons for the early closure of a study site by sponsor or Investigator may include but are not limited to:
  • Conditions that may warrant termination of the study include, but are not limited to:
  • sponsor shall promptly inform the Investigators, IRBs/IECs, regulatory authorities, and any contract research organization(s) used in the study of the reason for termination or suspension, as specified by the applicable regulatory requirements.
  • the Investigator shall promptly inform the participant and should assure appropriate participant therapy and/or follow-up.
  • Pregnancy testing Participants of childbearing potential should only be randomized after negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1 .
  • Table 15 Protocol-Required Clinical Laboratory Assessments Table 15: Protocol-Required Clinical Laboratory Assessments a Blood or urine are the preferred samples to screen for alcohol. If neither test method is available, alcohol may also be tested in exhaled breath. b If locally available, SVR should be documented or established at Screening.
  • AChR acetylcholine receptor
  • ALT alanine aminotransferase
  • anti-HBc hepatitis B core antibody
  • AST aspartate aminotransferase
  • BUN blood urea nitrogen
  • FSH follicle- stimulating hormone
  • hCG human chorionic gonadotropin
  • HBsAg hepatitis B surface antigen
  • HCV hepatitis C virus
  • HIV human immunodeficiency virus
  • MCH mean corpuscular hemoglobin
  • MCV mean corpuscular volume
  • RBC red blood cell
  • SGOT serum glutamic- oxaloacetic transaminase
  • SGPT serum glutamic-pyruvic transaminase
  • SVR sustained virologic response
  • WBC white blood cell
  • Unanticipated ADE means any serious adverse effect on health or safety or any life threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of participants.
  • MedWatch 3500A or CIOMS II Form or a series of similar USADEs in narrative format to health authorities/National Competent Authorities (NCA) and Investigators as required.
  • MedWatch 3500A or CIOMS II Forms submitted to Investigators are blinded to treatment assignment. In limited circumstances, the blind may be broken in the case of urgent safety issues that could compromise participant safety.
  • Reportable device events must be reported by sponsor at the same time to all NCAs where the clinical investigation has commenced.
  • Complaints are written, electronic, or oral communications that allege deficiencies about an investigational medical device’s identity, quality, durability, reliability, safety, or performance.
  • the site or participant Upon identification of a product complaint on the PFS-SD, the site or participant must contact sponsor or the designee using the local phone number in the IFU document. The site or participant must complete the Product Quality Complaints Form (see the Pharmacy Manual for details).
  • the Investigator is responsible for ensuring that all product complaints that occur after signing of the ICF through 30 days after the last dose of study intervention or at the end of the study, whichever is later, are reported.
  • Blood matrix (serum/plasma) samples are collected for biomarker analyses and the data are used for research (e.g., exploratory) related to study intervention or gMG.
  • the samples may also be used to develop tests/assays including diagnostic tests related to study intervention and gMG
  • the samples may be analyzed as part of a multi-study assessment of biomarkers in the response to the study intervention to understand study disease or related conditions.
  • the results of biomarker analyses may be reported in the clinical study report (CSR) or in a separate study summary.
  • CSR clinical study report
  • Participant reported Outcomes or Clinician reported Outcomes may be collected on paper or electronically.
  • Table 1 Abbreviations and Specialist Terms Table 1 : Abbreviations and Specialist Terms Table 1 : Abbreviations and Specialist Terms Table 1 : Abbreviations and Specialist Terms

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Description

DOSAGE AND ADMINISTRATION OF FUSION POLYPEPTIDES FOR TREATMENT OF MYASTHENIA GRAVIS
CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of priority to U.S. Application No. 63/348,622, filed June 3, 2022, which is incorporated by reference herein for all purposes.
BACKGROUND
The complement system acts in conjunction with other immunological systems of the body to defend against intrusion of cellular and viral pathogens. There are at least 25 complement proteins, which are found as a complex collection of plasma proteins and membrane cofactors. The plasma proteins make up about 10% of the globulins in vertebrate serum. Complement components achieve their immune defensive functions by interacting in a series of intricate but precise enzymatic cleavage and membrane binding events. The resulting complement cascade leads to the production of products with opsonic, immunoregulatory and lytic functions.
Myasthenia Gravis (MG) is a rare, debilitating, acquired autoimmune neurologic disorder of the neuromuscular junction (NMJ) caused by the failure of neuromuscular transmission, which results from the binding of auto-antibodies (auto-Abs) to proteins involved in signaling at the NMJ. These proteins include the nicotine acetylcholine receptors (AChRs) or, less frequently, a muscle-specific tyrosine kinase (MuSK) involved in AChR clustering.
MG may cause life-threatening respiratory failure, referred to as myasthenic crisis. MG has a prevalence of 14-20 per 100,000 in the U.S., affecting roughly 60,000 Americans. It affects males and females in equal ratio, although the incidence in females peaks in the 3rd decade as compared to males in whom the peak age at onset is in the 6th or 7th decade. About 15% to 20% of subjects experience a myasthenic crisis during the course of their disease, 75% within 2 years of diagnosis, requiring hospitalization and ventilatory support. Mortality from MG is approximately 4%, mostly due to respiratory failure.
Myasthenia gravis is clinically characterized by weakness and fatigability of voluntary skeletal muscles. MG may initially present with ocular muscle weakness affecting eye and eyelid movement, referred to as ocular MG (oMG). Ten percent of subjects have disease limited to ocular muscles. Ninety percent of subjects have generalized MG, with muscle weakness involving neck, head, spine, bulbar, respiratory or limb muscles. Bulbar weakness refers to muscles controlled by nerves originating from the bulb-like part of the brainstem and manifests as difficulty in talking, chewing, swallowing and control of the head.
Generalized myasthenia gravis (gMG) patients differ from the ocular myasthenia gravis (oMG) population in that neuromuscular inflammation and the resultant clinical findings are not just limited to the ocular muscles, but involve all voluntary muscle groups: the bulbar, respiratory, head, neck, trunk or peripheral muscles with or without involvement of the eyes. Profound weakness and devastating consequences, including slurred speech, dysarthria, dysphagia, disorienting vision, shortness of breath (both with activity and at rest), weakness of the upper and lower extremities, impaired mobility, marked reductions in the ability to perform activities of daily living (ADLs), extreme fatigue and episodes of pulmonary failure requiring mechanical ventilation are hallmarks of gMG. Compared with patients with isolated oMG, patients with gMG have a greater incidence of morbidities and a higher burden of disease. gMG is a rare disorder, having an estimated prevalence between 145 to 278 per million. Patients with gMG suffer from a devastating inflammatory neuromuscular disorder with limited therapeutic options.
Hospitalizations for gMG exacerbations are common, with the need for respiratory support, including mechanical ventilation secondary to respiratory failure (e.g.. myasthenic crisis) and gastrointestinal tube placement for nutritional support and prevention of dysphagia-associated aspiration. Patients with more advanced gMG have been reported to experience increased mortality of up to 40% at 10 years following diagnosis.
While there is no cure for MG, there are therapies that reduce muscle weakness and improve neuromuscular function. Current available treatments for myasthenia gravis aim to modulate neuromuscular transmission, inhibit the production or effects of pathogenic antibodies, or inhibit inflammatory cytokines. There is currently no specific treatment that targets the underlying pathophysiology of NMJ injury specifically- anti-AChR antibody-AChR interactions resulting in complement activation via the classical pathway and inflammation, with the resultant destruction of the NMJ. There is no specific treatment that corrects the autoimmune defect in MG. With immunosuppressive therapies (ISTs) representing the current standard of care, which usually combines cholinesterase inhibitors, corticosteroids and immunosuppressive drugs (most commonly azathioprine [AZA], cyclosporine, and mycophenolate mofetil [MMF]), the majority of subjects with MG can have their disease reasonably controlled. These therapies, however, may not be optimal for all patients, and there is a cohort of subjects who do not respond adequately to ISTs, or cannot tolerate ISTs, and those who require repeated treatments with plasma exchange (PE) and/or intravenous immunoglobulin (I Vlg) to maintain clinical stability.
In difficult-to-control cases, patients with gMG experience unrelenting inflammation, tissue destruction, and consequent severe morbidities including profound muscle weakness, impaired mobility, shortness of breath, pulmonary failure, extreme fatigue, risk for aspiration, and markedly impaired ADLs. These patients are typically diagnosed in the prime of their adult lives, with a median age of onset ranging from 36 to 60 years. As a result of the morbidities associated with gMG, many patients cannot work or have diminished work capacity, experience difficultly caring for themselves and others, and require assistance speaking, eating, ambulating, breathing and performing ADLs.
Uncontrolled terminal complement activation has been implicated in animal models of experimental autoimmune gMG as well as in other forms of autoimmune neuropathy in humans. Auto-Abs recognize targeted neural or muscle tissues, including the AChR, leading to uncontrolled terminal complement activation at the neural or muscle surface.
Autoantibody-driven uncontrolled terminal complement activation with membrane attack complex (MAC)-dependent lysis and activation, and C5a-dependent inflammation at the NMJ causes AChR loss and failure of neuromuscular transmission. Consistent with this model, both complement component C3 fragments (C3a and C3b) and the MAC C5b-9 have been found in NMJs of MG patients. As there is no cure for MG, and standard of care is not effective for all patients, there is a need to provide improved methods for treating these patients.
SUMMARY
In an aspect, the disclosure provides a method of treating myasthenia gravis (MG) in a human subject in need thereof, including administering to the human subject a therapeutically effective dose of a fusion protein including an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the engineered polypeptide that specifically binds to human complement component C5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 5, 6, and 7, respectively, and wherein the engineered polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2, and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 1 , 2, and 3, respectively.
In some embodiments, the polypeptide that specifically binds to human serum albumin includes a VHH domain. In some embodiments, the polypeptide that specifically binds to human serum albumin includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99%, or 100%) identical to SEQ ID NO: 4. In some embodiments, the polypeptide that specifically binds to human serum albumin includes an amino acid sequence of SEQ ID NO: 4.
In some embodiments, the polypeptide that specifically binds to human complement component C5 includes a VHH domain. In some embodiments, the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 8. In some embodiments, the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence of SEQ ID NO: 8. In some embodiments, the peptide linker includes the amino acid sequence of SEQ ID NO:10. In some embodiments, the fusion protein includes an amino acid sequence that is at least 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identical to SEQ ID NO: 9. In some embodiments, the fusion protein includes an amino acid sequence of SEQ ID NO: 9.
In some embodiments, the C-terminal residue of the polypeptide that specifically binds to human serum albumin is fused via the linker to the N-terminal residue of the polypeptide that specifically binds to human complement component C5.
In some embodiments, the subject is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR). In some embodiments, the MG is generalized myasthenia gravis (gMG). In some embodiments, the subject has been diagnosed with MG, e.g., anti-AChR positive gMG, for at least 3 months. In some embodiments, the subject is 18 years old or older in age. In some embodiments, the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification of between II and IV. In some embodiments, the patient has a Myasthenia Gravis Activities of Daily Living (MG-ADL) score greater than or equal to 5. In some embodiments, the subject is being administered one or more additional pharmaceutical compositions. In some embodiments, the pharmaceutical composition is an acetylcholinesterase inhibitor, an immunosuppressive therapy (1ST), or immunoglobulins. In some embodiments, 1ST is selected from the group consisting of a corticosteroid, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).
In some embodiments, the subject has not been administered a B cell-depleting therapy in the prior 6 months. In some embodiments, the B cell-depleting therapy is rituximab or ocrelizumab. In some embodiments, the subject has not been administered an FcRn inhibitor within 5 half-lives of the FcRn before administration of the fusion protein. In some embodiments, the subject has not been administered a complement inhibitor within 5 half-lives of the complement inhibitor before administration of the fusion protein.
In some embodiments, the subject weighs at least 40 kg. In some embodiments, the subject has a body mass index of > 18.5 kg/m2 and < 40 kg/m2 (e.gr, between 18.5 kg/m2 and 39.5 kg/m2, 20 kg/m2 and 35 kg/m2, 25 kg/m2 and 30 kg/m2, 25 kg/m2 and 39.5 kg/m2, and 18.5 kg/m2 and 35 kg/m2. In some embodiments, the therapeutically effective dose is based on the weight of the subject.
In some embodiments, the fusion protein is administered to a patient weighing < 80 kg once on Day 1 of the administration cycle at a loading dose of 600 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 300 mg. In some embodiments, fusion protein is administered at a dose of 300 mg every week after the administration cycle for up to two years. In some embodiments, the fusion protein is administered to a patient weighing > 80 kg once on Day 1 of the administration cycle at a loading dose of 900 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 600 mg. In some embodiments, fusion protein is administered at a dose of 600 mg every week after the administration cycle for up to two years
In some embodiments, the fusion protein is administered to the subject subcutaneously. In some embodiments, the fusion protein is administered to the subject using a pre-filled syringe. In some embodiments, the pre-filled syringe includes a passive needle safety device. In some embodiments, the fusion protein is administered to the subject using an autoinjector.
In some embodiments, the treatment results in the patient experiencing a change from baseline in MG-ADL score. In some embodiments, the treatment results in the patient experiencing a change from baseline in MG-ADL score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in the MG-ADL score after 26 weeks. In some embodiments, the reduction is at least 3.0 points. In some embodiments, the reduction is at least 4.0 points.
In some embodiments, the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis (QMG) score. In some embodiments, the treatment results in the patient experiencing a change from baseline in QMG score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in QMG score after 26 weeks. In some embodiments, the reduction is at least 2.0 points. In some embodiments, the reduction is at least 5.0 points. In some embodiments, the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis composite (MGC) score. In some embodiments, the treatment results in the patient experiencing a change from baseline in MGC score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in MGC score after 26 weeks.
In some embodiments, the treatment results in subject experiencing a change from baseline in serum free or total C5 concentration. In some embodiments, the treatment results in the patient experiencing a change from baseline in MG Quality of Life 15 (MG-QoL15r) score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in EQ-5D-5L score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in SF-36 score after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change from baseline in Neuro-QoL Fatigue (Quality of Life in Neurological Disorders Fatigue Short Form) score after 26 weeks. In some embodiments, the treatment results in the patient experiencing an MG-ADL score of 1 or less after 26 weeks. In some embodiments, the treatment results in the patient experiencing a change in MGFA postintervention status after 26 weeks.
In some embodiments, the treatment results in the patient experiencing a reduction in incidence of clinical deteriorations after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in incidence of hospitalizations after 26 weeks. In some embodiments, the treatment results in the patient experiencing a reduction in incidence of requiring rescue therapy after 26 weeks. In some embodiments, the treatment results in a change in concentration of one or more inflammation biomarkers. In some embodiments, the one or more inflammation biomarkers includes MMP-10 or IL-6. In some embodiments, the treatment results in a change in concentration of complement proteins or complement pathway regulators. In some embodiments, the treatment effect is maintained through week 26 after initiation of treatment. In some embodiments, the treatment effect is maintained through week 96 after initiation of treatment.
In another aspect, the disclosure provides a method of treating gMG in a human subject in need thereof, including administering to the human subject a therapeutically effective dose of a fusion protein including an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the polypeptide that specifically binds to human complement component C5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 5, 6 and 7, respectively, and wherein the polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2 and CDR3, including amino acid sequences as set forth in SEQ ID NOs: 1 , 2 and 3, respectively, wherein the subject is positive for anti-AChR; wherein the subject is 18 years old or older in age, wherein the fusion protein is administered to a patient weighing < 80 kg: once on Day 1 of the administration cycle at a loading dose of 600 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 300 mg, and wherein fusion protein is administered at a dose of 300 mg every week after the administration cycle for up to two years, or wherein the fusion protein is administered to a patient weighing > 80 kg: once on Day 1 of the administration cycle at a loading dose of 900 mg; and on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 600 mg, and wherein fusion protein is administered at a dose of 600 mg every week after the administration cycle for up to two years, and wherein the subject has an improvement from baseline in at least one measurement of gMG severity selected from the group consisting of MG-ADL, QMG, MGC, MG- QoL15r, EQ-5D-5L, SF-36, and Neuro-QoL Fatigue.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic drawing showing the study design for administration of the fusion polypeptide having the amino acid sequence of SEQ ID NO: 9.
FIG. 2A -FIG. 2C are tables showing the schedule of test and measurements that are performed over the course of the randomized controlled period. Abbreviations: AChR Ab = acetylcholine receptor antibody; ADA = antidrug antibody; ADE = adverse device effect; AE = adverse event; B = Baseline sample; C = Clinic Visit; C5 = complement component 5; C-SSRS = Columbia- Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; eCRF = electronic case report form; EQ-5D-5L = Euro Quality of Life-5 Dimensions-5 Levels; ET = Early Termination; FSH = follicle- stimulating hormone; HIV = human immunodeficiency virus; MG = myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia Gravis Composite; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS = Myasthenia Gravis Foundation of America Post-Intervention Status; MGQoL15r = revised 15-item Myasthenia Gravis Quality of Life -scale ; / meningitidis - Neisseria meningitidis', Neuro-QoL Fatigue = Quality of Life in Neurological Disorders Fatigue (Short Form); OLE = Open-label Extension; P = postdose sample;
PK/PD = pharmacokinetic(s)/pharmacodynamic(s); QMG = Quantitative Myasthenia Gravis score for disease severity; R = Remote Visit; RCT = Randomized Controlled Treatment; SADE = serious adverse device effect; SAE = serious adverse event; SoA = Schedule of Activities; SF-36 = Short Form Health Survey (36 question version); SVR = sustained virologic response; T = trough sample (predose); W = week(s).
FIG. 3A-FIG. 3D are tables showing the schedule of tests and measurements over the course of the open label extension. Abbreviations: ADA = antidrug antibody; ADE = adverse device effect; AE = adverse event; C = Clinic Visit; C5 = complement component 5; CSSRS = Columbia-Suicide Severity Rating Scale; D = day; ECG = electrocardiogram; eCRF = electronic case report form; EQ- 5D-5L = Euro Quality of Life-5 Dimensions-5 Levels; MG-ADL = Myasthenia Gravis-Activities of Daily Living; MGC = Myasthenia Gravis Composite; MGQoL15r = revised 15-item Myasthenia Gravis Quality of Life scale; Neuro-QoL Fatigue = Quality of Life in Neurological Disorders Fatigue (Short Form); OLE = Open-label Extension; P = postdose sample; PK/PD = pharmacokinetic(s)/pharmacodynamic(s); QMG = Quantitative Myasthenia Gravis score for disease severity; R = Remote Visit; RCT = Randomized Controlled Treatment; SADE = serious adverse device effect; SAE = serious adverse event; SoA = Schedule of Activities; SF-36 = Short Form Health Survey (36 question version); T = trough sample (predose); W = week(s). FIG. 4 shows a flow chart of pharmacokinetic, pharmacodynamic, and anti-drug antibody sampling before and after a subject is administered a rescue therapy.
FIG. 5 shows a diagram of an exemplary pre-filled syringe with a safety device.
Definitions
The term “antibody” as referred to herein includes whole antibodies and any antigen binding fragment (i.e., “antigen-binding portion”) or single chain version thereof. An “antibody” refers, in one preferred embodiment, to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1 , CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and L regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyterminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
A "heavy chain antibody" refers to an antibody that consists of two heavy chains and lacks the two light chains found in conventional antibodies. Camelids (members of the biological family Camelidae, the only currently living family in the suborder Tylopoda; extant camelids include dromedary camels, Bactrian camels, wild or feral camels, llamas, alpacas, vicunas and guanacos) are the only mammals with single chain VHH antibodies. About 50% of the antibodies in camelids are heavy chain antibodies with the other 50% being of the ordinary or conventional mammalian heavy/light chain antibody type.
"VHH domain" refers to variable domains present in naturally occurring heavy chain antibodies to distinguish them from the heavy chain variable domains that are present in conventional four chain antibodies (referred to herein as "VH domains") and from the light chain variable domains that present in conventional four chain antibodies (referred to herein as "VL domains").
VHH domains have a number of unique structural characteristics and functional properties that make isolated VHH domains (as well as sdAbs, which are based on VHH domains and share these structural characteristics and functional properties with the naturally occurring VHH domains) and proteins containing the VHH domains highly advantageous for use as functional antigen binding domains or proteins. For example, VHH domains, which bind to an antigen without the presence of a VL, and sdAbs can function as a single, relatively small, functional antigen binding structural unit, domain or protein. The small size of these molecules distinguishes VHH domains from the VH and VL domains of conventional four-chain antibodies. The use of VHH domains and sdAbs as single antigen-binding proteins or as antigen-binding domains (e.g., as part of a larger protein or polypeptide) offers a number of significant advantages over the use of conventional VH and VL domains, as well as scFv or conventional antibody fragments (such as Fab or F(ab')2 fragments). Only a single domain is required to bind an antigen with high affinity and with high selectivity, for example, so that there is no need to have two separate domains present, nor to assure that these two domains are present in a particular spatial conformation and configuration (e.g., through the use of specific linkers, as with an scFv). VHH domains and sdAbs can also be expressed from a single gene and require no post-translational folding or modifications. VHH domains and sdAbs can easily be engineered into multivalent and multi-specific formats. VHH domains and sdAbs are also highly soluble and do not have a tendency to aggregate (Ward, E. et al., Nature, 341 :544-6, 1989), and they are highly stable to heat, pH, proteases and other denaturing agents or conditions (Ewert, S. et al., Biochemistry, 41 :3628-36, 2002). VHH domains and sdAbs are relatively easy and cheap to prepare, even on a scale required for production. For example, VHH domains, sdAbs, and polypeptides containing VHH domains or sdAbs can be produced using microbial fermentation using methods known in the art and do not require the use of mammalian expression systems, as with, for example, conventional antibody fragments. VHH domains and sdAbs are relatively small (approximately 15 kDa, or 10 times smaller than a conventional IgG) compared to conventional four-chain antibodies and antigen-binding fragments thereof, and therefore show higher penetration into tissues (including but not limited to solid tumors and other dense tissues) than conventional four-chain antibodies and antigen-binding fragments thereof. VHH domains and sdAbs can show so-called "cavity-binding" properties (due to, for example, their extended CDR3 loop) and can access targets and epitopes not accessible to conventional four-chain antibodies and antigen-binding fragments thereof. It has been shown, for example, that VHH domains and sdAbs can inhibit enzymes (WO 97/49805; Transue, T. et al., Proteins, 32:515-22, 1998; Lauwereys, M. et al., EMBO J., 17:3512-20, 1998).
The term "single-domain antibody," or "sdAb," as used herein, is an antibody or fragment thereof consisting of a single monomeric variable antibody domain. It is not limited to a specific biological source or to a specific method of preparation. A sdAb can be obtained, for example, by (1) isolating the VHH domain of a naturally occurring heavy chain antibody; (2) expressing a nucleotide sequence encoding a naturally occurring VHH domain; (3) "humanization" of a naturally occurring VHH domain or by expression of a nucleic acid encoding such humanized VHH domain; (4) "camelization" of a naturally occurring VH domain from any animal species, in particular a species of mammal, such as from a human being, or by expression of a nucleic acid encoding such a camelized VH domain; (5) "camelization" of a "domain antibody" ("Dab") or by expression of a nucleic acid encoding such a camelized VH domain; (6) using synthetic or semi-synthetic techniques for preparing engineered polypeptides or fusion proteins; (7) preparing a nucleic acid encoding a sdAb using techniques for nucleic acid synthesis, followed by expression of the nucleic acid thus obtained; and/or (8) any combination of the above.
The fusion polypeptides or fusion proteins described herein can comprise, for example, amino acid sequences of naturally occurring VHH domains that have been "humanized," e.g., by replacing one or more amino acid residues in the amino acid sequence of the naturally occurring VHH sequence by one or more of the amino acid residues that occur at the corresponding positions in a VH domain from a human being.
The fusion polypeptides or fusion proteins described herein can comprise, for example, amino acid sequences of naturally occurring VH domains that have been "camelized," i.e., by replacing one or more amino acid residues in the amino acid sequence of a naturally occurring VH domain with one or more of the amino acid residues that occur at the corresponding positions in a VHH domain of, for example, a camelid antibody. This can be performed in a manner known in the art. Such camelization may preferentially occur at amino acid positions that are present at the VH-VL interface and at the so-called "Camelidae hallmark residues" (WO 94/04678). The VH domain or sequence that is used as a parental sequence or starting material for generating or designing the camelized sequence can be, for example, a VH sequence from a mammal, and in certain embodiments, the VH sequence of a human. It should be noted, however, that such camelized sequences can be obtained in any suitable manner known in the art and thus are not strictly limited to polypeptides that have been obtained using a polypeptide that comprises a naturally occurring parental VH domain.
Both "humanization" and "camelization" can be performed by providing a nucleotide sequence that encodes a naturally occurring VHH domain or VH domain, respectively, and then changing, in a manner known to those skilled in the art, one or more codons in the nucleotide sequence such that the new nucleotide sequence encodes a humanized or camelized sequence, respectively. Also, based on the amino acid sequence or nucleotide sequence of a naturally occurring VHH domain or VH domain, a nucleotide sequence encoding a desired humanized or camelized sequence can be designed and synthesized de novo using techniques for nucleic acid synthesis known in the art, after which the nucleotide sequence thus obtained can be expressed in a manner known in the art.
The terms "antigen" or "antigen target," as used herein, refer to a molecule or a portion of a molecule that is capable of being bound to by an antibody, one or more Ig binding domain, or other immunological binding moiety, including, for example, the engineered polypeptides or fusion polypeptides disclosed herein. An antigen is capable of being used in an animal to produce antibodies capable of binding to an epitope of that antigen. An antigen may have one or more epitopes.
The term “antigen-binding fragment” of an antibody (or simply “antibody fragment”), as used herein, refers to one or more fragments or portions of an antibody that retain the ability to specifically bind to an antigen. Such "fragments" are, for example between about 8 and about 1500 amino acids in length, suitably between about 8 and about 745 amino acids in length, suitably about 8 to about 300, for example about 8 to about 200 amino acids, or about 10 to about 50 or 100 amino acids in length. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term “antigen-binding fragment” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the V_, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341 :544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs, which may optionally be joined by a synthetic linker. Furthermore, although the two domains of the Fv fragment, VL and H, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (sFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term “antigen-binding fragment” of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies. Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.
As used herein, the term “binding domain” refers to the portion of a protein or antibody that comprises the amino acid residues that interact with an antigen. Binding domains include, but are not limited to, antibodies (e.g., full length antibodies), as well as antigen-binding portions thereof. The binding domain confers on the binding agent its specificity and affinity for the antigen. The term also covers any protein having a binding domain that is homologous or largely homologous to an immunoglobulin-binding domain.
As used herein, the phrase “clinical deterioration” refers to patients who experience an MG Crisis, which is defined as weakness from MG that is severe enough to necessitate intubation or to delay extubation following surgery, where the respiratory failure is due to weakness of respiratory muscles, severe bulbar (oropharyngeal) muscle weakness accompanies the respiratory muscle weakness, or is the predominant feature in a patient; or when there is significant symptomatic worsening to a score of 3 or a 2-point worsening from baseline on any one of the individual MG- Activities of Daily Living (MG-ADL) items other than double vision or eyelid droop; or administration of rescue therapy is provided to a patient whose, in the opinion of the investigator or investigator- designated physician, health would be in jeopardy, if rescue therapy were not given (e.g., emergent situations).
The term “epitope” or “antigenic determinant” refers to a site on an antigen to which an immunoglobulin or antibody specifically binds. Epitopes can be formed both from contiguous amino acids or noncontiguous amino acids juxtaposed by tertiary folding of a protein. Epitopes formed from contiguous amino acids are typically retained on exposure to denaturing solvents, whereas epitopes formed by tertiary folding are typically lost on treatment with denaturing solvents. An epitope typically includes at least 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14 or 15 amino acids in a unique spatial conformation. Methods for determining what epitopes are bound by a given antibody (/.e., epitope mapping) are well known in the art and include, for example, immunoblotting and immunoprecipitation assays, wherein overlapping or contiguous peptides from the antigen are tested for reactivity with the given antibody. Methods of determining spatial conformation of epitopes include techniques in the art and those described herein, for example, x-ray crystallography and 2-dimensional nuclear magnetic resonance (see, e.g., Epitope Mapping Protocols in Methods in Molecular Biology, Vol. 66, G. E. Morris, Ed. (1996)).
The term "bispecific" refers to a fusion polypeptide of the disclosure that is capable of binding two antigens.
The term “effective amount” refers to an amount of an agent that provides the desired biological, therapeutic and/or prophylactic result. That result can be reduction, amelioration, palliation, lessening, delaying and/or alleviation of one or more of the signs, symptoms or causes of a disease, or any other desired alteration of a biological system. In one example, an “effective amount” is the amount of fusion polypeptide or fragment thereof clinically proven to alleviate at least one symptom of MG. An effective amount can be administered in one or more administrations.
As used herein, “effective treatment” refers to treatment producing a beneficial effect, e.g., amelioration of at least one symptom of a disease or disorder. A beneficial effect can take the form of an improvement over baseline, i.e., an improvement over a measurement or observation made prior to initiation of therapy according to the method. Effective treatment may refer to alleviation of at least one symptom of MG.
The term "fused to" as used herein refers to a polypeptide made by combining more than one sequence, typically by cloning one sequence, e.g., a coding sequence, into an expression vector in frame with one or more second coding sequence(s) such that the two (or more) coding sequences are transcribed and translated into a single continuous polypeptide. In addition to being made by recombinant technology, parts of a polypeptide can be "fused to" each other by means of chemical reaction, or other means known in the art for making custom polypeptides.
As used herein, the terms “induction” and “induction phase” are used interchangeably and refer to the first phase of treatment in the clinical trial.
As used herein, the terms “loading dose” refers to the initial dose administered to the patient. In some embodiments, the loading dose is 500-1000 mg of the fusion polypeptide. In some embodiments, the loading dose is 600-900 mg, 700-900 mg, or 600-800 mg of the fusion polypeptide. In some embodiments, the loading dose is 800-1000 mg, 600-700 mg, or 700-1000 mg of the fusion polypeptide. In some embodiments, the loading dose is about 600 mg, about 700 mg, about 800, or about 900 mg of the fusion polypeptide. Loading doses may be titered based on body weight.
In some embodiments, patients with a body weight greater than or equal to 40 kg, but less than 80 kg is administered 200-700 mg, 300-600 mg, about 600 mg or 300 mg of the fusion polypeptide. In some embodiments, patients with a body weight greater than or equal to 80 kg, are administered 500-1000 mg, 600-900 mg, about 600 mg, or 900 mg of the fusion polypeptide.
As used herein, the terms “maintenance” and “maintenance phase” are used interchangeably and refer to the second phase of treatment in the clinical trial. In certain embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. The maintenance phase of the fusion polypeptide dosing can last for between 1 week and the life of the subject. According to other embodiments, the maintenance phase lasts for 26-52, 26- 78, 26-96, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more. In other embodiments, the maintenance phase lasts for greater than 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 78, 96, 104, 130, 156, or 182 weeks. According to other embodiments, the maintenance phase lasts for greater than 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80 or more years. In certain embodiments, the maintenance phase lasts for the remainder of the subject's life.
As used herein, the terms “maintenance dose” or “maintenance phase” refers to a dose administered to the patient after the loading dose. In some embodiments, the loading dose is 200- 700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 300-700 mg, 400-600 mg or 300-700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 200-600 mg, 200-500 mg, or 400-700 mg of the fusion polypeptide. In some embodiments, the maintenance dose is about 300 mg, about 200 mg, or about 400 mg of the fusion polypeptide. In some embodiments, the maintenance dose is 600 mg, 500 mg, or 700 mg of the fusion polypeptide. Maintenance doses may be titered based on body weight.
In some embodiments, patients with a body weight greater than or equal to 40 kg, but less than 80 kg is administered 200-400 mg, 300-400 mg, about 300 mg, or 200 mg of the fusion polypeptide. In some embodiments, patients with a body weight greater than or equal to 80 kg is administered 500-700 mg, 600-700 mg, about 600 mg, or 700 mg of the fusion polypeptide.
As used herein, the phrase “requires chronic plasma exchange” to maintain clinical stability refers to the use of plasma exchange therapy on a patient on a regular basis for the management of muscle weakness at least every 3 months over the last 12 months.
The term "peptide linker" as used herein refers to one or more amino acid residues inserted or included between the engineered polypeptides of the fusion polypeptide(s). The peptide linker can be, for example, inserted or included at the transition between the engineered polypeptides of the fusion polypeptide at the sequence level.
The terms "pharmaceutical composition" or "therapeutic composition," as used herein, refer to a compound or composition capable of inducing a desired therapeutic effect when administered to a patient.
The term "pharmaceutically acceptable carrier" or "physiologically acceptable carrier," as used herein, refers to one or more formulation materials suitable for accomplishing or enhancing the delivery of the engineered polypeptides or fusion polypeptides ofthe disclosure.
An antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or the engineered polypeptides or fusion polypeptides disclosed herein, are said to "specifically" bind an antigen when the molecule preferentially recognizes its antigen target in a complex mixture of proteins and/or macromolecules. The term "specifically binds," as used herein, refers to the ability of an antibody, immunoglobulin, or immunologically functional immunoglobulin fragment, or an engineered polypeptide or fusion polypeptide of the disclosure, to bind to an antigen containing an epitope with an KD of at least about 10’6 M,10'7 M, 10’8 M, 10'9 M, 10'1° M, 10'11 M, 10'12 M, or more, and/or to bind to an epitope with an affinity that is at least two-fold greater than its affinity for a nonspecific antigen.
As used herein, the term “subject” or “patient” is a human patient (e.g., a patient having myasthenia gravis (MG)). As used herein, the term “subject” and “patient” are interchangeable. The terms "treatment" or "treat," as used herein, refer to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include those having the disorder as well as those at risk of having the disorder orthose in which the disorder is to be prevented.
As used herein, the term ‘‘treatment effect” refers to a reduction in the Myasthenia Gravis Activities of Daily Living (MG-ADL) score, Myasthenia Gravis (QMG) score, Myasthenia Gravis (MG) Quality of Life Questionnaire (MGQOL15R) score, Neuro-QOL-Fatigue score, or another score that assesses the severity of MG, relative to baseline priorto initiation of a treatment. The reduction may be 1 point or greater.
DETAILED DESCRIPTION
The disclosure provides methods of treating myasthenia gravis (MG) in subjects in need thereof by administering a fusion polypeptide comprising an engineered polypeptide that specifically binds human complement component C5 fused to a polypeptide that specifically binds to human serum albumin by way of a peptide linker.
In certain embodiments, the fusion polypeptide includes an engineered polypeptide that specifically binds human serum albumin, having the sequence of SEQ ID NO: 4, fused to a polypeptide that specifically binds to human complement component 5, having the amino acid sequence of SEQ ID NO: 8.
Fusion Polypeptides That Specifically Bind Complement Component C5 and Serum Albumin Described herein are fusion polypeptides that comprise engineered polypeptides that specifically bind albumin and complement component C5, wherein the engineered polypeptides are fused directly or are linked via one or more suitable linkers or spacers. The peptide linker can be, for example, inserted or included at the transition between the engineered polypeptides of the fusion polypeptide at the sequence level. The identity and sequence of amino acid residues in the linker may vary depending on the desired secondary structure. For example, glycine, serine and alanine are useful for linkers having maximum flexibility. Any amino acid residue can be considered as a linker in combination with one or more other amino acid residues, which may be the same as or different from the first amino acid residue, to construct larger peptide linkers as necessary depending on the desired properties. In other embodiments, the linker is GGGGAGGGGAGGGGS (SEQ ID NO:10). One of skill in the art can select a linker, for example, to reduce or eliminate post-translational modification, e.g., glycosylation, e.g., xylosylation.
In some embodiments, the C-terminal residue of the albumin-binding domain of the fusion polypeptide can be fused either directly or via a peptide to the N-terminal residue of the complement component C5 binding domain.
In some embodiments, the polypeptide that specifically binds to human serum albumin includes three complementarity determining regions, CDR1 , CDR2 and CDR3, wherein CDR1 has an amino acid sequence of GRPVSNYA (SEQ ID NO: 1), CDR2 has an amino acid sequence of INWQKTAT (SEQ ID NO: 2) and CDR3 has an amino acid sequence of AAVFRVVAPKTQYDYDY (SEQ ID NO: 3). In some embodiments, the polypeptide that specifically binds to human complement component 5 includes three complementarity determining regions, CDR1 , CDR2 and CDR3, wherein CDR1 has an amino acid sequence of GRAHSDYAMA (SEQ ID NO: 5), CDR2 has an amino acid sequence of GIGWSGGDTLYADSVRG (SEQ ID NO: 6) and CDR3 has an amino acid sequence of AARQGQYIYSSMRSDSYDY (SEQ ID NO: 7).
In some embodiments, the polypeptide that specifically binds to human serum albumin includes an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to the VHH sequence:
EVQLVESGGGLVKPGGSLRLSCAASGRPVSNYAAAWFRQAPGKEREFVSAINWQKTATYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAAVFRVVAPKTQYDYDYWGQGTLVTV SS (SEQ ID NO: 4).
In some embodiments, the polypeptide that specifically binds to human serum albumin has an amino acid sequence of SEQ ID NO: 4.
In some embodiments, the polypeptide that specifically binds to human complement component C5 includes an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to the VHH sequence:
EVQLVESGGGLVQPGGSLRLSCAASGRAHSDYAMAWFRQAPGQEREFVAGIGWSGGDTL YADSVRGRFTNSRDNSKNTLYLQMNSLRAEDTAVYYCAARQGQYIYSSMRSDSYDYWGQG TLVTVSS (SEQ ID NO: 8).
In some embodiments, the polypeptide that specifically binds to human complement component C5 has an amino acid sequence of SEQ ID NO: 8.
In some embodiments, a fusion polypeptide comprises a complement component C5 binding comprising an amino acid sequences of SEQ ID NO: 8 or a fragment thereof; and the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence of SEQ ID NO: 4 or a fragment thereof. In some embodiments, the fusion polypeptide may have an amino acid sequence having 95% (e.g., 95%, 96%, 97%, 98%, 99% or 100%) identity to:
EVQLVESGGGLVKPGGSLRLSCAASGRPVSNYAAAWFRQAPGKEREFVSAINWQKTATYA DSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAAVFRVVAPKTQYDYDYWGQGTLVTV SSGGGGAGGGGAGGGGSEVQLVESGGGLVQPGGSLRLSCAASGRAHSDYAMAWFRQAP GQEREFVAGIGWSGGDTLYADSVRGRFTNSRDNSKNTLYLQMNSLRAEDTAVYYCAARQG QYIYSSMRSDSYDYWGQGTLVTVSS (SEQ ID NO: 9)
In some embodiments, the fusion polypeptide has an amino acid sequence of SEQ ID NO: 9. In the sequence of SEQ ID NO:9, the C-terminus of the sequence that specifically binds human serum albumin (SEQ ID NO:4) is fused to a GGGGAGGGGAGGGGS (SEQ ID NO:10) linker, which is fused to the N-terminus of the polypeptide that specifically binds human complement component C5 (SEQ ID NO:8).
The fusion polypeptides disclosed herein can be made by expressing in a host cell at least one nucleic acid molecule comprising a nucleotide sequence encoding the fusion polypeptide. Host cells can be mammalian, plant or microbial in origin. In addition to known mammalian host cells, yeast host cells, e.g., Pichia pastoris, Saccharomyces cerevisiae, and/or plant host cells can be used. The polypeptide has been studied in a Phase 1 , randomized, double-blind, placebo- controlled, single and multiple ascending dose study involving 97 healthy subjects (EudraCT 2018- 004500-19, NCT04920370). Single doses of the polypeptide ranged from 30 mg to 1700 mg SC, included 1700 mg SC combined with a recombinant human hyaluronidase, and intravenous (IV) administration of 300 mg. Multiple doses ranged from 100 to 300 mg SC Q1 W for 3 doses, and 600 mg SC Q1W following an initial (loading) dose of 900 mg, for a total of 8 doses. While a detailed analysis of the data from this Phase 1 study is still pending, preliminary findings indicate a favorable safety and tolerability profile. All adverse events (AEs)were of mild or moderate severity, and no serious adverse events (SAEs) were observed.
The purpose of the pivotal Phase 3 study described in this protocol is to test the safety and efficacy of the polypeptide(s) described herein, administered through SC injection using a pre-filled syringe with safety device (PFS-SD), for the treatment of adults with AChR+ gMG.
Methods of Treating Myasthenia Gravis
Provided herein are methods for treating MG (e.g., generalized MG (gMG), e.g., gMG when the patient is anti-AChR antibody positive) in a human patient, comprising administering to the patient a fusion polypeptide comprising an engineered polypeptide that specifically binds human complement component C5 fused to a polypeptide that specifically binds to human serum albumin by way of a peptide linker according to a particular clinical dosage regimen (/.e., at a particular dose amount and according to a specific dosing schedule).
In some embodiments, MG includes gMG. In some embodiments, gMG is characterized as including subjects or patients positive for auto-antibodies binding to AChR who continue to show marked generalized weakness or bulbar signs and symptoms of MG while receiving current standard of care for MG such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability.
In one embodiment, the fusion polypeptide is administered once on Day 1 of the administration cycle, once on Day 8 of the administration cycle, and every week thereafter. In some embodiments, the fusion polypeptide is administered every week after the administration cycle for an extension period up to two years (e.g., at a dose of 300 mg or 600 mg). In some embodiments, the fusion polypeptide is administered every week after the administration cycle for an extension period for the life of the subject (e.g., at a dose of 300 mg or 600 mg).
In another embodiment, the fusion polypeptide is administered for one or more administration cycles. In one embodiment, the administration cycle is 26 weeks. In another embodiment, the treatment comprises at least 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In another embodiment, the treatment is continued for the lifetime of the human patient.
In some embodiments, the dose of the fusion polypeptide is based on the weight of the patient. In one embodiment, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350, mg, 360 mg, 370 mg, 380 mg, 390 mg, 400 mg, 410 mg, 420 mg, 430 mg, 440 mg, 450 mg, 460 mg, 470 mg, 480 mg, 490 mg, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg or 650 mg of the fusion polypeptide is administered to a patient weighing < 80 kg. In some embodiments, the fusion polypeptide is administered to a patient weighing < 80 kg on Day 1 of the administration cycle in an amount of between 500 mg and 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing < 80 kg on Day 1 of the administration cycle in an amount of 600 mg. In some embodiments, the fusion polypeptide is administered to a patient weighing < 80 kg on Day 8 of the administration cycle at a maintenance does of between 200 mg and 400 mg (e.g., 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 260 mg, 270 mg, 280 mg, 290 mg, 300 mg, 310 mg, 320 mg, 330 mg, 340 mg, 350 mg, 360 mg, 370 mg, 380 mg, 390 mg or 400 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing < 80 kg on Day 8 of the administration cycle at a maintenance does of 600 mg.
In some embodiments, 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg, 700 mg, 710 mg, 720 mg, 730 mg, 740 mg, 750 mg, 760 mg, 770 mg, 780 mg, 790 mg, 800 mg, 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg of the fusion polypeptide is administered to a patient weighing > 80 kg.
In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 1 of the administration cycle in an amount of between 800 mg and 1000 mg (e.g., 810 mg, 820 mg, 830 mg, 840 mg, 850 mg, 860 mg, 870 mg, 880 mg, 890 mg, 900 mg, 910 mg, 920 mg, 930 mg, 940 mg, 950 mg, 960 mg, 970 mg, 980 mg, 990 mg or 1000 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 1 of the administration cycle in an amount of 900 mg. In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 8 of the administration cycle at a maintenance does of between 500 mg and 700 mg (e.g., 500 mg, 510 mg, 520 mg, 530 mg, 540 mg, 550 mg, 560 mg, 570 mg, 580 mg, 590 mg, 600 mg, 610 mg, 620 mg, 630 mg, 640 mg, 650 mg, 660 mg, 670 mg, 680 mg, 690 mg or 700 mg). In some embodiments, the fusion polypeptide is administered to a patient weighing > 80 kg on Day 8 of the administration cycle at a maintenance does of 600 mg.
In some embodiments, the fusion polypeptide is administered once per week, twice per week, three times per week, four times per week, five times per week, six times per week, or daily. In another embodiment, the fusion polypeptide is administered twice daily. In another embodiment, the fusion polypeptide is administered once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, once every eleven weeks, or once every twelve weeks. In another embodiment, the fusion polypeptide is administered at a loading dose on Day 1 , followed by a different maintenance dose on Day 8 and every week thereafter.
In some embodiments, the fusion polypeptide is administered using a pre-filled syringe. In other embodiments, the fusion polypeptide is administered using an autoinjector device. For example, the autoinjector device may include a single vial system, such as a pen injector device for solution delivery. Such devices are commercially available from manufacturers such as BD Pens, BD Autojector®, Humaject®, NovoPen®, B-D®Pen, AutoPen®, and OptiPen®, GenotropinPen®, Genotronorm Pen®, Humatro Pen®, Reco-Pen®, Roferon Pen®, Biojector®, Iject®, J-tip Needle-Free Injector®, DosePro®, Medi-Ject®, e.g., as made or developed by Becton Dickinson (Franklin Lakes, NJ), Ypsomed (Burgdorf, Switzerland, www.ypsomed.com; Bioject, Portland, OR.; National Medical Products, Weston Medical (Peterborough, UK), Medi-Ject Corp (Minneapolis, MN), and Zogenix, Inc, Emeryville, CA. Recognized devices comprising a dual vial system include those pen-injector systems for reconstituting a lyophilized drug in a cartridge for delivery of the reconstituted solution such as the HumatroPen®. In one embodiment, the autoinjector is a YpsoMate 2.25 or YpsoMate 2.25 Pro (Ypsomed) disposable injection device.
In some embodiments, the patients treated according to the methods described herein have been vaccinated against meningococcal infections within three years prior to, or at the time of, initiating study drug. In one embodiment, patients who initiate treatment less than two weeks after receiving a meningococcal vaccine receive treatment with appropriate prophylactic antibiotics until two weeks after vaccination. In another embodiment, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135 and/or B.
Outcomes
In some embodiments, treatment of MG includes the amelioration or improvement of one or more symptoms associated with MG. Symptoms associated with MG include muscle weakness and fatigability. Muscles primarily affected by MG include muscles that control eye and eyelid movement, facial expressions, chewing, talking, swallowing, breathing, neck movements, and limb movements.
In some embodiments, treatment of MG includes the improvement of a clinical marker for MG progression. These markers include MG-ADL scores, QMG score for disease severity, MGC, NIF, forced vital capacity, MGFA post-intervention status, and other quality of life measurements. In some embodiments, MG-ADL is the primary score for measuring improvement of MG.
The MG-ADL is an 8-point questionnaire that focuses on relevant symptoms and functional performance of activities of daily living (ADL) in MG subjects (Table 1). The 8 items of the MG- ADL were derived from symptom-based components of the original 13-item QMG to assess disability secondary to ocular (2 items), bulbar (3 items), respiratory (1 item), and gross motor or limb (2 items) impairment related to effects from MG. In this functional status instrument, each response is graded 0 (normal) to 3 (most severe). The range of total MG-ADL score is 0-24. A clinically meaningful improvement in a patient's MG-ADL in one embodiment is, for example, a 3 point or greater reduction in score after 26 weeks of treatment.
The current QMG scoring system consists of 13 items: ocular (2 items), facial (1 item), bulbar (2 items), gross motor (6 items), axial (1 item), and respiratory (1 item); each graded 0 to 3, with 3 being the most severe (Table 2). The range of total QMG score is 0-39. The QMG scoring system is an objective evaluation of therapy for MG and is based on quantitative testing of sentinel muscle groups. The MGFA task force has recommended that the QMG score be used in prospective studies of therapy for MG (Benatar, M. et al., Muscle Nerve, 45:909-17, 2012). A clinically meaningful improvement in a patient’s QMG in one embodiment is, for example, a 5 point or greater reduction in score after 26 weeks of treatment.
TABLE 1 : MG-ADL profile
Figure imgf000019_0001
TABLE 2: QMG score for disease severity
Figure imgf000020_0001
The MGC is a validated assessment tool for measuring clinical status of subjects with MG (16). The MGC assesses 10 important functional areas most frequently affected by MG and the scales are weighted for clinical significance that incorporates subject-reported outcomes (Table 3; Burns, T. et al., Muscle Nerve, 54:1015-22, 2016). MGC is administered at Screening, Day 1 , Weeks 1-4, 8, 12, 16, 20, and 26 or ET (Visits 1-6, 8, 10, 12, 14, and 17 or ET). A clinically meaningful improvement in a patient’s MGC in one embodiment is, for example, a 3 point or greater reduction in score after 26 weeks of treatment.
TABLE 3: MG composite scale
Figure imgf000021_0001
The revised Myasthenia Gravis Qualify of Life 15-item scale (MG-QOL15r) is a health-related
QoL evaluative instrument specific to patients with MG (Table 4). The MG-QOL15r was designed to provide information about patients’ perception of impairment and disability, determine the degree to which disease manifestations are tolerated, and to be administered and interpreted easily. The MG- QOL15r is completed by the patient. Higher scores indicate greater extent of and dissatisfaction with MG-related dysfunction. A clinically meaningful improvement in a patient's MG-QOL 15 is a decrease in score after 26 weeks of treatment.
TABLE 4: Revised MG-QOL15r scale
Figure imgf000022_0001
The Neuro-QOL Fatigue is a reliable and validated brief 19-item survey of fatigue completed by the subject or patient. Higher scores indicate greater fatigue and greater impact of MG on activities (Table 5; Gershon, R. et al., Qual. Life Res., 21 :475-86, 2012). A clinically meaningful improvement in a patient’s Neuro-QQL Fatigue score is reflected in a decrease in score after 26 weeks of treatment.
TABLE 5: Neuro-QOL fatigue
Figure imgf000023_0001
Figure imgf000024_0001
The Euro Quality of Life-5L (EQ-5D-5L) is a self-assessed, health-related QoL questionnaire. The EQ-5D-5L essentially consists of 2 pages: the EQ-5D descriptive scale system and the EQ visual analogue scale (EQ VAS). The scale measures QoL on a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each level is rated on a scale that describes the degree of problems in that area (e.g., I have no problems walking about, slight problems, moderate problems, severe problems, or unable to walk). The patient is asked to indicate his/her health state by ticking the box next to the most appropriate statement in each of the five dimensions. This decision results in a 1 -digit number that expresses the level selected for that dimension. The digits for the five dimensions can be combined into a 5- digit number that describes the patient’s health state. A clinically meaningful improvement in a patient’s EQ 5D is reflected as a decrease in scores in each category after 26 weeks of treatment. This tool also has an overall health scale (EQ VAS) where the rater selects a number between 1 - 100 to describe the condition of their health, 100 being the best imaginable. The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale, where the endpoints are labeled ‘The best health you can imagine’ and ‘The worst health you can imagine.’ The VAS can be used as a quantitative measure of health outcome that reflect the patient’s own judgement. A clinically meaningful improvement in a patient’s EQ VAS is reflected as an increase in score after 26 weeks of treatment. Convergent validity was demonstrated by a correlation between EQ-5D-5L and the dimensions of World Health Organization 5 Well Being questionnaires, (r = 0.43, p<0.001) (see, Janssen, M. et al., Qual. Life Res., 22:1717-27, 2013). The EQ-5D-5L approach is reliable, average test-retest reliability using interclass coefficients with mean of 0.78 and 0.73 (Brooks, R., Health Policy, 37:53-72, 1996; Chaudhury, C. et al., Biochemistry, 45:4983-90, 2006).
Subjects with increasingly severe MG can suffer from potentially fatal respiratory complications including profound respiratory muscle weakness. Respiratory function is monitored closely for evidence of respiratory failure in MG subjects and ventilator support is recommended in the event of consistent declines in serial measurements of Forced Vital Capacity (FVC) or NIF, loss of upper airway integrity (difficulty handling oral secretions, swallowing, or speaking) or in the setting of emerging respiratory failure. FVC as one of the test items in QMG is performed when QMG is performed. NIF was performed using the NIF Meter.
The MG clinical state is assessed using the MGFA Post-Intervention Status (MGFA-PIS). Change in status categories of Improved, Unchanged, Worse, Exacerbation and Died of MG as well as the Minimal Manifestation (MM) can be assessed (Table 6).
Figure imgf000025_0001
Patients administered the fusion polypeptide may show a reduced MG-ADL. In some embodiments, the subjects have an initial MG-ADL score of greater than or equal to 5 points. In some embodiments, the subjects have an initial MG-ADL score greater than 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22 or 23 points. In some embodiments, after a course of treatment with the fusion polypeptide, the MG-ADL score of the subject is reduced to less than 5 points. In some embodiments, the MG-ADL score is reduced at least 1 point, at least 2 points, at least 3 points, at least 4 points, at least 5 points, at least 6 points, at least 7 points, at least 8 points, at least 9 points, at least 10 points, at least 11 points, at least 12 points, at least 13 points, at least 14 points, at least 15 points, at least 16 points, at least 17 points, at least 18 points, at least 19 points, at least 20 points, at least 21 points, at least 22 points, at least 23 points, or at least 24 points after treatment with fusion polypeptide. In some embodiments, the MG-ADL score of the patient is reduced by at least 2 points after a course of treatment with the fusion polypeptide. In some embodiments, the MG-ADL of the patient is reduced by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23 or 24 points after a course of treatment with the fusion polypeptide.
According to some embodiments, the course of treatment with fusion polypeptide lasts for 26 weeks. According to some embodiments, the course of treatment lasts for 26-52, 26-78, 26-96, 26-104, 26-130, 26-156, 26-182, 26-208 weeks, or more. In some embodiments, the course of treatment lasts for greater than 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43,
44, 45, 46, 47, 48, 49, 50, 51 , 52, 78, 96, 104, 130, 156 or 182 weeks. According to some embodiments, the course of treatment lasts for greater than 1 , 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40,
45, 50, 55, 60, 65, 70, 75, 80, or more years. In some embodiments, the course of treatment lasts for the remainder of the subject’s life.
According to some embodiments, during the course of treatment, one or more symptoms or scores associated with MG improves during the course of treatment and is maintained at the improved level throughout treatment. MG-ADL can improve, for example, after 26 weeks of treatment with the fusion polypeptide and then remain at the improved level for the duration of the treatment, which is 96 weeks of treatment with the fusion polypeptide.
In some embodiments, the first sign of improvement occurs by 26 weeks of treatment with the fusion polypeptide. According to some embodiments, the first sign of improvement occurs between weeks 1-26, 26-52, 52-78, 26-96, 78-104, 104-130, 130-156, 156-182, or 182-208 of treatment with the fusion polypeptide. In some embodiments, the first sign of improvement occurs at week 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50, 51 , 52, 78, 96, 104, 130, 156 or 182.
In some embodiments, the subject has been diagnosed with MG for at least 3 months. In some embodiments, MG includes refractory gMG. In some embodiments, refractory gMG is characterized as including subjects or patients positive for auto-antibodies binding to AChR who continue to show marked generalized weakness or bulbar signs and symptoms of MG while receiving current standard of care for myasthenia gravis such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability. In some embodiments, refractory gMG is characterized as including subjects or patients who continue to show marked generalized weakness or bulbar signs and symptoms of myasthenia gravis while receiving current standard of care for MG such as cholinesterase inhibitor therapy and 1ST or who require chronic plasma exchange or chronic IVIg to maintain clinical stability. In some embodiments, the subject is 18 years old or older in age. In some embodiments, the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification of between II and IV.
In some embodiments, the subject is being administered one or more additional pharmaceutical compositions. In some embodiments, the pharmaceutical composition is an acetylcholinesterase inhibitor, an 1ST, or immunoglobulins. In some embodiments, 1ST is selected from the group consisting of a corticosteroid, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC). In some embodiments, the subject has not been administered a B cell-depleting therapy in the prior 6 months. In some embodiments, the B cell-depleting therapy is rituximab or ocrelizumab. In some embodiments, the subject has not been administered an FcRn inhibitor within 5 half-lives of the FcRn before administration of the fusion polypeptide.
Kits and Unit Dosage Forms
Also provided herein are kits that include a pharmaceutical composition containing a fusion polypeptide described herein, such as the fusion polypeptide having the amino acid sequence of SEQ ID NO: 9, and a pharmaceutically acceptable carrier, in a therapeutically effective amount adapted for use in the preceding methods. The kits can also optionally include instructions, e.g., comprising administration schedules, to allow a practitioner (e.g., a physician, nurse or patient) to administer the composition contained therein to administer the composition to a patient having MG. The kit also can include a syringe.
Kits can optionally include multiple packages of the single-dose pharmaceutical compositions each containing an effective amount of the fusion polypeptide for a single administration in accordance with the methods provided above. Instruments or devices necessary for administering the pharmaceutical composition(s) also may be included in the kits. A kit may provide one or more pre-filled syringes containing an amount of the fusion polypeptide. A kit may include one or more autoinjectors containing an amount of the fusion polypeptide.
The following examples are merely illustrative and should not be construed as limiting the scope of this disclosure in any way as many variations and equivalents will become apparent to those skilled in the art upon reading the present disclosure. The contents of all references, Genbank entries, patents and published patent applications cited throughout this application are expressly incorporated herein by reference.
EXAMPLES
The Examples that follow are illustrative of specific embodiments of the disclosure, and various uses thereof. They are set forth for explanatory purposes only, and they should not be construed as limiting the scope of the invention in any way.
Example 1. A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel, Multicenter Study to Evaluate the Safety and Efficacy of a C5-binding polypeptide in Adults with gMG
This study evaluates the safety, tolerability, pharmacokinetics, and efficacy of the fusion polypeptide described herein in treating MG. Specific objectives and corresponding endpoints for the study are outlined in Table 7. 1. Study Objectives, Estimands, and Endpoints
Table 7: Mapping Objectives and Estimands and/or Endpoints
Figure imgf000028_0001
Table 7: Mapping Objectives and Estimands and/or Endpoints
Figure imgf000029_0001
Table 7: Mapping Objectives and Estimands and/or Endpoints
Figure imgf000030_0001
Table 7: Mapping Objectives and Estimands and/or Endpoints
Figure imgf000031_0001
Abbreviations: AChR+ = anti-acetylcholine receptor antibody-positive; ADA = antidrug antibody;
ADE = adverse device effect; AE = adverse event; C5 = complement component 5;
ECG = electrocardiogram; EQ-5D-5L = Euro Quality of Life- 5 Dimensions-5 Levels; gMG = generalized myasthenia gravis; IL-6 = interleukin-6; MG-ADL = Myasthenia Gravis-Activities of Daily Living; MGC = Myasthenia Gravis Composite; MGFA-PIS = Myasthenia Gravis Foundation of America Post-Intervention Status; MG-QoL15r = revised 15-item Myasthenia Gravis Quality of Life scale ; MM = minimal manifestation; MMP-10 = matrix metalloproteinase-10; MSE = Minimal Symptom Expression; Neuro-QoL Fatigue = Quality of Life in Neurological Disorders Fatigue (Short Form); PD = pharmacodynamic(s); PFS-SD = prefilled syringe with safety device;
PK = pharmacokinetic(s); QMG = Quantitative Myasthenia Gravis score for disease severity; QoL = quality of life; SADE = serious adverse device effect; SAE = serious adverse event;
SF-36 = Short Form Health Survey (36 question version).
2. Primary Estimand(s)
The estimand corresponding to the primary objective is defined as follows:
The study compares the fusion polypeptide described herein with placebo in adults with AChR+ gMG. For the primary objective, the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the MG-ADL total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention. The difference between treatment groups in the mean change from Baseline in the MG-ADL total score at Week 26 is assessed.
3. Key Secondary Estimand
For the key secondary objective, the question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the Quantitative Myasthenia Gravis score for disease severity (QMG) total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention. The difference between treatment groups in the mean change from Baseline in the QMG total score at Week 26 is assessed. 3.1 Secondary Estimands
The other secondary objectives assess the efficacy of the fusion polypeptide described herein compared with placebo in the treatment of gMG based on the level of improvement in the QMG total score, the level of improvement in the MG-ADL total score, and the change in the Myasthenia Gravis Composite (MGC) total score.
The estimands corresponding to these secondary objectives are defined as follows: The question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the QMG total score at Week 26 by > 5 points from Baseline regardless ofwhether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention. The odds ratio of a reduction by > 5 points from Baseline in the QMG total score at Week 26 (the fusion polypeptide described herein compared to placebo) is calculated.
The question of interest is whether the fusion polypeptide described herein is superior to placebo in reducing the MG-ADL total score at Week 26 by > 3 points from Baseline regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention. The odds ratio of a reduction by > 3 points from Baseline in the MG-ADL total score at Week 26 (the fusion polypeptide described herein compared to placebo) is calculated.
The question of interest is whether the fusion polypeptide described herein is superior to placebo in improving the MGC total score at Week 26 regardless of whether participants experience any of the following intercurrent events: clinical deterioration, use of rescue therapy, change in concomitant gMG therapy, use of prohibited medication and therapy, or discontinuation of study intervention. The difference between treatment groups in the mean change from Baseline in the MGC total score at Week 26 is assessed.
4. STUDY DESIGN
4.1 .Overall Design
Described herein is a Phase-3, randomized, double-blind, placebo-controlled, parallel, multicenter study to evaluate the safety and efficacy of the fusion polypeptide described herein in adults with generalized myasthenia gravis (gMG). The study is conducted in North and South America, Europe, Asia, and the Pacific region. Approximately 200 eligible participants are stratified by geographical region and body weight (< 80 kg and > 80 kg) at Baseline and randomized 1 :1 to treatment with the fusion polypeptide described herein or placebo, both administered through weekly subcutaneous (SC) injection by using a PFS-SD. Randomization of participants with an MG-ADL total score < 7 and participants receiving concomitant periodic (chronic) intravenous (IVIg) or SC immunoglobulin (SCIg) treatment are restricted as specified in Section 4.1 .2.
The study comprises 3 periods: Screening (< 4 weeks), Randomized Control Trial (RCT) (26 weeks), and Open Label Extension (OLE) (96 weeks) (FIG. 1). Consenting participants are screened for study eligibility up to 4 weeks prior to Day 1 . Participants with confirmed gMG and a positive serological test for AChR antibodies are included if the severity of their disease is classified as between II and IV according to clinical criteria established by the Myasthenia Gravis Foundation of America (MGFA) (Jaretzki et al., Neurology, 55:16-23, 2000), and if their MG-ADL total score is > 5. MGFA Classes II to IV comprise a broad participant population, excluding only participants with solely ocular symptoms or signs (Class I) and participants requiring intubation (Class V).
Participants who satisfy all eligibility criteria are randomized into the RCT Period and receive a weight-based loading dose of the fusion polypeptide described herein or placebo on Day 1 , followed by weight based maintenance treatment with the fusion polypeptide described herein or placebo on Week 1 (Day 8) and once a week (Q1 ) thereafter for a total of 26 weeks. Doses in the RCT Period are based on participant body weight at Randomization. During their first 5 visits, participants and, if applicable, their caregivers are trained in administering the study intervention by designated study site personnel. Once training is complete and certified, participants may self-administerthe treatment at home unless the scheduled dose falls on the same day as an upcoming Clinic Visit. In this case, participants are asked to administer the study intervention at the clinic under supervision of the clinic staff to monitor their injection skills. Participants make every effort to maintain the weekly dosing intervals. However, deviations of ± 1 day are acceptable if they cannot be avoided.
Participants who complete the 26-week RCT Period continue the study through the 96-week OLE Period (FIG. 1), or until the product is registered or approved (in accordance with countryspecific regulations), or until the fusion polypeptide described herein can be provided via a sponsor post-trial access program (as allowed by local laws and regulations), whichever occurs first. Participants transition to open-label treatment with the fusion polypeptide described herein following completion of the Day 183 assessments. To maintain the blinding of participants for their treatment allocation in the previous RCT Period, the first dose upon entry to the OLE Period on Day 183 is administered by study site personnel. Participants who were in the placebo group during the RCT Period receive a blinded weight-based loading dose of the fusion polypeptide described herein. Participants who were in the fusion polypeptide group during the RCT Period receive a weight-based maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose. Participants resume the weekly self administered maintenance doses the following week (Day 190). Doses in the OLE Period are based on participant body weight at Day 183 and are reassessed approximately every 6 months as specified in the Schedule of Activities (SoA).
Final study assessments are performed in an EoS Visit at Week 122, 3 weeks after the last dose of the study intervention at Week 119. If a participant withdraws from the study or completes the study prior to Week 122 of the OLE Period, the participant is encouraged to return for an Early Termination (ET) Visit 3 weeks after the last dose of the study intervention is administered. The overall study duration for an individual participant is approximately 126 weeks (from Screening Visit through EoS Visit).
Participants treated with AChE inhibitors or immunosuppressive therapy (1ST) including corticosteroids at the time of the Screening Visit may continue taking their therapy throughout the RCT and OLE periods. However, during the RCT Period, the dosage of AChE inhibitor or ISTs must not be changed, discontinued, or new AChE inhibitor or 1ST added, unless deemed medically necessary by the Investigator. ISTs that are not permitted are listed in Section 6.5.2. During the OLE Period, i.e., after 26 weeks of RCT, therapy with AChE inhibitor or ISTs can be changed at the discretion of the Investigator.
Throughout the study, rescue therapy is allowed when a participant’s health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences a Clinical Deterioration as defined in Section 4.2.1 . Rescue therapy may consist of plasmapheresis (PP), plasma exchange (PE), IVIg, SCIg, or short-term use of high-dose corticosteroids (Section 6.5.3). The therapy used in the individual participant is, within these boundaries, be determined at the discretion of the Investigator.
Study staff designated as Clinical Evaluators must be properly trained and certified in administering MG-ADL and other relevant disease assessments (Section 4.2.2). Clinical Evaluators may be a neurologist (including a neurology resident in training) or other qualified study team member assigned by the Investigator. Section 4.2.2 describes responsibilities for clinical evaluations and study assessments in greater detail.
4.1 .1 . Screening Period (< 4 Weeks)
After obtaining informed consent, the participant is screened over a period of up to 4 weeks (< 28 days) for study eligibility through a review of demographic data, medical history, physical examination, and laboratory tests. Medical history covers date of the diagnosis of MG, initial clinical presentation (ocular or gMG), time to the manifestation of gMG (if the initial clinical presentation was limited to ocular symptoms or signs), maximum MGFA Classification and requirement of ventilatory support since diagnosis, dates of gMG exacerbations or crises, diagnosis of thymoma or thymic carcinoma, thymectomy if applicable, and any hospitalizations related to MG in the 2 years prior to Screening. Medical treatment and physical therapy related to MG over the 2 years prior to Screening is also be recorded. Additional information about such treatment in earlier years should be documented, if available.
Participants are be vaccinated against Neisseria meningitidis (N meningitidis) during screening or at the time of treatment initiation as a prophylaxis against meningococcal infection. Vaccination is not required if participants have been vaccinated against N meningitidis including serogroups A, C, W135, Y (and where available, serogroup B), within 3 years prior to randomization, and vaccination against these serogroups is documented or confirmed by the treating physician. Participants who initiate study intervention < 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination (see Section 6.5.4).
Sponsor must be notified if a participant experiences a Clinical Deterioration including a myasthenic crisis during the Screening Period.
4.1 .2 Randomization
At the time of randomization, all participants are reassessed for eligibility based on the inclusion and exclusion criteria of the study. All vaccinated participants who continue to meet the eligibility criteria at Day 1 are be randomized 1 :1 to the fusion polypeptide described herein or placebo. Randomization is carried out using a centralized interactive response technology (IRT) application. The randomization is stratified by geographical region and body weight (< 80 kg and > 80 kg), as specified in the statistical analysis plan (SAP). Randomization of participants with an MG-ADL total score < 7 and participants receiving concomitant periodic (chronic) IVIg or SCIg administrations is limited to approximately 10% each.
4.1 .3 Randomized Controlled Treatment Period (26 Weeks)
The fusion polypeptide described herein and placebo is administered through SC injection. Study intervention consists of a loading dose followed by weekly maintenance doses (Table 2). Both loading and maintenance doses are based on the participant’s body weight (< 80 kg or > 80 kg) as determined at Randomization. Assessments ofthe disease status, safety and outcome measures of efficacy, and other procedures are performed at regular visits specified in the SoA in FIG. 2A-FIG.2C.
Throughout the study, rescue therapy is allowed when a participant’s health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences Clinical Deterioration, including a crisis related to gMG, as defined in Section 4.2.1 . Management of a Clinical Deterioration always includes treatment directed at the precipitating condition, e.g., an infection, if applicable. The Investigator or designee determines whether the participant meets the definition of Clinical Deterioration and intervene accordingly. Rescue therapy may consist of PP, PE, IVIg, SCIg, or high-dose corticosteroids. Supplemental dosing of the study intervention is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details). The appropriate intervention for the individual participant, within these boundaries, is chosen at the discretion of the Investigator (see also Section 6.5.3). Current treatment guidance should be considered (Narayanaswami et al., Neurology, 96:114-122, 2021 ; Sanders et al., Neurology, 87:419- 425, 2016). Following the intervention, treatment should return to the standard of care administered before the Deterioration.
4.1 .4 Open-Label Extension Period (96 weeks)
Following completion of the study assessments at the Week 26 (Day 183) Visit in the RCT Period, participants receive open-label treatment with the fusion polypeptide described herein. To maintain the blinding of participants for their previous treatment allocation in the RCT Period, a weight-based blinded dose is administered on Day 183 by designated study site personnel who are not permitted to participate in any safety or efficacy assessments (see Section 0 on Blinding). Participants who were in the placebo group during the RCT Period receive a weight-based loading dose of the fusion polypeptide described herein to ensure rapid and complete C5 inhibition before the next scheduled maintenance dose. Participants who were in the fusion polypeptide group during the RCT Period receive a weight-based maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose. Weekly open-label maintenance doses resume the following week (Day 190).
The OLE Period for each participant begins when the participant receives their study intervention on Day 183 and continues, for 96 weeks, or until the fusion polypeptide described herein is registered or approved (in accordance with country-specific regulations), or until the fusion polypeptide described herein can be provided via a sponsor post-trial access program (as allowed by local laws and regulations), whichever occurs first.
Assessments of the disease status, safety and outcome measures of efficacy, and other procedures are performed at regular visits specified in the SoA in FIG. 3A-FIG.3D.
4.1 .5 Study Visit Conduct
There are 2 types of planned study visits: Clinic Visits and Remote Visits.
• Clinic Visit:
Scheduled study visits conducted at the investigational site, including all associated activities per the SoA.
• Remote Visit:
Scheduled study visits conducted when the participants are not present at the investigational site.
Data for scheduled assessments are collected via remote interaction, which may include one or a combination of the following methods: digital device, phone, or virtual meeting with the study site staff via video conferencing platform. The method of interaction must comply with local and institutional requirements of data privacy and regulation.
Only if exceptional circumstances, e.g., an outbreak of the COVID-19 pandemic, prevent a participant from attending a Clinic Visit, the Investigator collects as many of the scheduled assessments as possible remotely instead, to avoid missing data. At a minimum, the information collected remotely comprises the MG-ADL, concomitant medication including physical and other non-pharmaceutical therapy, and the hospitalization status of the participant. For more details on specific potential risks and mitigation measures put in place in light of the COVID-19 pandemic, see Table 7.
If any symptoms or signs reported during a remote visit indicate an SAE or clinically relevant worsening of MG symptoms, further evaluation of the participant at the study site or an emergency care facility is initiated. Suspected SAEs or worsening of MG symptoms require immediate notification of the Investigator. Information related to such incidents needs to be captured as described in the guidelines and training materials for completing the electronic case report form (eCRF).
Only under exceptional circumstances are additional (unscheduled) visits outside the specified visits permitted at the discretion of the Investigator. Procedures, tests, and assessments during unscheduled visits are performed at the discretion of the Investigator and efforts are made to map the corresponding data to the visit schedule, if appropriate, as described in the guidelines and training materials for completing the eCRF. Justification of such visits must be documented in the eCRF.
However, participants may request additional training in the administration of the study intervention by designated personnel at the study site; these retraining visits are not considered Clinic Visits. Personnel designated to training participants and caregivers in the administration of the study intervention must not have any other role in the study and, specifically, are not permitted to participate in any safety or efficacy assessments (see Section 6.3.2 on Blinding).
4.2 Standard Protocol Definitions
A full glossary of terms is provided in Section 10.12.
4.2.1 . Clinical Deterioration of Myasthenia Gravis
Throughout the study, rescue therapy is allowed when a participant’s health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences a Clinical Deterioration, including a crisis related to gMG. For the purpose of this study, Clinical Deterioration is defined as any of the following:
• Worsening of symptoms or signs related to gMG that results in an increase of the total MG- ADL total score by > 3 points or an increase by > 2 points of a subscore for any individual MG-ADL item other than double vision or eyelid droop, and is clinically significant as determined by the Investigator.
• Weakness related to gMG that is severe enough to necessitate intubation or delay extubation, e.g., following surgery. Respiratory failure must be related to weakness of respiratory or bulbar (oropharyngeal) muscles.
Participants must be informed of potential signs and symptoms of Clinical Deterioration and instructed to contact the Investigator if they occur. A suspected Clinical Deterioration should be evaluated within 48 hours of the Investigator’s notification, if feasible. At the Clinical Deterioration Visit, the Investigator or the Investigator’s designee performs clinical and laboratory assessments as specified in the SoAs. Additional assessments may be performed, and additional evaluation visits may be scheduled at the discretion of the Investigator or designee.
The Investigator or designee determines whether the criteria of a Clinical Deterioration are met and intervene accordingly. Rescue therapy may consist of PP, PE, I Vlg or SCIg, or high-dose corticosteroids. Supplemental dosing is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details and Figure 5). The appropriate intervention for the individual participant is, within these boundaries, chosen at the discretion of the Investigator. Current treatment guidance should be considered. Management of a Clinical Deterioration always includes treatment directed at the precipitating condition, for example, an infection, if applicable. Following the intervention, treatment should return to the standard of care administered before the Clinical Deterioration.
Information related to a Clinical Deterioration is collected from the signing of the informed consent form (ICF) until the EoS or ET Visit and must be documented in the eCRF. The collected information must include the administration of rescue therapy, if applicable, a description of the chosen therapy, and if applicable, supplemental dosing of the study intervention.
4.2.2 Clinical Evaluation of gMG
Clinical Evaluators may be a neurologist or other qualified study team member assigned by the Investigator, as specified in Table 8. Clinical Evaluators are study staff that have been trained and certified in administering the MG-ADL profile and other relevant assessments related to disease severity as specified in Table 8. Only Clinical Evaluators may administer these assessments. Clinical Evaluator training and certification for this study may take place either at an Investigator Meeting or through an online training program.
Throughout the study, MG assessments should be performed in the morning and at approximately the same time of day and preferably by the same evaluator for each participant. The MG-ADL profile should always be performed first, followed by the QMG, MGC, then other assessments of the disease status.
Table 8: Responsibility forthe Clinical Evaluation of gMG
Figure imgf000038_0001
a Can be an appropriately qualified senior neurology resident in training. b Neurologist or appropriately qualified other study team member, e.g., senior neurology resident in training, physician assistant, or nurse practitioner. Vital capacity, which is part of the QMG assessment, may also be measured by a qualified physical therapist.
Abbreviations: gMG = generalized myasthenia gravis; MG-ADL = Myasthenia Gravis Activities of Daily Living; MGC = Myasthenia Gravis Composite; MGFA = Myasthenia Gravis Foundation of America; MGFA-PIS, MGFA Post-Intervention Status; QMG = Quantitative Myasthenia Gravis score for disease severity
4.3. Scientific Rationale for Study Design
The goal of this study is to assess the safety and efficacy of the fusion polypeptide described herein compared with placebo in the treatment of adults with gMG based on the ability of participants to perform activities of daily living, and participants’ muscle strength. Primary and key secondary objectives reflect this goal:
• The MG-ADL profile is a valid and sensitive instrument to assess the impact of gMG and measure treatment-associated changes in disease severity. A decrease in the MG-ADL by 2 points compared to Baseline is considered an indicator of clinical improvement (Muppidi et al., Muscle Nerve, 44:727-731 , 2011).
• QMG involves quantitative testing of sentinel muscle groups and yields a valid objective score of muscle strength (Jaretzki et al., Neurology, 55:16-23, 2000). The study examines other measures of treatment efficacy and assess the safety and tolerability of the study intervention, the pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of the fusion polypeptide described herein, as well as biomarkers of complement activity that are relevant to the mechanism of action of the fusion polypeptide described herein.
Length of the RCT Period and determination of primary and secondary endpoints at Week 26 are designed to demonstrate durable changes in symptoms and signs, which is critical in a chronic disease such as gMG.
Eligibility criteria and outcome measures have been chosen based on a review of comparable clinical studies, recommendations provided by the Task Force on MG Study Design of the Medical Scientific Advisory Board of the MGFA (Benatar ef al., Muscle Nerve, 45:909-917, 2012), and advice from experts in the field of gMG research.
The study includes adults (> 18 years old) with gMG corresponding to MGFA Classification Grades II, III, or IV to evaluate the therapeutic potential of the fusion polypeptide described herein in a broad participant population with mild, moderate, or severe disease, respectively. If successful, the fusion polypeptide described herein provides these participants with a treatment option that they can administer themselves, at home, at convenient weekly dosing intervals.
A weight-based dosage regimen was selected based on modeling and dosing simulations using clinical PK, PD and antidrug antibody (ADA) data from a first-in-human Phase 1 study of the fusion polypeptide described herein.
4.3.1 Patient Input into Design
Six members of a patient insight group provided their input. Patients described their experiences and challenges with previous clinical studies and shared ideas on how to improve clinical study conduct. These patients commented specifically on topics including the completion of questionnaires, if appropriate, ahead of Clinic Visits, as well as limiting the withholding of AChE inhibitor treatment to the relevant assessments and prioritizing these assessments for early completion during a Clinic Visit. Responding to recommendations from this patient group, study sites are encouraged to allow for breaks of 5 to 10 minutes between assessment blocks, and rest time of 45 to 60 minutes if the duration of a Clinic Visit exceeds 4 hours.
4.4. Justification for Dose
The dosage regimen for the fusion polypeptide described herein in this Phase 3 study (Table 12) leverages prior experience in treating complement-mediated diseases (including gMG) with the C5 inhibitors eculizumab and ravulizumab. Using PK/PD data from healthy participants in the healthy volunteer study (HV-101), a population PK/PD model was developed and used to generate dosing simulations to determine the dosage regimen predicted to achieve rapid and complete terminal complement inhibition (Table 12).
Targeting sustained terminal complement inhibition in patients with gMG has shown favorable benefit/risk profiles following therapeutic dosing with eculizumab and ravulizumab. Based on the totality of PK, PD, ADA, safety, and efficacy data obtained during the development of eculizumab and ravulizumab and approved treatment with eculizumab, the proposed dosage regimen based on body weight is expected to be beneficial in treating participants with gMG.
Delayed doses, defined as doses administered > 1 day later than scheduled, is administered as soon as possible and not later than the next scheduled dose. Replacement of missed doses is determined on an individual basis.
Supplemental dosing is required if PP or PE is used as rescue therapy on non-dosing days. If PP or PE falls on the same day as a scheduled administration of the study intervention, no supplemental dosing is required, but the scheduled dose of the study intervention is administered within 60 minutes after the completion of the PP or PE, if feasible. If PP or PE is performed in the interval between 2 scheduled doses of the study intervention, supplemental administration of the study intervention within 4 hours after the PP or PE session is recommended, if feasible (see Section 6.5.3.1 for details).
To maintain the blinding of treatment allocation in the RCT Period, participants who are in the placebo group during the RCT Period receive a blinded weight-based loading dose of the fusion polypeptide described herein at the start of the OLE Period on Day 183. Participants who are in the fusion polypeptide group during the RCT Period receive a blinded maintenance dose and one additional injection of placebo to match the number of injections required for a weight-based loading dose. Weekly open-label maintenance doses resume the following week (Day 190).
Safety and tolerability of the fusion polypeptide described herein have been established over a wide range of PK exposures, including those expected under the proposed gMG dosage regimens, in healthy volunteers.
4.5. End of Study Definition
A participant is considered to have completed the study if they complete all scheduled study visits in the RCT Period and the OLE Period. If the study is terminated early or the study intervention becomes registered or approved in accordance with country-specific regulations, a participant is also considered to have completed the study if they complete all scheduled study visits in the applicable periods of the study, including the EoS Visit, until study termination.
The end of the study is defined as the date of the last visit of the last participant in the study, or the last scheduled procedure shown in the SoAs for the last participant in the study.
5. STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers or exemptions, is not permitted.
5.1 Inclusion Criteria
Participants are eligible to be included in the study if all of the following criteria apply: Age
Must be > 18 years of age at the time of signing the informed consent Participant and Disease Characteristics 1. Documented diagnosis of gMG > 3 months (90 days) prior to Screening, based on clinical disease features and at least 1 of the following confirmatory tests. Test results may be collected from existing participant records or obtained during Screening, unless otherwise specified: a. Positive response in an AChE inhibitor test, for example, the edrophonium chloride test, or b. Abnormal neuromuscular transmission demonstrated by repetitive nerve stimulation or single fiber electromyography, or c. Previous improvement of symptoms or signs related to MG by treatment with an oral AChE inhibitor, as confirmed by the treating physician
2. Positive serological test for AChR autoantibodies at Screening (previous test results, if applicable, must be confirmed by central laboratory during Screening)
3. MGFA Classification II to IV at Screening
4. MG-ADL total score of > 5 at Screening and on Day 1 , before randomization
5. Participants receiving treatment with any of the medications listed in Table 9 must have been on a stable dose for the specified periods prior to Screening, with no changes to the regimen expected during Screening or RCT Period.
Table 9: Allowed Medications and Therapies
Figure imgf000041_0001
Note: If a participant has recently discontinued any of the above medications, a period of time equal to the stable dose requirement listed above forthat medication (e.g., > 2 months for azathioprine or > 4 weeks for corticosteroids) must have passed prior to the first day of the Screening Period. a Intermittent use of an AChE inhibitor is not permitted during the study. b A maximum dose of 20 mg/day prednisone or equivalent is recommended. Investigators should notify the Medical Monitor if they intend to maintain a higher corticosteroid dosage during the RCT Period. c Requirement of a stable dose does not apply to IVIg or SCIg administered as rescue therapy, e.g., for a myasthenic crisis
Abbreviations: AChE = acetylcholine esterase; IVIg = intravenous immunoglobulin;
RCT = Randomized Controlled Treatment; SCIg = subcutaneous immunoglobulin
Rescue therapy including PP, PE, IVIg, SCIg, or high-dose corticosteroids for a participant experiencing a deterioration of gMG symptoms or signs, e.g., in a myasthenic crisis, during Screening is not a reason for exclusion. However, participants requiring rescue therapy during Screening should only be randomized after > 4 weeks have passed since completion of the rescue therapy. Participants rescreened outside of the Screening window are required to sign a new IGF (Section 10.1 .3).
6. To reduce the risk of meningococcal infection, all participants must be vaccinated against /V meningitidis serogroups A, C, W135, Y, (and where available, serogroup B) within 3 years prior to Day 1 . Participants who do not meet this requirement are vaccinated against these N meningitidis serogroups before receiving the first dose of the study intervention. If Day 1 occurs < 2 weeks after the vaccination, participants receive prophylactic antibiotics until 2 weeks after the vaccination. Vaccinations must follow national/local guidelines.
7. Participants must weigh > 40 kg, with a body mass index > 18.5 kg/m2 and < 40 kg/m2
8. Assigned male or female at birth.
9. Participants of childbearing potential must follow the contraception measures specified in this protocol.
10. Capable of giving signed informed consent as described in Section 10.1 .3, which includes compliance with the requirements and restrictions listed in the ICF and in this protocol.
5.2 Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
11 . Medical conditions (e.g., cardiac, pulmonary, renal, oncologic, neurological or psychiatric disorder) or risk factor that, in the opinion of the Investigator or the Medical Monitor, might interfere with participation in the study, pose any added risk to the participant, or confound the assessment of safety or efficacy of the study intervention
12. History of thymectomy or any other thymic surgery within 12 months prior to Screening
13. Any untreated thymic malignancy, carcinoma, or thymoma
Participants with a history of treated thymic malignancy or carcinoma are eligible if they meet all of the following conditions: a. T reatment completed > 5 years prior to the Screening Visit b. No recurrence within the 5 years prior to the Screening Visit c. No radiological indication of recurrence in a computed tomography (CT) or magnetic resonance imaging (MRI) scan, including administration of IV contrast, performed within 6 months of Randomization on Day 1
Participants with a history of treated benign thymoma are eligible if they meet all of the following conditions: d. Histopathological or equivalent records confirming the diagnosis of benign thymoma e. Treatment completed > 12 months prior to the Screening Visit f. No known recurrence within the 12 months prior to the Screening Visit g. No radiological indication of recurrence in a CT or MRI scan, including administration of IV contrast, performed within 6 months of Randomization on Day 1 h. If adequate records confirming the diagnosis of benign thymoma are not available, the participant must satisfy the eligibility criteria for thymic malignancy or carcinoma stated above.
14. History of /V meningitidis infection
15. History of any persistent or recurrent infections in the past 12 months that might pose an additional risk for the participant
16. Active systemic bacterial, viral, or fungal infection < 14 days prior to Randomization on Day 1
17. History of hypersensitivity to any ingredient contained in the study intervention including its device components (see Table 10 and Section 0)
18. History of malignancy within 5 years of Screening.
Exceptions not requiring exclusion from the study are skin cancer other than malignant melanoma and cervix carcinoma in situ that have been treated, with no evidence of recurrence.
19. Known or suspected history of alcohol or substance use disorder, based on current diagnostic criteria provided in the Diagnostic and Statistical Manual of Mental Disorders (DSM), within 12 months prior to Screening.
Prior/Concomitant Therapy
20. Concomitant treatment with any of the following medications, or prior treatment for the time periods specified below is not permitted:
• Complement inhibitor: received within < 5 half-lives before Randomization on Day 1 . Participants receiving prior treatment with a complement inhibitor > 5 half-lives before Randomization on Day 1 may be enrolled but must have tolerated such treatment well, without side effects that, in the opinion of the Investigator or the Medical Monitor, might interfere with participation in the study, pose any added risk to the participant, or confound the assessment of safety or efficacy of the study intervention.
• Human neonatal Fc receptor (FcRn) inhibitor: received within < 5 half-lives before Randomization on Day 1 . Participants receiving prior treatment with an FcRn inhibitor > 5 half-lives before Randomization on Day 1 may be enrolled but the total immunoglobulin G (IgG) level must be above the lower limit of normal (LLN) before these participants can be randomized.
• Rituximab, ocrelizumab or other B cell-depleting therapy: received or scheduled within < 6 months (180 days) before Randomization on Day 1.
Sponsor does not recommend discontinuation of any treatment for the sole purpose of qualifying for participation in this study. Prior/Concurrent Clinical Study Experience
21 . Participation in another study investigating a drug, biological product, device, or combination product, procedure, or any other intervention within 5 half-lives of the treatment (if known) or 30 days, whichever is longer, before the first dose of study intervention.
22. Concurrent participation in another study involving an investigational drug, biological product, device, combination product, procedure, or any other intervention, at any time during this study.
Diagnostic Assessments
23. History of human immunodeficiency virus (HIV) infection or a positive serological test for HIV- 1 or HIV-2
24. Evidence of hepatitis B (positive hepatitis B surface antigen [HBsAg] or positive core antibody [anti-HBc]) with negative surface antibody [anti-HBs]), or hepatitis C virus infection (HCV antibody positive, except for participants with documented successful treatment). If locally available, sustained virologic response (SVR) should be documented or established at Screening.
25. Participants who have a positive pregnancy test at Screening or Day 1
26. Fever as documented by a body temperature > 38°C (100.4°F) within 7 days prior to Randomization on Day 1
27. Laboratory abnormalities at the Screening Visit, including: a. Alanine aminotransferase (ALT) > 2 x the upper limit of normal (ULN) b. Direct bilirubin > 2 x ULN c. Estimated glomerular filtration rate < 30 mL/min/1 .73 m2 or participant on dialysis d. Any other clinically significant laboratory abnormality that, in the opinion of the Investigator, would make participation in the study inappropriate or put the participant at undue risk.
Other Exclusions
28. Pregnant, breastfeeding, or intending to conceive during the course of the study.
29. Participant or caregiver unable or not willing to administer the study intervention.
30. Inability or unwillingness to adhere to the protocol requirements and restrictions, including participation in scheduled study visits
5.3. Lifestyle Considerations
No restrictions are required in this study.
5.4. Screen Failures
Screen failures are defined as enrolled participants who consent to participate in the clinical study but are subsequently not randomly assigned to study intervention. A minimal set of screen failure information is required to ensure transparent reporting, meet the publishing requirements for Consolidated Standards of Reporting Trials and respond to queries from regulatory authorities. Minimal information includes demographic data about the participant, screen failure details (e.g., failed eligibility criteria), and AEs, and any related concomitant medication, during the Screening Period. Laboratory tests with results outside of the reference range at Screening may be repeated at the Investigator’s discretion for the purpose of further determining eligibility. Individuals who do not meet the criteria for participation in this study (screen failure) for any other reason that is expected to resolve or has resolved, may be rescreened after consultation of the Medical Monitor. Participants who are rescreened outside of the Screening window are required to sign a new ICF (Section 10.1.3).
6. STUDY INTERVENTION AND MEDICAL DEVICE
Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol. For the purposes of this study, study intervention refers to the combination product consisting of a PFS-SD containing the fusion polypeptide described herein or placebo.
6.1 Study Intervention(s) Administered
The PFS-SD is a single-use, disposable device to deliver the fusion polypeptide described herein or placebo subcutaneously. The prefilled glass syringe is equipped with the accessory safety device to prevent needlestick injuries and improve its ergonomic use. The safety device is designed to automatically retract the needle into the syringe after the injection is administered. Details regarding the study intervention are presented in Table 10.
All investigational products are manufactured in accordance with current Good Manufacturing Practice.
Table 10: Study Intervention
Figure imgf000045_0001
Figure imgf000046_0001
Abbreviations: IMP = investigational medicinal product; LD = loading dose; MD = maintenance dose;
OLE = Open-label Extension; PFS-SD = prefilled syringe with safety device; Q1 W= once every week; ROT = Randomized Controlled Treatment; SC = subcutaneous; w/v= weight per volume
6.1 .1 Study Interventions) Packaging and Labeling The fusion polypeptide described herein and placebo PFS-SD are packaged and labeled according to Section 6.1 .2.1 .
6.1 .2 Medical Device Components
The PFS-SD combination product is a single-use, disposable device comprised of the fusion polypeptide or placebo formulation (2 mL) in a prefilled syringe with a needle safety device (BD UltraSafe Plus™ Passive). The PFS-SD is designed to enable the SC administration of the fusion polypeptide or placebo and provide an automated safety mechanism to reduce the risk of accidental needlestick injuries by retracting the needle into the syringe after the injection is given. Participants and, if applicable, their caregivers will be trained in the use of the PFS-SD so that they can inject themselves during the study. The PFS-SD constitutes a container closure system that is the sum of packaging components that together contain and protect fusion polypeptide or placebo (Figure 5). Main parts of the device constituent are provided in Table 11 . Table 11 : Device Constituent Parts for the PFS-SD
Figure imgf000047_0001
The PFS-SD are distributed with IFU. The study intervention must be administered as specified in the IFU.
All medical device deficiencies, including malfunction, use errors and inadequate labeling shall be documented and reported by the Investigator (see Section 0) and appropriately addressed by Sponsor.
All adverse device effects (ADEs) shall be documented and all serious adverse device effects (SADEs), whether or not associated with a device deficiency, shall be documented and reported (Section 10.4). 6.1 .2.1 Device Packaging and Labeling
The PFS-SD is packaged in a carton with an insert that holds the device in place within the carton. Each PFS-SD has a single panel label attached that contains a unique identifying kit number and other minimum required information such as Sponsor’s name, product description, protocol number, lot number to allow for traceability of the device. Secondary packaging (carton) is labeled either with single-panel or booklet label that includes investigational biologic cautionary statement and a “For Clinical Trial Use only” statement, as needed, as well as other required information. 6.1 .3. Dose Administration
The dosage regimen for the study intervention in the RCT Period is based on the participant’s body weight at Randomization on Day 1 (Table 12).
Table 12: Weight-Based Dosing During the RCT Period
Figure imgf000048_0001
a One PFS-SD contains 300 mg fusion polypeptide or placebo.
Abbreviations: PFS-SD = prefilled syringe with safety device; Q1W = once per week
For details on the dosing at the transition from the RCT Period to the OLE Period, see Section 4.1 .4. As described in Section 0, the maintenance dose may be adjusted at the beginning of the OLE Period and approximately every 6 months thereafter if the weight group (< 80 kg or > 80 kg) of the participant changes. Adjustments of the maintenance dose, if applicable, do not require administration of an additional loading dose.
The first doses of study intervention on Day 1 (Baseline) and Day 8 (Week 1) shall only be administered by trained and certified study site personnel specifically designated to the administration of the study intervention and the training of participants and caregivers in the administration of the study intervention (see Section 6.3.2). In the first 4 weeks of the study, participants and if applicable, caregivers, are trained on how to administer study intervention under supervision of the designated study site personnel. After completion of the training and if certified by the training personnel, participants receive kits containing the study intervention and accessories, so that they can selfadminister the study intervention at home. At any time, participants may request additional training in the administration of the study intervention by the designated personnel at the study site; these retraining visits are not considered Clinic Visits. Participants shall make every effort to maintain the weekly dosing intervals. However, deviations of ± 1 day are acceptable if they cannot be avoided. Participants must document each study intervention administration in the eDiary (Section 6.4).
Once training is complete and certified, participants should self-administer the treatment at home unless the scheduled dose falls on the same day as an upcoming Clinic Visit. On such days, participants are asked to administer the study intervention at the clinic under supervision of the designated clinic staff to monitor their injection skills. If an upcoming Clinic Visit falls outside of the ± 1 day window for the administration of the study intervention, participants shall administer study intervention at home to maintain regular weekly dosing intervals. In this situation, no planned PK/PD or ADA assessments need to be performed at the Clinic Visit.
Injection sites include the abdomen and the anterior thigh. A caregiver administering the study intervention may also choose the backside of the participant’s upper arm for injection. Injection sites should be rotated such that the participant receives the study intervention at a different anatomical site in consecutive weeks. Participants and caregivers must follow the IFU. The IFU describes the injection technique, including the activation of the safety device when the plunger of the PFS-SD is fully depressed. Retraction of the needle is a safety feature forthe prevention of needlesticks injuries after the injection.
In the event of a PFS-SD malfunction in which no dose or only a partial dose is delivered, the participant should use a new PFS-SD to ensure the required dose is administered and record the event in the eDiary (refer to Section 10.5). Participants should report the malfunctioning or deficient device as specified in the IFU irrespective of the need to use a new PFS-SD. Malfunctioning or deficient devices need to be returned to the study site at the next Clinic Visit (see Section 8.5.5 and refer to the Pharmacy Manual for further reporting requirements of device malfunctions and deficiencies).
6.2. Preparation/Handling/Storage/Accountability
1 . The Investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study intervention received. The Investigator must report any discrepancies and resolve them before use ofthe study intervention. Study interventions are shipped and have to be stored at 2°C - 8°C (36°F - 46°F) at all times up until administration of study intervention. Details on reporting temperature excursions can be found in the Pharmacy Manual.
2. Only authorized site staff may supply or administer the study intervention. Only participants randomized in the study or their caregivers who were trained and certified by study site personnel may receive and administer the study intervention. Authorized caregivers may administer the study intervention only to the participant they care for. All study intervention must be stored in a secure, environmentally controlled, and manually or automatically monitored area in accordance with the labeled storage conditions. Access to the study intervention must be limited to the Investigator and authorized site staff.
3. Authorized site staff must explain the proper handling and storage of study intervention kits for off-site administration to participants and caregivers. The Investigator, institution, or the head of the medical institution (where applicable) is responsible for study intervention accountability, reconciliation, and record maintenance (i.e. , receipt, reconciliation, and final disposition records). a. This responsibility includes the immediate reporting of any temperature excursions and product complaints to sponsor. A product complaint is defined as any written, electronic, or oral communication that alleges deficiencies related to the identity, quality, durability, reliability, usability, safety, effectiveness, or performance of a product or clinical study material and/or its packaging components after it is has been released for distribution to an end user that affects the performance of such product or material.
4. Further guidance regarding preparation, handling, storage, and accountability and information for the final disposition of unused study intervention is provided in the Pharmacy Manual and the IFU. 6.3. Measures to Minimize Bias: Randomization and Blinding
6.3.1. Randomization
Participants are randomized on Day 1 after the Investigator has verified that they are eligible. Participants are stratified by geographical region (e.g., North America, Europe) and weight group (< 80 kg or > 80 kg) as specified in the SAP, and randomized 1 :1 to the fusion polypeptide described herein or placebo using a centralized IRT.
6.3.2. Blinding
PFS-SDs containing the fusion polypeptide described herein or placebo are provided in identical study intervention kits and with identical labels for all participants in the RCT Period. Yellow transparent tape covers the PFS-SDs to conceal a color difference between the fusion polypeptide described herein and placebo. Because the viscosity of the fusion polypeptide described herein also differs from the placebo formulation, a moderately different injection force is required for its administration. To maintain the blind despite this difference in viscosity, study sites are required to designate an independent staff member who can:
• Administer the study intervention during the initial Clinic Visits
• Train participants and, if applicable, their caregivers, for doses that are self-administered
These designated staff members can be a nurse, study coordinator, or subinvestigator trained to administer the study intervention. They remain blinded to the participant’s assigned study intervention and are not permitted to communicate observations related to the injection force required to administer the intervention to the study participant, a caregiver, other site personnel, sponsor staff or designees, or any other personnel associated with the conduct of the study. They must not have any other role in the study and, specifically, are not permitted to participate in any safety or efficacy assessments.
Investigators receive only blinded information unless unblinded information is judged necessary for safety reasons. In case of an emergency, the Investigator has the sole responsibility for determining if unblinding of a participants’ intervention assignment is warranted. Participant safety must always be the first consideration in making such a determination. If the Investigator decides that unblinding is warranted, the Investigator should make every effort to contact sponsor prior to unblinding a participant’s intervention assignment unless this could delay emergency treatment of the participant. If unblinding is deemed necessary, the Investigator is able to unblind the participant’s intervention assignment using the IRT. If a participant's intervention assignment is unblinded, sponsor must be notified within 24 hours after breaking the blind.
In the event of a suspected unexpected serious adverse reaction (SUSAR) or unexpected serious adverse device effect (USADE), reporting guidance in Section 0 and Section 0 must be followed. The blind is maintained for persons responsible for the ongoing conduct of the study (e.g., Monitors, Investigators) and those responsible for data analysis and interpretation of results. Except for these emergency situations, unblinded information is only accessible to those who are involved in safety reporting to Health Authorities, Independent Ethics Committees (lECs), and/or Institutional Review Boards (IRBs). 6.4. Study Intervention Compliance
When participants are dosed at the study site by the designated site staff (described in Section 6.1 .3), the date and time of each dose administered in the clinic is recorded in the source documents and the eCRF.
When participants or caregivers administer the study intervention at home, compliance with the study intervention is assessed by reviewing the participant’s entries in the electronic diary (eDiary) during each Clinic Visit. The results of the review need to be recorded in the source documents. If required, site personnel can contact the participant remotely using telecommunication technologies such as phone calls as needed to query maintenance of the study intervention. Deviation(s) from the prescribed dosage regimen must be recorded in the eCRF.
A record of the quantity of study intervention dispensed and administered to each participant must be maintained and reconciled with study intervention and compliance records. Intervention start and stop dates, including dates of intervention delays or dose changes is also recorded in the eCRF.
6.5. Concomitant Therapy
Medications (including vitamins and herbal preparations), and procedures (including therapeutic interventions such as surgery or physical therapy) received by the participant within 28 days prior to the start of Screening until the first dose of study intervention, is recorded in the participant’s eCRF. Information about previously prescribed medications or administered procedures as it relates to the eligibility criteria (Section 5.1 and Section 5.2) must also be documented in the eCRF. MG-specific medication or therapy (e.g., thymectomy, ISTs including corticosteroids and rescue therapy) within 2 years prior to Screening is recorded. Additional information about such medication or therapy in earlier years should be documented, if available. In addition, history of meningococcal vaccination must be collected for the 3 years prior to first dose of study intervention.
Participants are allowed to continue previously prescribed therapy for gMG including ISTs except for the medications listed in Section 6.5.2. Concomitant therapy for gMG has to be stable for defined periods before Screening (see Section 5.1) and must not be modified before randomization without the sponsor’s agreement, unless modification is deemed necessary by the Investigator to address a Clinical Deterioration or mitigate side effects that require adjustment of the therapy. Sponsor must be informed of any such modification during the Screening Period to determine whether it affects the participant’s eligibility for the trial.
Any medication (including over-the-counter or prescription medicines, vitamins, and herbal supplements, vaccination), or procedure that the participant is receiving at the time of enrollment or during the study must be recorded along with:
• Reason (indication) for use
• Dates of administration or procedure, including start and end dates
• Dose and frequency of the administration or procedure
The Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy. 6.5.1 . Allowed Medicine and Therapy
Palliative and supportive care during the study is permitted.
Participants receiving treatment with any of the medications listed in Table 9 must have been receiving this treatment at a stable dose for the specified time periods prior to the Screening Visit. During the Screening or RCT Period, the dosage of AChE inhibitor or ISTs must not be changed, discontinued, and new AChE inhibitor or ISTs must not be added, unless deemed medically necessary by the Investigator. Rescue therapy including PP, PE, IVIg, SCIg, or high-dose corticosteroids for a participant experiencing a deterioration of gMG symptoms or signs, e.g., in a myasthenic crisis, is permitted (see Section 6.5.3 for details).
If a participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the MGC and QMG assessments. Treatment with the AChE inhibitor can resume once QMG and MGC assessments are complete.
6.5.2. Disallowed Medicine and Therapy
The following concurrent medications are prohibited during the study:
• Other complement inhibitors
• FcRn inhibitors
Rituximab, ocrelizumab and other B cell-depleting therapies
6.5.3. Rescue Medicine
Rescue therapy including PP/PE, IVIg, SCIg, or short-term use of high-dose corticosteroid is allowed when a participant's health would be in jeopardy without such therapy (e.g., in an emergent situation), or when a participant experiences a Clinical Deterioration (as defined in Section 4.2.1). The appropriate intervention for the individual participant is chosen, within these boundaries, at the discretion of the Investigator. Current treatment guidance should be considered. Participants who require rescue medication may continue the study. However, the Investigator should notify sponsor or its designee within 24 hours of the initiation of rescue therapy. Following the intervention, treatment should return to the standard of care administered before the Clinical Deterioration. Additional PK/PD/ADA blood samples should be collected before and after receiving rescue therapy. Supplemental dosing of the study intervention is required if PE or PP is used as rescue therapy on non-dosing days (see Section 6.5.3.1 for details).
Description, dates, and dosage regimen of the rescue therapy must be recorded on the participant’s eCRF.
6.5.3.1. PP/PE
Supplemental dosing of study intervention is required if PP/PE rescue therapy is performed on days that do not coincide with administration of the study intervention; if PP/PE is performed on a dosing day, no supplemental study intervention is required but the PP/PE session must occur prior to administration of the study intervention.
If PP/PE is performed on days that do not coincide with administration of the study intervention, a supplemental dose of 1 PFS-SD should be administered, if feasible, within 4 hours following every second PP/PE session for participants with a body weight < 80 kg, or following each PP/PE session for participants with a body weight > 80 kg (Table 13).
Table 13: Weight-Based Supplemental Dose Following PP/PE
Figure imgf000053_0001
a One PFS-SD contains 300 mg fusion polypeptide or placebo.
Abbreviations: PE = plasma exchange; PFS-SD = prefilled syringe with safety device;
PP = plasmapheresis
If supplemental dosing is not feasible according to the schedule in Table , a supplemental dose equivalent to 300 mg fusion polypeptide or placebo (1 PFS-SD), should be administered prior to or with the next weekly maintenance dose of the study intervention.
6.5.4. Vaccination and Antibiotic Prophylaxis
To reduce the risk of meningococcal infection, all participants must be vaccinated against N meningitidis serogroups A, C, W135, Y (and serogroup B, where available) within 3 years prior to Day 1 . Participants who do not meet this requirement is vaccinated against these N meningitidis serogroups before receiving the first dose of the study intervention. If Day 1 occurs < 2 weeks after the vaccination, participants receive prophylactic antibiotics until 2 weeks after the vaccination. Vaccinations must follow national/local guidelines.
Vaccinations against N meningitidis and the use of prophylactic antibiotics, if applicable, is recorded on the participant’s eCRF.
All participants should be monitored for early signs of meningococcal infection, evaluated immediately if an infection is suspected, and treated with appropriate antibiotics, if necessary.
To increase risk awareness and promote quick disclosure of any potential signs or symptoms of infection, participants are provided a Patient Safety Card that they must carry with them at all times (see Section 8.3.10).
Participants should be vaccinated or revaccinated against other pathogens according to national vaccination guidelines or local standard of care.
6.6. Dose Modification
The dosage regimen of the study intervention, including loading and maintenance doses, is based on the participant’s body weight. The weight at Randomization is determined the doses administered in the RCT Period. The dosage regimen is adjusted at the beginning of the OLE Period and approximately every 6 months thereafter if the weight group (< 80 kg or > 80 kg) of the participant changes. Adjustments of the maintenance dose, if applicable, do not require administration of an additional loading dose.
6.7. Intervention after the End of the Study
Upon completion of the last study visit, participants return to the care of their treating physician.
7. DISCONTINUATION OF STUDY INTERVENTION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL
7.1 . Discontinuation of Study Intervention
In rare instances, it may be necessary for a participant to permanently discontinue the study intervention. If the study intervention is definitively discontinued, the participant should remain in the study to be evaluated for safety.
The Investigator notifies the Medical Monitor as soon as possible of any discontinuation or consideration to discontinue the study intervention. If a participant permanently discontinues treatment, the Investigator attempts to follow participants up for safety and perform, if the participant agrees, assessments specified for the ET Visit (see SoA). If an ET Visit cannot be arranged, the Investigator attempts to follow up by phone 3 weeks after the last dose of study intervention has been administered. Time and scope ofthe communication is recorded in the eCRF.
Participants must be considered for discontinuation of the study intervention if any of the following occur:
• Serious hypersensitivity reaction with, e.g., bronchospasm or other respiratory reaction requiring ventilator support, symptomatic hypotension, or serum sickness-like reaction manifesting within 14 days after administration of the study intervention
• AE that would, in the opinion of the Investigator, make continued participation in the study an unacceptable risk
• Severe uncontrolled infection
• Concomitant use of disallowed medication
• Pregnancy or planning of a pregnancy
• Investigator or sponsor deems discontinuation to be in the best interest of the participant The reason for treatment discontinuation is recorded in the eCRF. If study intervention is discontinued because of a participant’s pregnancy, the Investigator makes a reasonable attempt to follow up, in accordance with local laws and regulations, until the outcome of the pregnancy is known.
Participants who discontinue the study intervention are not replaced.
7.2. Participant Withdrawal from the Study
• All efforts should be made to ensure prospective participants are willing to comply with the requirements of study participation prior to conducting the screening procedures. a. If feasible, the Investigator should contact sponsor and their site before withdrawing a participant or discontinuing the study intervention. The reason for participant discontinuation must be recorded in the source documents and eCRF. b. A participant may withdraw from the study at any time at his/her own request, or may be withdrawn at any time at the discretion of the Investigator for safety, behavioral, compliance, or administrative reasons. Participant withdrawals are expected to be uncommon.
At the time of discontinuing from the study, if possible, an ET Visit should be conducted, as shown in the SoA. Refer to the SoA for data to be collected at the time of study discontinuation and follow-up, and for any further evaluations that need to be completed. Once an ET Visit has been completed, the participant is permanently discontinued from both the study intervention and the study.
- If the participant withdraws consent for disclosure of future information, sponsor may retain and continue to use any data collected before such a withdrawal of consent.
- If a participant withdraws from the study, the participant may request destruction of any samples taken and not tested, and the Investigator must document this in the site study records.
Participants who withdraw or are withdrawn from the study are not replaced.
7.3. Lost to Follow-up
A participant is considered lost to follow-up if the participant repeatedly fails to return for scheduled visits and cannot be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required study visit:
1 . The site must attempt to contact the participant to reschedule the missed visit as soon as possible, counsel the participant on the importance of maintaining the assigned visit schedule, and ascertain whether or not the participant wishes to and should continue in the study.
2. Before a participant is deemed lost to follow-up, the Investigator or designee must make every effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, a certified letter to the participant’s last known mailing address or local equivalent methods). These contact attempts should be documented in the participant’s medical record.
3. Should the participant continue to be unreachable, they are considered lost to followup.
Discontinuation of specific sites or of the study as a whole are handled as part of Section 10.1 .9.
8. STUDY ASSESSMENTS AND PROCEDURES
1. Study assessment and their timing are summarized in the SoA. Adherence to the study design requirements is essential and required for study conduct. Protocol exemptions or waivers are not allowed.
2. Refer to Section 4.1 .5 for definitions of study visits. 3. Safety concerns should be discussed with sponsor immediately upon occurrence or awareness to determine if the participant should continue or discontinue study intervention.
4. All screening evaluations must be completed and reviewed to confirm that potential participants meet all eligibility criteria. The Investigator maintains a log to record details of all participants screened and to confirm eligibility or record reasons for screening failure, as applicable.
5. Procedures conducted as part of the participant’s routine clinical management (e.g., blood count) and obtained before signing of the ICF may be utilized for screening or baseline purposes provided the procedures meet the protocol-specified criteria and were performed within the time frame defined in the SoA.
6. See Section 10.2 for the list of clinical laboratory tests.
Repeat or unscheduled samples may be obtained for safety reasons or for technical issues related to sample collection, processing, or analysis.
8.1 . Efficacy Assessments
8.1.1. MG-ADL
The MG-ADL Profile is a questionnaire that focuses on activities of daily living that are likely to be impaired by gMG. The 8 items of the MG-ADL assess disability secondary to ocular (2 items), oropharyngeal (3 items), respiratory (1 item), and extremity (2 items) functions. Each response is graded 0 (normal) to 3 (most severe). The MG-ADL total score ranges from 0 to 24, with higher scores indicating greater impairment. The recall period for the MG-ADL Profile is the preceding 7 days or time past since the last visit, if the visit interval is shorter than 7 days.
The MG-ADL Profile must be administered by a properly trained Clinical Evaluator. The MG-ADL should be performed in the morning and at approximately the same time of the day throughout the study. For consistency, the same evaluator should administer the questionnaire throughout the study. It is anticipated that the form takes < 10 minutes to complete. If multiple efficacy assessments are scheduled, the MG-ADL must be performed first, followed in this order, by QMG, MGC and the remaining tests.
8.1.2. QMG
The QMG total score provides a quantitative evaluation of function in sentinel muscle groups. The QMG total score consists of 13 items: ocular (and facial) (3 items), oropharyngeal (2 items), extremity (and head lift) (7 items), and respiratory (1 item) functions. Strength in each of the muscle groups is graded 0 to 3, with 3 indicating severe impairment. The QMG total score ranges from 0 to 39. The MGFA recommends that the QMG total score be used as one outcome measure in prospective interventional studies in MG (Benatar ef al., Muscle Nerve, 2012;45:909-917, 2012). The QMG total score must be administered by a neurologist or an appropriately qualified other study team member, e.g., senior neurology resident in training, physician assistant, or nurse practitioner. The QMG should be performed in the morning and at approximately the same time of the day throughout the study. Vital capacity may be measured by a qualified physical therapist. For consistency, the same evaluator should administer the assessment throughout the study. If a participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the assessment. The time from the last dose to the QMG assessment should be documented and kept similar between visits. If multiple efficacy assessments are scheduled, the QMG is required to be performed after the MG-ADL, before the MGC and other remaining tests.
8.1.3. MGC
The MGC combines participant-reported and Investigator-reported test items to assess the clinical status of MG by measuring both symptoms and objective signs of the disease. The MGC assesses 10 functional areas commonly affected by MG. Grading scales are weighted for clinical significance (see, e.g., Burns et al. Neurology 74:1434-1440, 2010). The MGC total score ranges from 0 to 50., 2010). The MGC total score ranges from 0 to 50.
The MGC must be administered by a neurologist or appropriately qualified other study team member, e.g., senior neurology resident in training, physician assistant, or nurse practitioner. The MGC should be performed in the morning and at approximately the same time of the day throughout the study. For consistency, the same evaluator should administer the assessment throughout the study. If a participant is taking an AChE inhibitor, the dose must be withheld for at least 8 hours prior to the assessment. The time from the last dose to the MGC assessment should be documented and kept similar between visits. If multiple efficacy assessments are scheduled, the MGC is required to be performed after MG-ADL and QMG, but before any other tests.
8.1.4. MG-QoL15r
The revised 15-item Myasthenia Gravis Quality of Life scale (MG-QoL15r) evaluates the quality of life (QoL) as it relates specifically to participants with MG. The MG-QoL15r is designed to provide information about participants’ perception of impairment and disability and determine the degree to which disease manifestations are tolerated (Burns et al., Muscle Nerve, 54:1015-1022, 2016). The MG-QoL15r is completed by the participant. Higher scores indicate greater MG-related dysfunction and dissatisfaction with the current disease status.
8.1 .5. Neuro-QoL Fatigue (Short Form)
This study uses the 8-item Short Form of the Neuro-QoL™ Fatigue. The Quality of Life in Neurological Disorders Fatigue (Neuro-QoL Fatigue) scale is one of the Quality of Life in Neurological Disorders (Neuro-QoL) measures developed through a research initiative in collaboration with the National Institute of Neurological Disorders and Stroke (NINDS). It is a brief survey, completed by the participant (Celia Measuring Quality of Life in Neurological Disorders; Final Report of the Neuro-QOL Study September 2010. 2010). Higher scores indicate greater fatigue and greater impact of MG on activities of daily life.
8.1.6. Euro QoL 5D-5L
The Euro Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L) is a self-assessed, standardized instrument to measure the health-related quality of life that has been used in a wide range of health conditions. The EQ-5D-5L describes mobility, self-care, usual activities, pain and discomfort, and anxiety and depression by using 5 response levels ranging from “no problems” to inability to perform activities or “extreme problems.”
8.1 .7. Short Form Health Survey
The Short Form Health Survey (36 question version) (SF-36) is a 36-item self-report of health-related quality of life (Stewart et al., Med. Care, 26:724-735, 1988; Ware et al., Med. Care, 30:473-483, 1992). It contains 8 subscales measuring different domains including physical functioning, role limitations due to physical problems, bodily pain, general health perceptions, vitality, social functioning, role limitations due to emotional problems, and mental health. The 2 summary scores are the physical component summary and the mental component summary.
8.1 .8. Minimal Symptom Expression
Minimal Symptom Expression (MSE) is an efficacy endpoint in gMG research that uses the participant-reported outcome measures of MG-ADL to determine improvement during therapy. MSE is achieved if the MG-ADL total score is reduced to 0-1 .
8.1 .9. MGFA Post-Intervention Status
Improvement during therapy is also assessed by using a modified version of the MGFA PostIntervention Status (MGFA-PIS) (Jaretzki et al., Neurology, 55:16-23, 2000). Post- Intervention Status (PIS) categories of Improved, Unchanged, or Worse, as well as Minimal Manifestation (MM) is recorded. MM subscores is not used.
The PIS including achievement of MM must be determined by a neurologist or an appropriately qualified neurology resident in training skilled in the evaluation of participants with MG. For consistency, the same evaluator should administer the assessment throughout the study.
8.2. Device Use Assessments
8.2.1 . Device User Experience Questionnaire
The experience of participants or, if applicable, their caregivers with the use of the PFS-SD is evaluated using a 4-item questionnaire. The questionnaire assesses the overall confidence, convenience and comfort of users with the SC injection of the study intervention. The instrument also collects information on whether participants would recommend this route of self-administration to another patient. Each item is answered on a 5-point Likert scale.
8.3. Safety Assessments
Time points for all safety assessments are provided in the SoA.
8.3.1. Physical Examinations
• A complete physical examination includes, at a minimum, assessments of the cardiovascular, respiratory, gastrointestinal, and neurological systems.
• An abbreviated physical examination is performed, if necessary, based on the participant’s health status and the clinical judgment of the Investigator. A symptom-based neurologic examination should be performed if the participant has any complaints or clinical findings attributable to the nervous system. If neurological findings are revealed, a full neurologic examination should follow immediately and be repeated at future assessments as needed based on the clinical judgement of the Investigator. A full neurologic examination comprises mental status, cranial nerve examination, motor examination, reflex status, sensory examination, and examination of coordination and gait.
8.3.2. Vital Signs
1. Body temperature (degrees Celsius [°C]), respiratory rate, pulse rate (beats/minute), pulse oximetry (oxygen saturation), and systolic and diastolic blood pressure (mmHg) is assessed.
2. Vital signs (to be taken before blood collection for laboratory tests) consist of a single pulse check and a single blood pressure measurement.
3. Pulse and blood pressure measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g., television, cell phones). Ideally, the same arm for each participant should be used for measurements.
Pulse and blood pressure should be assessed with the participant in a supine or seated position, and by using an automated device. Manual measurements of pulse and blood pressure should only be used if an automated device is not available.
8.3.3. Electrocardiogram
• A single 12-lead electrocardiogram (ECG) is conducted as outlined in the SoA to obtain heart rate, PR interval (time from the onset of the P wave to the start of the QRS complex), combination of the Q wave, R wave, and S wave (QRS) interval, interval between the start of the Q wave and the end of the T wave (QT), and corrected QT interval (QTc). The QT interval is corrected for heart rate using Fridericia’s formula.
• Participants must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection.
• The Investigator is responsible for reviewing the ECG to assess whether the ECG is within normal limits and determine the clinical significance of the results.
Results are recorded on the eCRF. Clinically significant findings should be recorded on the AE form.
8.3.4. Clinical Safety Laboratory Assessments
1 . The Investigator must review the laboratory report, document this review, and record any clinically relevant changes occurring during the study in the AE section of the eCRF. The laboratory reports must be filed with the source documents. Clinically significant abnormal laboratory findings are those that are not associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the participant’s condition. 2. All laboratory tests with abnormal values and considered clinically significant by the Investigator during the study or within 3 weeks after the last dose of study intervention should be repeated until the values return to normal or Baseline or are no longer considered clinically significant by the Investigator or Medical Monitor.
If such values do not return to normal/Baseline within a period of time judged reasonable by the Investigator, the etiology should be identified, and sponsor notified.
All protocol-required laboratory assessments, as defined in Section 10.2, must be collected in accordance with the Laboratory Manual and the SoA.
Laboratory assessments performed at the institution’s local laboratory that require a change in participant management or are considered clinically significant by the Investigator must be recorded in the AE or SAE form. When possible, values outside of the reference range should be entered, e.g., in a free text field.
8.3.4.1. Virus Serology
Testing for HIV-1 and HIV-2 is required for all participants prior to randomization. Participants who are positive for HIV antibodies is not randomized.
Similarly, participants who are positive for HBsAg, positive anti-HBc with negative anti-HBs, or HCV antibodies is not randomized unless successful treatment and, if locally available, SVR are documented.
8.3.4.2. Urinalysis
Urine samples are analyzed for the parameters listed in Section 0. A microscopic examination of urine samples is performed if the results of the macroscopic analysis are abnormal.
8.3.4.3. Follicle-Stimulating Hormone
Follicle-stimulating hormone (FSH) may be obtained to confirm postmenopausal status in female participants who are considered postmenopausal. A high FSH level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormone replacement therapy (HRT).
This test is not needed in participants of childbearing potential.
8.3.5. Hospitalization Status
Information related to hospitalization, defined as admissions to a healthcare facility (hospital, rehabilitation center, or hospice), is collected irrespective of the relation to MG. Dates of admission, discharge, reason for hospitalization, relationship to MG, and other relevant information is recorded on the eCRF.
8.3.6. Suicidal Ideation and Behavior Risk Monitoring
The NINDS in collaboration with regulatory agencies has developed a set of data to be collected in clinical studies of a neurological indication.
Participants receiving study intervention should be monitored and observed closely for suicidal ideation and behavior, or any other unusual changes in behavior, especially at the beginning and end of the course of intervention, or at the time of dose changes. Discontinuation of the study intervention should be considered in participants who experience signs of suicidal ideation or behavior.
Families and caregivers of participants being treated with study intervention should be alerted about the need to monitor participants for the emergence of unusual changes in behavior, including the emergence of suicidal ideation or behavior, and the need to report such symptoms immediately to the study Investigator.
Suicidal ideation and behavior are assessed by the Columbia-Suicide Severity Rating Scale (C-SSRS) at Baseline. Intervention-emergent suicidal ideation and behavior is monitored using the C-SSRS Since Last Visit.
The C-SSRS is performed by the Investigator or an appropriately trained designee at visits specified in the SoA to ensure that participants who are experiencing suicidal thoughts or behavior are recognized and adequately managed, or referred for further evaluation. Additional C-SSRS assessments are permitted as needed.
8.3.7. Injection-site reactions
Injection site reactions may occur with any agent administered SC. Monitoring for injection site reactions is part of the routine safety assessments for this study. Injection-site reactions may include erythema, pruritus (itch), pain and bruising at the site of the administration of the study intervention. These reactions are typically observed during or shortly after an injection but may occur with a delay of up to 2 or 3 days. Injection site reactions should not be recorded as AEs unless they are judged by the Investigator to be clinically significant.
8.3.8. Systemic Reactions
Systemic injection-related reactions may be mediated by immune or nonimmune mechanisms and occur generally during the administration of a drug or biological treatment, or within hours after the administration. Immune-mediated reactions may include allergic reactions, e.g., fever, chills, flushing, alterations in heart rate and blood pressure, dyspnea, generalized skin rash or anaphylaxis. Nonimmune-mediated reactions may produce less specific symptoms, e.g., headache, dizziness, nausea, vomiting or diarrhea. Monitoring for these reactions is part of routine safety assessments for this study.
8.3.9. Pregnancy
A serum or urine pregnancy test is administered in all participants of childbearing potential. A negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1 are required for eligibility to enter the study.
Pregnancy data from participants of childbearing potential and pregnant partners of participants is collected from the first dose of study intervention and at the time points specified in the SoA. Any female participant who becomes pregnant while participating in the study discontinues study intervention or be withdrawn from the study. If a pregnancy is reported, the Investigator must inform sponsor within 24 hours of awareness of the pregnancy and follow the procedures outlined. 8.3.10. Patient Safety Card
Before the first dose of the study intervention, participants receive a Patient Safety Card that they must carry with them at all times until 5.5 terminal half-lives (92 days) after the last dose of study intervention. The Patient Safety Card is provided to increase participant awareness of the risk of meningococcal infection, promote quick recognition and disclosure of any potential signs or symptoms of such an infection during the study, and to inform participants about actions that must be taken if they are experiencing these symptoms or signs.
At each Clinic Visit throughout the study, the study staff ensures that the participant has the Patient Safety Card with them and review the information provided on the card.
8.4. Adverse Events and Serious Adverse Events
Any AEs and/or any SAEs reported in this study undergoes causality assessment by the Investigator for causal relationship with the study intervention, inclusive of both the drug and device constituents.
The definitions of AEs and SAEs can be found in Section 10.3.
All AEs are reported to the Investigator or qualified designee by the participant (or, when appropriate, by a caregiver, surrogate, or the participant’s legally authorized representative)
The Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an AE or SAE and remain responsible for following up AEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study intervention (Section 7).
Procedures for recording, evaluating, follow-up, and reporting AEs and SAEs are outlined in Section 10.3.
8.4.1 . Time Period and Frequency for Collecting AE and SAE Information
AEs and SAEs are collected from the signing of the ICF at the time points specified in the SoA.
All SAEs are recorded and reported to sponsor immediately and under no circumstance should this exceed 24 hours, as indicated in Section 10.3. The Investigator submits any updated SAE data to sponsor within 24 hours of the date the investigational site became aware of the event.
Investigators are not obligated to actively seek AE or SAE data after conclusion of the study participation. However, if Investigators learn of any SAE, including a death, at any time after a participant has been discharged from the study, and they consider the event to be reasonably related to the study intervention or study participation, the Investigator must promptly notify sponsor.
8.4.2. Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures for completing and transmitting SAE reports are provided in Section 10.3.
Care is taken not to introduce bias when detecting adverse device effects (ADEs) or serious adverse device effects (SADEs). Open-ended and non-leading verbal questioning of the participant is the preferred method to inquire about ADE or SADE occurrences. Investigators should attempt to associate each ADE or SADE with 1 unit (kit) of the study device. Once an ADE or SADE is suspected, the unique identifying kit serial number and lot number should be immediately acquired and recorded along with the corresponding event.
8.4.3. Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow-up on each participant at subsequent visits/contacts. All SAEs are followed up until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is provided in Section 10.3.
8.4.4. Regulatory Reporting Requirements for SAEs a. Prompt notification of an SAE by the Investigator to sponsor is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met. b. Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. Sponsor complies with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators. c. Sponsor is required to submit individual SUSAR reports (defined in Section 10.3.2) in the format of MedWatch 3500 or Council for International Organizations of Medical Sciences (CIOMS) I Form to health authorities and Investigators as required. Forms submitted to Investigators are blinded to treatment assignment. In limited circumstances, e.g., if urgent safety issues that could compromise participant safety, the blind may be broken. d. An Investigator who receives an Investigator safety report describing an SAE or other specific safety information (e.g., summary or listing of SAEs) from sponsor reviews the information and notify the IRB/IEC, if appropriate according to local requirements.
8.4.5. Adverse Events of Special Interest
Meningococcal infections are recorded as adverse events of special interest (AESIs) for this study.
8.5. Medical Device Deficiencies, Adverse Device Effects, Unanticipated Serious Adverse Device Effect, and Serious Adverse Device Effects
The definitions of device-related safety events, (medical device deficiencies, ADEs, SADEs, and USADEs), can be found in Section 0.
All ADEs are reported to the Investigator or qualified designee by the participant or, when appropriate, by a caregiver, site staff who operate the device, or others who may incur any untoward medical occurrences associated with the device or use of the device.
The Investigator and any qualified designees are responsible for detecting, documenting, and recording events that meet the definition of an ADE or SADE and remain responsible for following up ADEs that are serious, considered related to the study intervention or study procedures, or that caused the participant to discontinue the study intervention (see Section 7). Procedures for recording, evaluating, follow-up, and reporting ADEs and SADEs are outlined in Section 10.4.
8.5.1 . Time Period and Frequency for Collecting ADE and SADE Information
All ADEs and SADEs are collected from the signing of the ICF at the time points specified in the SoA.
All SADEs are recorded and reported to sponsor immediately and under no circumstance should this exceed 24 hours, as indicated in Section 10.4. The Investigator submits any updated SADE data to sponsor within 24 hours of the date the investigational site became aware of the event.
Investigators are not obligated to actively seek ADE or SADE data after conclusion of the study participation. However, if Investigators learn of any SADE, including a death, at any time after a participant has been discharged from the study, and they consider the event to be reasonably related to the study intervention or study participation, the Investigator must promptly notify sponsor.
8.5.2. Method of Detecting ADEs and SADEs
The method of recording, evaluating, and assessing causality of ADE and SADE and the procedures for completing and transmitting SADE reports are provided in Section 10.4.
Care is taken not to introduce bias when detecting ADEs or SADEs. Open-ended and non-leading verbal questioning of the participant is the preferred method to inquire about ADE or SADE occurrences. Investigators should attempt to associate each ADE or SADE with 1 unit (kit) of the study device. Once an ADE or SADE is suspected, the unique identifying kit serial number and lot number should be immediately acquired and recorded along with the corresponding event.
8.5.3. Follow-up of ADEs and SADEs
After the initial ADE or SADE report, the Investigator is required to proactively follow-up on each participant at subsequent visits/contacts. All SADEs are followed up until resolution, stabilization, the event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further information on follow-up procedures is provided in Section 10.4.
8.5.4. Regulatory Reporting Requirements for SADEs
• Prompt notification of an SADE by the Investigator to sponsor is essential so that legal obligations and ethical responsibilities towards the safety of participants and the safety of a study intervention under clinical investigation are met.
• Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study intervention under clinical investigation. Sponsor complies with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRBs/IECs, and Investigators.
• Sponsor is required to submit individual USADE reports (defined in Section 10.4.2) in the format of MedWatch 3500 or CIOMS I Form to health authorities and Investigators as required. Forms submitted to Investigators are blinded to treatment assignment. In limited circumstances, e.g., if urgent safety issues that could compromise participant safety, the blind may be broken.
• An Investigator who receives an Investigator safety report describing an SADE or other specific safety information (e.g., summary or listing of SADEs) from sponsor reviews the information and notify the IRB/IEC, if appropriate according to local requirements.
8.5.5. Medical Device Deficiencies
To fulfill regulatory reporting obligations worldwide, the Investigator is responsible for the identification and documentation of events meeting the definition of medical device deficiency that occur during the study. Medical device deficiencies include malfunctions, use errors, and inadequate labeling (Section 10.4.3).
Deficiencies fulfilling the definition of an ADE or SADE (see Section 10.4.1 and Section 10.4.2) also follow the detecting, follow-up and reporting processes outlined in Section 8.5.3 and Section 10.4 of the protocol.
8.5.5.1 Time Period for Detecting Medical Device Deficiencies
• Medical device deficiencies with or without resulting ADEs/SADEs are identified, documented, and reported during all periods of the study in which the medical device is used.
• Investigators are not obligated to actively seek device deficiency data after conclusion of the study participation. However, if Investigators learn of a medical device deficiency, at any time after a participant has been discharged from the study, and such deficiency is considered reasonably related to an investigational medical device, the Investigator must promptly notify sponsor.
The method of documenting medical device deficiency is provided in Section 10.4.
8.5.5.2. Follow-up of Medical Device Deficiencies
• The Investigator is responsible for ensuring that all device deficiencies that occur after signing of the ICF through 30 days after the last dose of study intervention or at the end of the study, whichever is later, are reported.
• After the initial deficiency report, the Investigator may be required to follow-up participants, including those who discontinue study intervention, and perform or arrange for the conduct of supplemental investigations as medically indicated or requested by sponsor to elucidate the nature and causality of a device deficiency as fully as possible.
8.5.5.3. Prompt Reporting of Medical Device Deficiencies to Sponsor
• Investigators and participants must record all medical device deficiencies observed during the study (see Section 10.5) using the eCRF. Further details of the medical device deficiencies reporting process and reporting time frames are specified in the Pharmacy Manual.
• Devices with a reported malfunction, e.g., involving the safety device or needle, must be collected and sent to sponsor or a designated laboratory according to the procedures in the Pharmacy Manual for further investigation. Sponsor may request collection and further investigation of other types of device deficiencies during the study.
8.6. Treatment of Overdose
Any blinded dose of the study intervention that is greater than the dose specified in the protocol is considered a suspected overdose. However, replacement doses that compensate for incomplete or missing delivery of the study intervention, e.g., following a user error or malfunction of the PFS-SD, or supplemental doses that are administered as required after PP/PE (Section 6.5.3.1), do not constitute an overdose.
Overdoses are medication errors that are not considered AEs or ADEs unless there is an untoward medical occurrence resulting from the overdose. Sponsor recommends general symptom- oriented measures after an overdose with the fusion polypeptide described herein. Specific treatment, e.g., related to the mechanism of action, is not required.
In the event of an overdose or suspected overdose, the Investigator should:
• Contact the Medical Monitor immediately.
• Closely monitor the participant for any AE/SAE.
• Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on a case-by-case basis).
• Document the quantity of the excess dose as well as the frequency of the overdose in the eCRF.
8.7. Pharmacokinetics
• Whole blood samples are collected for measurement of serum concentrations of the fusion polypeptide described herein as specified in the SoA. Samples may be collected at additional time points during the study if warranted and agreed upon between the Investigator and sponsor.
• Instructions for the collection and handling of samples are provided by sponsor. The actual date and time (24-hour clock time) of each sample must be recorded.
• All efforts are made to obtain the PK samples at the exact nominal time relative to dosing.
Samples collected for analyses of the fusion polypeptide serum concentration may also be used to evaluate safety or efficacy aspects related to concerns arising during or after the study.
8.8. Pharmacodynamics
• Whole blood samples are collected for measurement of serum concentrations of free and total C5 as specified in the SoA. Samples may be collected at additional time points during the study if warranted and agreed upon between the Investigator and sponsor.
• Instructions for the collection and handling of PD samples are provided in the Laboratory Manual. The actual date and time (24-hour clock time) of each sample must be recorded. • All efforts are made to obtain the PD samples at the exact nominal time relative to dosing. PD samples collected out-of-window are recorded as a protocol deviation.
• Samples collected for PD analyses may also be used for research purposes or to evaluate safety or efficacy aspects during or after the study.
8.9. Biomarkers
Samples are collected for analyses that may include, but are not limited to, evaluation of complement components, functional assays, anti-AChR antibody functional assays, markers of inflammation, and other nongenetic exploratory biomarkers in adults with gMG.
Blood samples for biomarker research are collected from all participants in this study as specified in the SoA. Additional details regarding how biomarkers are collected and analyzed are provided in Section 10.7.
8.10. Immunogenicity Assessments
Serum samples for ADA analysis are collected according to the SoA. All efforts are made to obtain the immunogenicity samples at the specified nominal time relative to dosing. ADA samples collected out-of-window are recorded as a protocol deviation.
8.10.1. ADA Variables
ADA variables include ADA response category incidence and titer over the duration of the study as follows. ADA response category definitions and titer thresholds are provided in the SAP.
ADA response categories
• ADA Negative
• ADA Positive
Participants who are ADA positive are categorized as follows:
• Pre-existing Immunoreactivity
• Treatment-emergent ADA Responses
Persistent Treatment-emergent Responses
Indeterminant Treatment-emergent Responses
Transient Treatment-emergent Reponses
• Treatment-boosted ADA Responses
ADA Maximum Titer Value Categories:
• Lower Titer
• Moderate Titer
• High Titer
8.11 . Health Economics Data and/or Medical Resource Utilization
Health economics data and/or medical resource utilization parameters are not evaluated in this study. 8.12. Other Assessments and Procedures
8.12.1. Informed Consent
Participants or their legally authorized representative must be consented per the informed consent process outlined in Section 10.1 .3.
8.12.2. Inclusion/Exclusion Criteria
All inclusion (Section 5.1) and exclusion (Section 5.2) criteria must be reviewed by the Investigator or qualified designee to ensure the participant qualifies for study participation.
8.12.3. Medical History
The participant’s relevant medical and surgical history, including prior and concomitant conditions or disorders, is evaluated at Screening by the Investigator, or qualified designee. Specific aspects of the history of MG are required, including:
• Date of symptom onset
• Date of the diagnosis
• Initial clinical presentation (ocular or generalized MG)
• Time to generalized symptoms and signs, if initial clinical presentation was limited to ocular muscles
• Maximum MGFA Classification since diagnosis
• Ventilatory support since diagnosis
• Dates of MG exacerbations or crises
• Hospitalizations related to MG in the 2 years prior to Screening
• Medications or other forms of therapy related to MG within 2 years prior to Screening and if available, additional information about such medication or therapy in earlier years
Collected data are documented in the source documents and eCRF. Any changes to medical history occurring prior to Day 1 are documented before administration of the study intervention.
8.12.4. Demographics
A review of demographic parameters, including age, sex, race, and ethnicity is performed at Screening, if allowed per country specific regulations, and documented in the eCRF.
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Regulatory, Ethical, and Study Oversight Considerations
10.1.1. Regulatory and Ethical Considerations
This study is conducted in accordance with the protocol and the following:
Consensus ethical principles derived from international guidelines including the
Declaration of Helsinki and CIOMS International Ethical Guidelines
Applicable ICH Good Clinical Practice (GCP) Guidelines
Applicable laws and regulations The protocol, substantial protocol amendments, ICF, IB, and other relevant documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator/sponsor, and reviewed and approved by the IRB/IEC before the study is initiated.
If any of these documents require regulatory/health authority approval per local regulations, sponsor also obtains such approval before the study is initiated.
Any substantial amendments to the protocol require IRB/IEC and regulatory/health authority approval before implementation of changes made to the study design, except for changes necessary to eliminate an immediate hazard to study participants.
The Investigator notifies the IRB/IEC of deviations from the study protocol or GCP as defined by Clinical Trial Regulation EU No 536/2014 as a serious breach or as required by IRB/IEC procedures.
The Investigator is responsible for the following:
Providing written summaries of the status of the study to the IRB/IEC annually or more frequently in accordance with the requirements, policies, and procedures established by the IRB/IEC
Notifying the IRB/IEC of SAEs or other significant safety findings as required by IRB/IEC procedures
Providing oversight of the conduct of the study at the site and adherence to requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB/IEC, Directive 2001/20/EC, European regulation 536/2014 for clinical studies (if applicable), and all other applicable local regulations
10.1.3. Informed Consent Process
It is the responsibility of the Investigator or designee to obtain signed (written or electronic signature) informed consent from all study participants, or the participant’s legally authorized representative, prior to performing any study-related procedures including screening assessments.
The Investigator or designee explains the nature of the study (including but not limited to the objectives, potential benefits and risks, inconveniences, and the participant’s rights and responsibilities) to the participant or his/her legally authorized representative, defined according to local and country regulations where the study is taking place, and answer all questions regarding the study.
Participants must be informed that their participation is voluntary. Participants or their legally authorized representative is required to sign a statement of informed consent or a certified translation, if applicable, that meets the requirements of 21 CFR 50, local regulations, European Union (EU) General Data Protection Regulation (GDPR), ICH GCP guidelines, Health Insurance Portability and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study center.
The participant’s medical record must include a statement that signed (written or electronic) informed consent was obtained before any screening procedures were performed with a participant, and the date the written consent was obtained. The authorized person obtaining the informed consent must also sign the ICF(s). Participants must be reconsented to the most current version of the ICF(s) during their participation in the study, as applicable.
A copy of the signed (written or electronic) informed consent documentation (j.e., a complete set of participant information sheets and fully executed signature pages) must be provided to the participant or the participant’s legally authorized representative, as applicable. This document may require translation into the local language. Original signed (written or electronic) consent forms must remain in each participant’s study file and must be available for verification at any time.
Participants who are rescreened outside of the Screening window are required to sign a new ICF (Section 5.4).
10.1 .9. Study and Site Start and Closure
The study start date is the date on which the first participant is consented.
Sponsor reserves the right to close the study site or terminate the study at any time for any reason at its sole discretion. Study sites are closed after the study is completed or following the decision to close or terminate the study. A study site is considered closed when all participants have completed the EoS or ET Visit, all data have been collected and entered into the electronic data capture (EDC) system, all required documents and study supplies have been collected and reconciled, and a study-site closure visit has been performed.
The Investigator may initiate study-site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by sponsor or Investigator may include but are not limited to:
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC or local health authorities, sponsor’s procedures, or ICH GCP guidelines
Inadequate recruitment of participants by the Investigator Discontinuation of further study intervention development
Sponsor or health authority may terminate the study for reasonable cause. Conditions that may warrant termination of the study include, but are not limited to:
Discovery of an unexpected, serious, or unacceptable risk of the study intervention to participants enrolled or continuing in the study
Sponsor decision to suspend or discontinue testing, evaluation, or development of the study intervention
If the study is prematurely terminated or suspended, sponsor shall promptly inform the Investigators, IRBs/IECs, regulatory authorities, and any contract research organization(s) used in the study of the reason for termination or suspension, as specified by the applicable regulatory requirements. The Investigator shall promptly inform the participant and should assure appropriate participant therapy and/or follow-up.
10.2. Clinical Laboratory Tests
The tests detailed in Table are performed by the central laboratory unless otherwise noted. Local laboratory results are only required in the event that the central laboratory results are not available in time for response evaluation. If a local sample is required, it is important that the sample for central analysis is obtained at the same time. Additionally, if the local laboratory results are used to make either a study intervention decision or response evaluation, the results must be available in the participant’s source documents.
Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section
5. Additional tests may be performed at any time during the study as determined necessary by the Investigator or required by local regulations.
Pregnancy testing: Participants of childbearing potential should only be randomized after negative serum pregnancy test at the Screening Visit and a negative urine pregnancy test at Day 1 .
Additional urine pregnancy testing is standard for the protocol unless serum testing is required by site policies, local regulation, or IRB/IEC and should be performed per the time points specified in the SoA.
Investigators must document their review of each laboratory report. Clinically significant findings resulting in an assessment of a TEAE should be recorded on the AE eCRF.
Laboratory/analyte results that could unblind the study is not reported to investigational sites or other blinded personnel until the study has been unblinded.
Table 15: Protocol-Required Clinical Laboratory Assessments
Figure imgf000071_0001
Table 15: Protocol-Required Clinical Laboratory Assessments
Figure imgf000072_0001
a Blood or urine are the preferred samples to screen for alcohol. If neither test method is available, alcohol may also be tested in exhaled breath. b If locally available, SVR should be documented or established at Screening.
Abbreviations: AChR = acetylcholine receptor; ALT = alanine aminotransferase; anti-HBc = hepatitis B core antibody; AST = aspartate aminotransferase; BUN = blood urea nitrogen; FSH = follicle- stimulating hormone; hCG = human chorionic gonadotropin; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human immunodeficiency virus; MCH = mean corpuscular hemoglobin; MCV = mean corpuscular volume; RBC = red blood cell; SGOT = serum glutamic- oxaloacetic transaminase; SGPT = serum glutamic-pyruvic transaminase; SVR = sustained virologic response; WBC = white blood cell
10.3. Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting
10.3.1 . Definition of AE
Figure imgf000073_0001
Figure imgf000073_0002
Figure imgf000073_0003
Figure imgf000074_0001
10.3.2 Definition of SAE
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease).
Figure imgf000074_0002
Figure imgf000075_0001
Figure imgf000075_0002
10.3.3. Recording and Follow-up of AE and/or SAE
Figure imgf000075_0003
Figure imgf000076_0001
Figure imgf000076_0002
Figure imgf000077_0001
Figure imgf000077_0002
10.3.4. Reporting of SAEs
Figure imgf000077_0003
Figure imgf000078_0001
10.4 Adverse Device Effects, Serious Adverse Device Effects and Medical Device Deficiencies: Definition and Procedures for Recording, Evaluating, Follow-up, and Reporting
The definitions and procedures detailed in this section are in accordance with ISO 14155. Both the Investigator and sponsor will comply with all local medical device reporting requirements. The detection and documentation procedures described in this protocol apply to the PFS-SD medical devices provided for use in the study (Section 6.1 .2).
10.4.1 Definition of Adverse Device Effect
Figure imgf000079_0001
10.4.2. Definition of Serious Adverse Device Effect and Unanticipated Serious Adverse
Device Effect If an event is not an ADE per definition above, then it cannot be a SADE even if serious conditions are met (e.g., hospitalization for signs/symptoms of the disease under study, death due to progression of disease).
Figure imgf000079_0002
10.4.3. Definition of Medical Device Deficiency
Figure imgf000079_0003
10.4.4. Recording and Follow-up of Adverse Device Effects and/or Serious Adverse Device Effects, and Medical Device Deficiencies
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000081_0002
10.4.5. Reporting of Serious Adverse Device Effects
Figure imgf000081_0003
Figure imgf000082_0001
10.4.6. Adverse Device Effect, Serious Adverse Device Effect, and Unanticipated Serious Adverse Device Effect Regulatory Reporting Requirements
Unanticipated Adverse Device Effect Reporting Requirements
Unanticipated ADE means any serious adverse effect on health or safety or any life threatening problem or death caused by, or associated with, a device, if that effect, problem, or death was not previously identified in nature, severity, or degree of incidence in the investigational plan or application (including a supplementary plan or application), or any other unanticipated serious problem associated with a device that relates to the rights, safety, or welfare of participants.
Sponsor is required to send individual USADE safety reports in the format of
MedWatch 3500A or CIOMS II Form, or a series of similar USADEs in narrative format to health authorities/National Competent Authorities (NCA) and Investigators as required.
For blinded Phase 3 studies, MedWatch 3500A or CIOMS II Forms submitted to Investigators are blinded to treatment assignment. In limited circumstances, the blind may be broken in the case of urgent safety issues that could compromise participant safety.
10.4.6.2. Serious Adverse Device Effect Reporting Requirement in Other Jurisdictions
The following events are considered reportable events in accordance with other jurisdictions: Any SAE
Any medical device deficiency that might have led to an SAE if:
Suitable action had not been taken.
Intervention had not been made.
If circumstances had been less fortunate.
New findings/updates in relation to already reported events.
To fulfill regulatory reporting requirements, medical device deficiencies as well as SAEs need to be documented during the course of the clinical investigation and reported to competent authorities.
Reportable device events must be reported by sponsor at the same time to all NCAs where the clinical investigation has commenced.
For all reportable events, which indicate an imminent risk of death, serious injury, or serious illness and that requires prompt remedial action for other study participants, users or other persons or a new finding to it: immediately, but not later than 2 calendar days after awareness by sponsor of a new reportable event or of new information in relation with an already reported event.
Any other reportable events or a new finding/update to it: immediately, but not later than
7 calendar days following the date of awareness by sponsor of the new reportable event or of new information in relation with an already reported event.
10.5 Investigational Medical Product or Device Complaints
If the use of an investigational medical product or device led to an AE or ADE as defined in Section 10.3 and Section 10.4, respectively, the event is evaluated by sponsor’s GDS and the recording and reporting procedures are followed as described.
Complaints are written, electronic, or oral communications that allege deficiencies about an investigational medical device’s identity, quality, durability, reliability, safety, or performance. Upon identification of a product complaint on the PFS-SD, the site or participant must contact sponsor or the designee using the local phone number in the IFU document. The site or participant must complete the Product Quality Complaints Form (see the Pharmacy Manual for details).
The following includes potential issues that may warrant lodging a complaint:
• Medical device failure: the PFS-SD is used in compliance with the IFU, but does not perform as described (e.g., incomplete dose or no dose delivered)
• Labeling irregularity (e.g., missing or illegible information on any part of the packaging or IFU)
• Change in appearance of the study intervention (e.g., color change or presence of particulate matter in the cartridge)
• Evidence of tampering or compromised packaging of the PFS-SD kit
• User error: The PFS-SD is not used in compliance with the IFU. Additional details are provided in the IFU.
The Investigator is responsible for ensuring that all product complaints that occur after signing of the ICF through 30 days after the last dose of study intervention or at the end of the study, whichever is later, are reported.
10.7 Biomarkers
Blood matrix (serum/plasma) samples are collected for biomarker analyses and the data are used for research (e.g., exploratory) related to study intervention or gMG. The samples may also be used to develop tests/assays including diagnostic tests related to study intervention and gMG
The samples may be analyzed as part of a multi-study assessment of biomarkers in the response to the study intervention to understand study disease or related conditions. The results of biomarker analyses may be reported in the clinical study report (CSR) or in a separate study summary.
• Sponsor or designee stores the samples obtained for biomarker analyses in a secure storage space with adequate measures to protect confidentiality.
• The samples are retained while research on study intervention continues but no longer than 25 years after the study ends or other period/time point per local requirements. 10.8. Participant or Clinician-Reported Outcome Instruments
Participant reported Outcomes or Clinician reported Outcomes (Clinical Outcome Assessments) may be collected on paper or electronically.
10.11 Abbreviations The following abbreviations and terms are used in this study protocol in Table 18.
Table 1 : Abbreviations and Specialist Terms
Figure imgf000084_0001
Table 1 : Abbreviations and Specialist Terms
Figure imgf000085_0001
Table 1 : Abbreviations and Specialist Terms
Figure imgf000086_0001
Table 1 : Abbreviations and Specialist Terms
Figure imgf000087_0001
10.12 Glossary of Terms
Table 2: Glossary of Terms
Figure imgf000087_0002
Table 2: Glossary of Terms
Figure imgf000088_0001
OTHER EMBODIMENTS
Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, the descriptions and examples should not be construed as limiting the scope of the invention. The disclosures of all patent and scientific literature cited herein are expressly incorporated in their entirety by reference.

Claims

CLAIMS What is claimed is:
1 . A method of treating myasthenia gravis (MG) in a human subject in need thereof, comprising administering to the human subject a therapeutically effective dose of a fusion protein comprising an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the engineered polypeptide that specifically binds to human complement component C5 comprises three complementarity determining regions, CDR1 , CDR2 and CDR3, comprising amino acid sequences as set forth in SEQ ID NOs: 5, 6 and 7, respectively, and wherein the engineered polypeptide that specifically binds to human serum albumin comprises three complementarity determining regions, CDR1 , CDR2 and CDR3, comprising amino acid sequences as set forth in SEQ ID NOs: 1 , 2 and 3, respectively.
2. The method of claim 1 , wherein the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 4.
3. The method of claim 2, wherein the polypeptide that specifically binds to human serum albumin comprises an amino acid sequence of SEQ ID NO: 4.
4. The method of any one of claims 1 -3, wherein the polypeptide that specifically binds to human complement component C5 comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 8.
5. The method of claim 4, wherein the polypeptide that specifically binds to human complement component C5 comprises an amino acid sequence of SEQ ID NO: 8.
6. The method of any one of claims 1 -5, wherein the peptide linker comprises the amino acid sequence of SEQ ID NO:10.
7. The method of any one of claims 1-6, wherein the fusion protein comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 9.
8. The method of claim 7, wherein the fusion protein comprises an amino acid sequence of SEQ ID NO: 9.
9. The method of any one of claims 1-8, wherein the subject is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR).
10. The method of any one of claims 1-9, wherein the MG is generalized myasthenia gravis (gMG).
11 . The method of any one of claims 1-10, wherein the subject has been diagnosed with MG for at least 3 months.
12. The method of any one of claims 1-11 , wherein the subject is 18 years old or older in age.
13. The method of any one of claims 1-12, wherein the subject has a Myasthenia Gravis Foundation of America (MGFA) clinical classification of between II and IV.
14. The method of any one of claims 1-13, wherein the patient has a Myasthenia Gravis Activities of Daily Living (MG-ADL) score greater than or equal to 5.
15. The method of any one of claims 1-14, wherein the subject is being administered one or more additional pharmaceutical compositions.
16. The method of claim 15, wherein the pharmaceutical composition is an acetylcholinesterase inhibitor, an immunosuppressive therapy (1ST), or immunoglobulins.
17. The method of claim 16, wherein 1ST is selected from the group consisting of a corticosteroid, azathioprine (AZA), mycophenolate mofetil (MMF), methotrexate (MTX), cyclosporine, cyclophosphamide, and tacrolimus (TAC).
18. The method of any one of claims 1-17, wherein the subject has not been administered a B cell-depleting therapy in the prior 6 months.
19. The method of claim 18, wherein the B cell-depleting therapy is rituximab or ocrelizumab.
20. The method of any one of claims 1-19, wherein the subject has not been administered an FcRn inhibitor within 5 half-lives of the FcRn before administration of the fusion protein.
21 . The method of any one of claims 1 -20, wherein the subject has not been administered a complement inhibitor within 5 half-lives of the complement inhibitor before administration of the fusion protein.
22. The method of any one of claims 1-21 , wherein the subject weighs at least 40 kg.
23. The method of any one of claims 1 -22, wherein the subject has a body mass index of > 18.5 kg/m2 and < 40 kg/m2.
24. The method of any one of claims 1 -23, wherein the therapeutically effective dose is based on the weight of the subject.
25. The method of any one of claims 1-24 wherein the fusion protein is administered to a patient weighing < 80 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 600 mg; and
(b) on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 300 mg.
26. The method of claim 25, wherein fusion protein is administered at a dose of 300 mg every week after the administration cycle for up to two years.
27. The method of any one of claims 1-24, wherein the fusion protein is administered to a patient weighing > 80 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 900 mg; and
(b) on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 600 mg.
28. The method of claim 27, wherein fusion protein is administered at a dose of 600 mg every week after the administration cycle for up to two years
29. The method of any one of claims 1 -28, wherein the fusion protein is administered to the subject subcutaneously.
30. The method of any one of claims 1 -29, wherein the fusion protein is administered to the subject using a pre-filled syringe.
31 . The method of claim 30, wherein the pre-filled syringe comprises a passive needle safety device.
32. The method of any one of claims 1 -31 , wherein the treatment results in the patient experiencing a change from baseline in MG-ADL score.
33. The method of any one of claims 1 -32 wherein the treatment results in the patient experiencing a change from baseline in MG-ADL score after 26 weeks.
34. The method of any one of claims 1-33, wherein the treatment results in the patient experiencing a reduction in the MG-ADL score after 26 weeks.
35. The method of claim 34, wherein the reduction is at least 3.0 points.
36. The method of claim 34, wherein the reduction is at least 4.0 points.
37. The method of any one of claims 1-36, wherein the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis (QMG) score.
38. The method of any one of claims 1 -37, wherein the treatment results in the patient experiencing a change from baseline in QMG score after 26 weeks.
39. The method of any one of claims 1-38, wherein the treatment results in the patient experiencing a reduction in QMG score after 26 weeks.
40. The method of claim 39, wherein the reduction is at least 2.0 points.
41 . The method of claim 39, wherein the reduction is at least 5.0 points.
42. The method of any one of claims 1 -41 , wherein the treatment results in the patient experiencing a change from baseline in quantitative Myasthenia Gravis composite (MGC) score.
43. The method of any one of claims 1 -42, wherein the treatment results in the patient experiencing a change from baseline in MGC score after 26 weeks.
44. The method of any one of claims 1-43, wherein the treatment results in the patient experiencing a reduction in MGC score after 26 weeks.
45. The method of any one of claims 1 -44, wherein the treatment results in subject experiencing a change from baseline in serum free or total C5 concentration.
46. The method of any one of claims 1 -45, wherein the treatment results in the patient experiencing a change from baseline in MG Quality of Life 15 (MG-QoL15r) score after 26 weeks.
47. The method of any one of claims 1-46, wherein the treatment results in the patient experiencing a change from baseline in EQ-5D-5L score after 26 weeks.
48. The method of any one of claims 1 -47, wherein the treatment results in the patient experiencing a change from baseline in SF-36 score after 26 weeks.
49. The method of any one of claims 1-48, wherein the treatment results in the patient experiencing a change from baseline in Neuro-QoL Fatigue (Quality of Life in Neurological Disorders Fatigue Short Form)) score after 26 weeks.
50. The method of any one of claims 1-49, wherein the treatment results in the patient experiencing an MG-ADL score of 1 or less after 26 weeks.
51 . The method of any one of claims 1 -50, wherein the treatment results in the patient experiencing a change in MGFA postintervention status after 26 weeks.
52. The method of any one of claims 1 -51 , wherein the treatment results in the patient experiencing a reduction in incidence of clinical deteriorations after 26 weeks.
53. The method of any one of claims 1-52, wherein the treatment results in the patient experiencing a reduction in incidence of hospitalizations after 26 weeks.
54. The method of any one of claims 1 -53, wherein the treatment results in the patient experiencing a reduction in incidence of requiring rescue therapy after 26 weeks.
55. The method of any one of claims 1-54, wherein the treatment results in a change in concentration of one or more inflammation biomarkers.
56. The method of claim 55, wherein the one or more inflammation biomarkers comprises MMP- 10 or IL-6.
57. The method of any one of claims 1-56, wherein the treatment results in a change in concentration of complement proteins or complement pathway regulators.
58. The method of any one of claims 1 -57, wherein the treatment effect is maintained through week 26 after initiation of treatment.
59. The method of any one of claims 1 -58, wherein the treatment effect is maintained through week 96 after initiation of treatment.
60. A method of treating gMG in a human subject in need thereof, comprising administering to the human subject a therapeutically effective dose of a fusion protein comprising an engineered polypeptide that specifically binds human complement component C5 fused to an engineered polypeptide that specifically binds to human serum albumin, wherein the engineered polypeptide that specifically binds to human complement component C5 is fused to the engineered polypeptide that specifically binds to human serum albumin via a peptide linker, wherein the engineered polypeptide that specifically binds to human complement component C5 comprises three complementarity determining regions, CDR1 , CDR2 and CDR3, comprising amino acid sequences as set forth in SEQ ID NOs: 5, 6 and 7, respectively, and wherein the engineered polypeptide that specifically binds to human serum albumin comprises three complementarity determining regions, CDR1 , CDR2 and CDR3, comprising amino acid sequences as set forth in SEQ ID NOs: 1 , 2 and 3, respectively, wherein the subject is positive for auto-antibodies binding to nicotinic acetylcholine receptor (anti-AChR); wherein the subject is 18 years old or older in age,
(a) wherein the fusion protein is administered to a patient weighing < 80 kg:
(i) once on Day 1 of the administration cycle at a loading dose of 600 mg; and
(ii) on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 300 mg, and wherein fusion protein is administered at a dose of 300 mg every week after the administration cycle for up to two years, or
(b) wherein the fusion protein is administered to a patient weighing > 80 kg:
(i) once on Day 1 of the administration cycle at a loading dose of 900 mg; and
(ii) on Day 8 of the administration cycle and every week thereafter at a maintenance dose of 600 mg, and wherein fusion protein is administered at a dose of 600 mg every week after the administration cycle for up to two years, and wherein the subject has an improvement from baseline in at least one measurement of gMG severity selected from the group consisting of MG-ADL, QMG, MGC, MG-QoL15r, EQ-5D-5L, SF-36 and Neuro-QoL Fatigue.
PCT/US2023/024252 2022-06-03 2023-06-02 Dosage and administration of fusion polypeptides for treatment of myasthenia gravis WO2023235545A2 (en)

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