WO2021263056A1 - Dosage and administration of anti-c5 antibodies for treatment of amyotrophic lateral sclerosis - Google Patents

Dosage and administration of anti-c5 antibodies for treatment of amyotrophic lateral sclerosis Download PDF

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Publication number
WO2021263056A1
WO2021263056A1 PCT/US2021/039002 US2021039002W WO2021263056A1 WO 2021263056 A1 WO2021263056 A1 WO 2021263056A1 US 2021039002 W US2021039002 W US 2021039002W WO 2021263056 A1 WO2021263056 A1 WO 2021263056A1
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antibody
treatment
patient
antigen binding
binding fragment
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PCT/US2021/039002
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French (fr)
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WO2021263056A9 (en
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Cori ABIKOFF
Kaushik Patra
Steve Han
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Alexion Pharmaceuticals, Inc.
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Publication of WO2021263056A9 publication Critical patent/WO2021263056A9/en

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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding

Definitions

  • ALS Amyotrophic lateral sclerosis
  • ALS Amyotrophic lateral sclerosis
  • the burden of ALS is substantial with an average life expectancy from symptom onset between 2 and 5 years (Mehta, 2018).
  • the onset of ALS occurs in the fifth or sixth decade of life and is marked by a progressive loss of motor neurons leading to variable amounts of weakness and spasticity in the limb, bulbar, and respiratory muscles (Swinnen, 2014).
  • limb onset also referred to as spinal onset
  • weakness may be of bulbar onset manifesting as dysarthria or dysphagia.
  • Bulbar onset patients have a poorer prognosis. Patients develop progressive disability limiting ambulation, communication, nourishment, and independence. Declining respiratory function can lead to respiratory insufficiency and failure which often is the cause for death, unless permanent mechanical ventilation is elected (Paulukonis, 2015).
  • ALS While the etiology of ALS is largely unknown, neuroinflammation may be a key event in disease pathology (Boillee, 2006; Kjaeldgaard, 2018). Immune dysregulation and neuroinflammation in both the central and peripheral nervous system are common features of familial and sporadic ALS and have negative influences on motor neuron viability in ALS (Beers, 2019).
  • the complement system is a major component of the innate immune system that comprises more than 30 proteins and plays an essential role in pathogen killing, stimulation of phagocytosis, chemoattraction of inflammatory cells, and disposal of self debris (Chen, 2010).
  • Terminal complement specifically, has been shown to play an important role in the pathology of ALS (Parker, 2019). While plasma levels of proximal complement are similar in ALS patients and normal controls, serum levels of the membrane attack complex, as well as serum and leukocyte levels of C5a, are increased in ALS patients (Mantovani, 2014). Terminal complement is also found to correlate with mediators of neuroinflammation in ALS. Inflammatory Ml macrophages and microglia are associated with disease progression in ALS and these invading cells at the neuromuscular junction express the complement receptor C5aRl (Lee, 2017; Liao, 2012).
  • ALS central nervous system
  • neuromuscular junction As there is no cure for ALS, and standard of care is not effective for all patients, there is a need to provide improved methods for treating these patients.
  • compositions and methods for treating ALS are provided herein.
  • the disclosure also provides ravulizumab for use in the treatment of ALS in a human patient according to any of the embodiments, described above.
  • FIG. 1 is a schematic depicting the design of a clinical trial in ALS patients.
  • FIG. 2 is the El Escorial diagnostic criteria of possible, probable, probable laboratory supported, or definite ALS, used in the clinical trial disclosed herein.
  • FIG. 3 is the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) used to measure physical function in performance of daily living activities in patients with ALS, used in the clinical trial disclosed herein.
  • ALSFRS-R Revised Amyotrophic Lateral Sclerosis Functional Rating Scale
  • FIG. 4 is the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) used to measuring quality of life in patients with ALS, used in the clinical trial disclosed herein.
  • ALSAQ-40 Amyotrophic Lateral Sclerosis Assessment Questionnaire
  • FIG. 5 is the in-clinic version of the European Quality of Life 5 Dimensions (EQ-5D- 5L) standardized instrument to measure health-related quality of life, used in the clinical trial disclosed herein.
  • FIG. 6 is the phone interview version of the EQ-5D-5L standardized instrument to measure health-related quality of life, used in the clinical trial disclosed herein.
  • FIG. 7 is the in-clinic version of the Short Form Health Survey (SF-36) health-related quality of life survey, used in the clinical trial disclosed herein.
  • SF-36 Short Form Health Survey
  • FIG. 8 is the phone interview version of the SF-36 health-related quality of life survey, used in the clinical trial disclosed herein.
  • FIG. 9 is the Treatment Satisfaction Questionnaire for Medication (TSQM-9) used to asses three key dimensions of treatment satisfaction, used in the clinical trial disclosed herein.
  • FIG. 10 is the Columbia-Suicide Severity Rating Scale (C-SSRS) as measured at the patient’s baseline/screening.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • FIG. 11 is the C-SSRS as measured since the time of the patient’s last visit.
  • the term “subject” or “patient” is a human patient (e.g. , a patient having ALS).
  • the terms “subject” and “patient” are interchangeable.
  • “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, for example, alleviation of at least one symptom of ALS.
  • 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 anti-C5 antibody or antigen binding fragment thereof useful, e.g., clinically proven, to alleviate at least one symptom of ALS.
  • An effective amount can be administered in one or more administrations.
  • randomized controlled period refers to the first phase of a dosing regimen.
  • loading dose refers to the initial dose administered to the patient, e.g., during the randomized control period of a dosing regimen.
  • a loading dose may be, for example, 2400 mg, 2700 mg, or 3000 mg. Loading doses may be fixed or titered based on body weight.
  • 2400 mg is administered to a patient weighing > 40 to ⁇ 60 kg
  • 2700 mg is administered to a patient weighing > 60 to ⁇ 100 kg
  • 3000 mg is administered to a patient weighing > 100 kg.
  • the loading dose is administered at day 1 of treatment.
  • the term “maintenance phase” refers to the second phase of a dosing regimen. In some embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. In some embodiments, the maintenance phase begins on day 15 if treatment. According to some embodiments, the maintenance phase lasts for 50-76, 50-102, 50-128, 50-154, 50-180, 50-206 weeks, or more. In some embodiments, the maintenance phase lasts for greater than 50, 51, 52, 53, 54, 55, 56,
  • 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 years, or more. In some embodiments, the maintenance phase lasts for the remainder of the subject's life.
  • the term “maintenance dose” refers to a dose administered to the patient after the loading dose.
  • the maintenance dose is provided during the maintenance phase.
  • a maintenance dose may be 3000 mg, 3300 mg, or 3600 mg.
  • Maintenance doses may be titered based on body weight.
  • 3000 mg is administered to a patient weighing > 40 to ⁇ 60 kg
  • 3300 mg is administered to a patient weighing > 60 to ⁇ 100 kg
  • 3600 mg is administered to a patient weighing > 100 kg.
  • serum trough concentration refers to the lowest concentration at which the agent (e.g, the anti-C5 antibody or antigen binding fragment thereof) or medicine is present in serum.
  • a “peak serum level” refers to the highest concentration of the agent in serum.
  • the “average serum concentration” refers to the mean concentration of the agent in serum over time.
  • the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 150 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 200 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 250 pg/mL or greater.
  • the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 300 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 350 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 400 pg/mL or greater.
  • the treatment regimens described are sufficient to maintain particular serum trough concentrations of the anti-C5 antibody or antigen binding fragment thereof.
  • the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof, of 50, 55, 60, 65,
  • the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of between 100 pg/mL and 200 pg/mL, 200 pg/mL and 300 pg/mL, or 300 pg/mL and 400 pg/mL.
  • the treatment described herein reduces free C5 concentration by greater than 90% throughout the treatment period. In some embodiments, the treatment described herein reduces free C5 concentration by greater than 95% throughout the treatment period. In some embodiments, the treatment described herein reduces free C5 concentration by greater than 99% throughout the treatment period. In some embodiments, the treatment reduces free C5 concentration greater than 99.5% throughout the treatment period.
  • antibody describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or CDR).
  • Antibodies include known forms of antibodies.
  • the antibody can be, for example, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody or a camelid antibody.
  • the antibody also can be a Fab, Fab’2, scFv, SMIP, Affibody ® , nanobody or a single domain antibody.
  • the antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, and IgE, and hybrid isotypes, e.g., IgG2/4.
  • the antibody may be a naturally occurring antibody or may be an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to anon-antibody moiety).
  • An antibody may include, for example one or more variant amino acids (compared to a naturally occurring antibody), which changes a property (e.g., a functional property) of the antibody. Numerous such alterations are known in the art that affect, e.g., half-life, effector function, and/or immune responses to the antibody in a patient.
  • the term antibody also includes artificial or engineered polypeptide constructs that comprise at least one antibody- derived antigen binding site.
  • anti-C5 antibodies described herein bind to complement component C5 (e.g., human complement C5) and inhibit the cleavage of C5 into fragments C5a and C5b.
  • complement component C5 e.g., human complement C5
  • Anti-C5 antibodies (or VH/VL domains or other antigen binding fragments derived therefrom) suitable for use herein can be generated using methods known in the art. Art-recognized anti- C5 antibodies can also be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 also can also be used.
  • Eculizumab (also known as Soliris ® ) is an anti-C5 antibody comprising heavy and light chains having sequences shown in SEQ ID NO: 10 and 11, respectively, or antigen binding fragments and variants thereof. Eculizumab is described in PCT/US2007/006606, the teachings of which are hereby incorporated by reference.
  • the anti-C5 antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of eculizumab having the sequence set forth in SEQ ID NO:7, and the CDR1, CDR2 and CDR3 domains of the VL region of eculizumab having the sequence set forth in SEQ ID NO: 8.
  • the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2 and 3, respectively, and light chain CDR1,
  • the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively.
  • Ravulizumab (also known as BNJ441, ALXN1210, or Ultomiris ® ) is an anti-C5 antibody comprising heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen binding fragments and variants thereof.
  • Ravulizumab is described in PCT/US2015/019225 and US Patent No. 9,079,949, the teachings of which are hereby incorporated by reference.
  • Ravulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation.
  • This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation (e.g ., C3 and C3b) essential for the opsonization of microorganisms and clearance of immune complexes.
  • MAC cytolytic pore-forming membrane attack complex
  • the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Accordingly, in some embodiments, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
  • Another exemplary anti-C5 antibody is antibody BNJ421 comprising heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively, or antigen binding fragments and variants thereof.
  • BNJ421 is described in PCT/US2015/019225 and US Patent No. 9,079,949, the entire teachings of which are hereby incorporated by reference.
  • the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Accordingly, in some embodiments, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
  • the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Rabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD] In such cases, the CDRs can be referred to as “Rabat CDRs” (e.g., “Rabat LCDR2” or “Rabat HCDR1”).
  • the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al.
  • these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”).
  • the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Rabat- Chothia combined definition.
  • these regions can be referred to as “combined Rabat-Chothia CDRs” (Thomas, T. et aI.,MoI. Immunol., 33:1389-401, 1996).
  • Another exemplary anti-C5 antibody is the 7086 antibody described in US Patent Nos. 8,241,628 and 8,883,158.
  • the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158).
  • the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 24, 25 and 26, respectively.
  • the antibody or antigen binding fragment thereof comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.
  • the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody.
  • the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 32, 33 and 34, respectively.
  • the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.
  • the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody.
  • the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively.
  • the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:43, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:44.
  • Another exemplary anti-C5 antibody is the SKY59 antibody (FukuzawaT. et al., Sci. Rep., 7:1080, 2017).
  • the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.
  • Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT/US2017/037226 and US2017/0355757A1.
  • the antibody comprises the heavy and light chain CDRs or variable regions of the H4H12166PP antibody.
  • the antibody or antigen binding fragment thereof comprises the VH region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO:47, and the VL region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO:48.
  • the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:49 and a light chain comprising SEQ ID NO: 50.
  • a patient is treated with eculizumab and then switched to treatment with the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody, the H4H12166PP antibody or ravulizumab.
  • the patient is switched from an anti-C5 antibody (e.g., eculizumab, the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody or the H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.
  • an anti-C5 antibody e.g., eculizumab, the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody or the H4H12166PP antibody
  • another anti-C5 antibody e.g., ravulizumab
  • an anti-C5 antibody described herein comprises a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19).
  • an anti-C5 antibody described herein comprises a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18).
  • an anti-C5 antibody described herein comprises a heavy chain variable region comprising the following amino acid sequence:
  • an anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:
  • An anti-C5 antibody described herein can, in some embodiments, comprise a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn) with greater affinity than that of the native human Fc constant region from which the variant human Fc constant region was derived.
  • the Fc constant region can comprise, for example, one or more (e.g., two, three, four, five, six, seven or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction.
  • substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn include, e.g., (1) the M252Y/S254T/T256E triple substitution (Dall’Acqua, W. etal., J. Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q/M428L substitutions (Hinton, P. et ak, J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et ak, J. Immunol., 176:346-56, 2006); and (3) N434A or T307/E380A/N434A substitutions (Petkova, S.
  • the variant constant region has a substitution at EU amino acid residue 255 for valine.
  • the variant constant region has a substitution at EU amino acid residue 309 for asparagine.
  • the variant constant region has a substitution at EU amino acid residue 312 for isoleucine.
  • the variant constant region has a substitution at EU amino acid residue 386.
  • the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions or deletions relative to the native constant region from which it was derived.
  • the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I and V308F.
  • the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434, each in EU numbering.
  • the variant Fc constant region comprises a428L/434S double substitution as described in, e.g., U.S. Patent No. 8,088,376.
  • the precise location of these mutations may be shifted from the native human Fc constant region position due to antibody engineering.
  • the 428L/434S double substitution when used in a IgG2/4 chimeric Fc may correspond to 429L and 435S as in the M429L and N435S variants found in BNJ441 (ravulizumab) and described in US Patent Number 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.
  • the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382,
  • the substitution is selected from the group consisting of: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, is
  • Suitable anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and/or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
  • the anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:20 and/or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
  • the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875,
  • KD affinity dissociation constant
  • the KD of the anti-C5 antibody or antigen binding fragment thereof is no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2) nM.
  • the [(KD of the antibody for C5 at pH 6.0 at 25°C)/(KD of the antibody for C5 at pH 7.4 at 25°C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150,
  • binding of an antibody to a protein antigen can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) method (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA) (see, e.g., Benny K. C.
  • SPR surface plasmon resonance
  • ELISA enzyme-linked immunosorbent assay
  • k a refers to the rate constant for association of an antibody to an antigen.
  • kd refers to the rate constant for dissociation of an antibody from the antibody/antigen complex.
  • the kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0, 6.5 and 6.0 via surface plasmon resonance (SPR) on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.
  • SPR surface plasmon resonance
  • Inhibition of human complement component C5 can reduce the cell-lysing ability of complement in a subject’s body fluids.
  • Such reductions of the cell-lysing ability of complement present in the body fluid(s) can be measured by methods known in the art such as, for example, by a conventional hemolytic assay such as the hemolysis assay described by Kabat and Mayer (eds.), “Experimental Immunochemistry, 2 nd Edition,” 135- 240, Springfield, IL, CC Thomas (1961), pages 135-139, or a conventional variation of that assay such as the chicken erythrocyte hemolysis method (Hillmen, P.
  • C5a and C5b concentration and/or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art.
  • concentration and/or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art.
  • hemolytic assays or assays for soluble C5b-9 as discussed herein can be used.
  • Other assays known in the art can also be used. Using these or other suitable assays, candidate agents capable of inhibiting human complement component C5 can be screened.
  • Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and/or its split products to determine the ability of an anti-C5 antibody or antigen binding fragment thereof to inhibit conversion of C5 into biologically active products.
  • C5a generation is measured.
  • C5b-9 neoepitope-specific antibodies are used to detect the formation of terminal complement.
  • Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody or antigen binding fragment thereof on complement activation.
  • an anti-C5 antibody or antigen binding fragment thereof on classical complement pathway-mediated hemolysis in a serum test solution in vitro, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibody are used as target cells.
  • the percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor.
  • the classical complement pathway is activated by a human IgM antibody, for example, as utilized in the Wieslab ® Classical Pathway Complement Kit (Wieslab ® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or antigen binding fragment thereof in the presence of a human IgM antibody. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.
  • the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide.
  • the percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor.
  • the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as utilized in the Wieslab ® Alternative Pathway Complement Kit (Wieslab ® COMPL AP330, Euro-Diagnostica, Sweden).
  • test serum is incubated with an anti-C5 antibody or antigen binding fragment thereof in the presence of lipopolysaccharide.
  • the amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength.
  • test serum is incubated in the absence of the anti-C5 antibody or antigen binding fragment thereof.
  • C5 activity, or inhibition thereof is quantified using a CH50eq assay.
  • the CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized erythrocytes as the activator of the classical complement pathway and various dilutions of the test serum to determine the amount required to give 50% lysis (CH50). The percent hemolysis can be determined, for example, using a spectrophotometer.
  • the CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since the TCC themselves are directly responsible for the hemolysis that is measured.
  • TCC terminal complement complex
  • undiluted serum samples e.g., reconstituted human serum samples
  • microassay wells containing the antibody-sensitized erythrocytes to thereby generate TCC.
  • the activated serum samples are diluted in microassay wells, which are coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC).
  • the TCC present in the activated samples bind to the monoclonal antibodies coating the surface of the microassay wells.
  • the wells are washed and to each well is added a detection reagent that is detectably labeled and recognizes the bound TCC.
  • the detectable label can be, e.g., a fluorescent label or an enzymatic label.
  • the assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq/mL).
  • Inhibition e.g., as it pertains to terminal complement activity, includes at least a 5 (e.g., at least a 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % decrease in the activity of terminal complement in, e.g., a hemolytic assay or CH50eq assay as compared to the effect of a control antibody (or antigen-binding fragment thereol) under similar conditions and at an equimolar concentration.
  • Substantial inhibition refers to inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 or greater) %.
  • an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:l-6), yet retains at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95) % of the complement inhibitory activity of eculizumab in a hemolytic assay or CH50eq assay.
  • An anti-C5 antibody described herein has a serum half-life in humans that is at least 20 (e.g., at least 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
  • the anti-C5 antibody described herein has a serum half-life in humans that is at least 40 days. In some embodiments, the anti-C5 antibody described herein has a serum half-life in humans that is approximately 43 days. In some embodiments, the anti-C5 antibody described herein has a serum half-life in humans that is between 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art.
  • an anti-C5 antibody or antigen binding fragment thereof described herein has a serum half-life that is at least 20 (e.g, at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500) % greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., the C5- deficient/NOD/scid mouse or hFcRn transgenic mouse model system).
  • the antibody competes for binding with, and/or binds to the same epitope on C5 as an antibody described herein.
  • the term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method.
  • Techniques for determining whether antibodies bind to the “same epitope on C5” with the antibodies described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigen: antibody complexes that provides atomic resolution of the epitope and hydrogen/deuterium exchange mass spectrometry (HDX-MS).
  • Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In some embodiments, an antibody competes with and inhibits binding of another antibody to a target by at least 10%, 20%,
  • Competing antibodies can bind, for example, to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).
  • Anti-C5 antibodies or antigen-binding fragments thereof described herein, used in the methods described herein, can be generated using a variety of art-recognized techniques. Monoclonal antibodies may be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art.
  • Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host.
  • compositions comprising ravulizumab, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers are provided.
  • the pharmaceutical compositions comprising ravulizumab provided herein are for use in, for example, diagnosing, detecting or monitoring a disorder, in preventing, treating, managing or ameliorating a disorder or one or more symptoms thereof, and/or in research.
  • Formulations of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are known in the art.
  • compositions comprising an anti-C5 antibody or antigen binding fragment thereof for use in the treatment methods described herein, wherein a patient is switched from one anti-C5 antibody (e.g., eculizumab) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.
  • the composition can be formulated as a pharmaceutical solution, e.g., for administration to a subject for the treatment or prevention of ALS.
  • the pharmaceutical composition can include a pharmaceutically acceptable carrier.
  • a “pharmaceutically acceptable carrier” refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the composition can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.
  • composition can be formulated according to known methods (Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20 th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7 th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3 rd Edition (ISBN: 091733096X)).
  • a composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8°C (e.g., 4°C).
  • a composition can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C).
  • the composition can be formulated for storage for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1 1 ⁇ 2 years or 2 years) at 2-8°C (e.g., 4°C).
  • the compositions described herein are stable in storage for at least 1 year at 2- 8°C (e.g, 4°C).
  • compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories.
  • liquid solutions e.g., injectable and infusible solutions
  • dispersions or suspensions tablets, pills, powders, liposomes and suppositories.
  • the preferred form depends, in part, on the intended mode of administration and therapeutic application.
  • Compositions containing a composition intended for systemic or local delivery can, for example, be in the form of injectable or infusible solutions.
  • the compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection).
  • Parenteral administration refers to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrastemal injection and infusion.
  • the antibodies are formulated for intravenous administration.
  • An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibodies such as eculizumab, BNJ 421, 7086,
  • dosage 8110, SKY59 and H4H12166PP provided herein is 600-5000 mg, for example, 2000-4000 mg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed methods.
  • An anti-C5 antibody provided herein also can be administered with one or more additional medicaments or therapeutic agents useful in the treatment of ALS.
  • the additional agent can be, for example, a therapeutic agent art-recognized as being useful to treat ALS.
  • the combination can also include more than one additional agents, e.g., two or three additional agents.
  • the binding agent in various embodiments is administered with an agent that is a protein, a peptide, a carbohydrate, a drug, a small molecule, or a genetic material (e.g., DNA or RNA).
  • complement-associated disorder(s) e.g., ALS
  • methods for treating complement-associated disorder(s) comprising administering to the patient an anti-C5 antibody or antigen binding fragment thereof wherein the anti-C5 antibody or antigen binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).
  • ALS is defined in a subject or patient in accordance with the King’s ALS clinical staging system (Roche, J.C. etal., Brain, 135(Part 3):847-852, 2012).
  • the King’s ALS system categorizes the extent to which ALS has progressed in a patient or subject based upon the occurrence of discrete milestones, defined as the first occurrence of ALS symptoms (e.g., functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb, or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, and a need for gastrostomy and non-invasive ventilation.
  • ALS symptoms e.g., functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb, or diaphragmatic
  • the King’s system classifies ALS progress according to four stages: Stage 1 - symptom onset with involvement of a first region; Stage 2 A - diagnosis; Stage 2B - involvement of second region; Stage 3 - involvement of third region; Stage 4A - need for gastrostomy; and Stage 4B - need for non-invasive ventilation.
  • ALS is defined in a subject or patient as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria, as described in FIG. 2.
  • the subject or patient is diagnosed with ALS onset, defined as the time of onset of first muscle weakness (e.g., limb weakness, dysarthria, dysphagia, and/or shortness of breath), no more than 36 months prior to being evaluated for treatment with the anti-C5 antibody or antigen binding fragment thereof.
  • the subject or patient has an ALSFRS-R progression of 0.3 points per month or worse in the period from disease onset to the time of evaluation for treatment with the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, the subject or patient has an upright slow vital capacity (SVC) of at least 65% at the time of evaluation for treatment with the anti-C5 antibody or antigen binding fragment thereof.
  • SVC slow vital capacity
  • the anti-C5 antibody or antigen binding fragment thereof is administered once on Day 1 of the administration cycle, once on Day 15 of the administration cycle, and every eight weeks thereafter. In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered every eight weeks after the administration cycle for an extension period up to two years (e.g., at a dose of 3000 mg, 3300 mg or 3600 mg).
  • the anti-C5 antibody or antigen binding fragment thereof is administered for one or more administration cycles. In some embodiments, the administration cycle is 50 weeks. In some embodiments, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In some embodiments, the treatment is continued for the lifetime of the human patient.
  • a patient switches from receiving one C5 inhibitor to a different C5 inhibitor during the course of treatment.
  • Different anti-C5 antibodies can be administered during separate treatment periods.
  • a method of treating a human patient having a complement-associated disorder (e.g., ALS) who is being treated with eculizumab is provided, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor.
  • a method of treating a human patient having a complement- associated disorder who is being treated with ravulizumab is provided, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.
  • Exemplary alternative complement inhibitors include, but are not limited to antibodies or antigen binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNA and aptamers.
  • the alternative complement inhibitor inhibits one or more of complement components Cl, C2, C3, C4, C5, C6, C7, C8, C9, Factor D, Factor B, properdin, MBL, MASP-1, MASP-2, or biologically active fragments thereof.
  • the alternative complement inhibitor inhibits the anaphylatoxic activity associated with C5a and/or the assembly of the membrane attack complex associated with C5b.
  • the alternative complement inhibitor is selected from the group consisting of CR1, LEX-CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, complestatin and K76 COOH.
  • Exemplary alternative anti-C5 antibodies included, but are not limited to, (i) eculizumab, (ii), an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 24, 25 and 26, respectively, (iii) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO:27 and a light chain variable region comprising SEQ ID NO:28, (iv) an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 32, 33 and 34, respectively, (v) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO:35 and a light chain variable region comprising SEQ
  • the patient is treated with ravulizumab and then switched to treatment with the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody, the H4H12166PP antibody or eculizumab.
  • the patient is switched from an anti-C5 antibody (e.g., eculizumab, the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody or the H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.
  • the patient is switched from eculizumab to ravulizumab during the course of treatment.
  • the anti-C5 antibody is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular dose amount and/or according to a specific dosing schedule).
  • the anti-C5 antibody is administered at a fixed dose that is fixed irrespective of the weight of the patient.
  • the terms “fixed dose,” “flat dose” and “flat-fixed dose” are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient.
  • the fixed or flat dose is therefore, not provided as a mg/kg dose, but rather as an absolute amount of the anti-C5 antibody or antigen binding fragment thereof.
  • the anti-C5 antibody is administered at a fixed dose of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,
  • the dose of the anti-C5 antibody is based on the weight of the patient. In some embodiments, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg,
  • the anti-C5 antibody is administered at a milligram per kilogram (mg/kg) dose. In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered at a dose of 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg,
  • the anti-C5 antibody 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 some embodiments, the anti-C5 antibody is administered twice daily. In some embodiments, the anti-C5 antibody 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 some embodiments, the anti-C5 antibody is administered at a loading dose on Day 1, followed by a different maintenance dose on Day 15 and every eight weeks thereafter.
  • 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 some embodiments, 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 some embodiments, patients treated according to the methods described herein are vaccinated against meningococcal serotypes A, C, Y, W135, and/or B.
  • treatment of ALS includes the amelioration or improvement of one or more symptoms associated with ALS.
  • Symptoms associated with ALS include a progressive loss of motor neurons leading to variable amounts of weakness and spasticity in the limb, bulbar, and respiratory muscles.
  • treatment of ALS includes an improvement of a clinical marker for ALS progression.
  • clinical markers for ALS progression include:
  • VAFS Ventilation Assistance-Free Survival
  • TQM Treatment Satisfaction Questionnaire for Medication
  • C-SSRS Columbia-suicide severity rating scale
  • ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised
  • the ALSFRS-Revised (Cedarbaum, 1999) is a validated instrument for evaluating the levels of the functional status of patients with ALS in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions (FIG. 3).
  • the scale includes 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicates greater retention of function.
  • the ALSFRS-R will be assessed as indicated in the Schedule of Activities. The endpoint for this primary measurement of efficacy is change from baseline in ALSFRS-R total score at Week 50.
  • VAFS Ventilation Assistance-Free Survival
  • Ventilation Assistance-Free Survival is a composite endpoint of survival and severe and irreversible respiratory decline.
  • the use of VAFS allows for the collection of survival data that is not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which can prolong life without impacting underlying disease progression.
  • the composite endpoint of VAFS (Paganoni, 2014) that will be used as a secondary endpoint for this trial will be defined as the first occurrence of: all-cause mortality; first use of NIV for > 22 hours per day for > 10 consecutive days; or first use of PAV for > 22 hours per day for > 7 consecutive days.
  • Slow vital capacity is a spirometry technique that utilizes slow and gradual expulsion of air from the lungs.
  • the full volume of expired air is measured as a proportion of the expected vital capacity of the patient based on biometric features such as height, weight, and sex.
  • the endpoint for this secondary measurement of efficacy is change from baseline in percent (%) predicted SVC at Week 50.
  • Handheld dynamometry (Shefner, 2016) is a procedure for quantitative strength testing. Muscle strength testing will be performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements recorded. Handheld dynamometry will be assessed at screening and time points specified in the Schedule of Activities. The endpoint for this secondary measurement of efficacy is percent change in combined muscle megascore from baseline at Week 50 as assessed by HHD.
  • a single index score is created by adding all of the responses (0, 1, 2, 3, or 4) of 40 items of ALSAQ-40, dividing this total score by the maximal score of 160 and finally multiplying by 100 (FIG. 4).
  • An index score of 0 indicates perfect health and 100 indicates worst possible health status.
  • the treatment effect on ALSAQ-40 index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline ALSAQ-40 index score, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
  • the Kenward Rogers method will be used to estimate the denominator degrees of freedom.
  • the European Quality of Life (EQ-5D-5L) is a self-assessed, standardized instrument to measure health-related quality of life and has been used in a wide range of health conditions, including ALS (Schrag, 2000).
  • the EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) (FIG. 5 and FIG. 6).
  • EQ-5D-5L descriptive system is a 5-component scale including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.
  • the EQ-5D-5L Visual Analog Scale is an overall health state scale where the patient selects a number between 0 and 100 to describe the condition of their health, with 100 being ‘The best health state you can imagine’ and 0 being ‘The worst health state you can imagine’. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Previously published studies by EuroQol Group members showed preliminary evidence of the instrument’s feasibility, reliability, and validity. The endpoint for this exploratory measurement of efficacy is change from baseline in EQ 5D 5L at Week 50.
  • the SF-36 is a 36-item self-report of health-related quality of life (Stewart, 1988; Ware, 1992). It contains 8 subscales measuring different domains of health-related quality of life: 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 (FIG. 7 and FIG. 8).
  • the SF-36 will be conducted at screening and at timepoints specified per Schedule of Activities.
  • the two (2) summary scores are the physical component summary and the mental component summary. There is no single overall score for the SF-36.
  • the endpoint for this exploratory measurement of efficacy is change from baseline in SF-36 at Week 50
  • TQM Treatment Satisfaction Questionnaire for Medication
  • the Treatment Satisfaction Questionnaire for Medication assesses 3 key dimensions of treatment satisfaction: Effectiveness (3 items); Convenience (3 items); and Global Satisfaction (3 items) (Bharmal, 2009) (FIG. 9).
  • Effectiveness 3 items
  • Convenience 3 items
  • Global Satisfaction 3 items
  • the instrument has been validated in chronic diseases including ALS (Meyer, 2019).
  • the recall period for the TSQM is the previous 2 to 3 weeks or since last use.
  • the TSQM-9 can be used to estimate total TSQM score, score for effectiveness, and score for convenience.
  • the TSQM-9 will be administered at Day 1 and at timepoints specified in the Schedule of Activities.
  • C-SSRS Columbia-Suicide Severity Rating Scale
  • C-SSRS Columbia-suicide severity rating scale
  • the course of treatment with ravulizumab lasts for 50 weeks.
  • the course of treatment lasts for 50-76, 50- 102, 50-128, 50-154, 50-180, 50-206 weeks, or more.
  • the course of treatment lasts for 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 102, 128, 154, 180, or 206 weeks, or more.
  • the maintenance phase lasts for greater than 1, 2, 3, 4, 5, 10, 15, 20,
  • the maintenance phase lasts for the remainder of the subject's life.
  • one or more symptoms or scores associated with ALS improves during the course of treatment and is maintained at the improved level throughout treatment.
  • ALS can improve, for example, after 50 weeks of treatment with a therapeutic antibody that specifically binds C5 and then remain at the improved level for the remaining duration of the treatment with a therapeutic antibody that specifically binds C5.
  • a therapeutic antibody that binds C5 is ravulizumab.
  • the first sign of improvement occurs by 50 weeks of treatment with a therapeutic antibody that specifically binds C5. According to some embodiments, the first sign of improvement occurs between weeks 50-76, 76-102, 102- 128, 128-154, 154-180, 180-206 weeks of treatment with a therapeutic antibody that specifically binds C5. In some embodiments, the first sign of improvement occurs at week
  • kits that include a pharmaceutical composition containing an anti-C5 antibody or antigen binding fragment thereof, such as ravulizumab, 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 ALS.
  • 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 anti-C5 antibody or antigen binding fragment thereof 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 anti-C5 antibody or antigen binding fragment thereof.
  • EXAMPLE 1 A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RAVULIZUMAB IN ADULT PATIENTS WITH ALS.
  • This study is a Phase 3, double-blind, randomized, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of ravulizumab in adult patients with ALS. There are 3 periods in this study: Screening Period, Randomized Controlled Period, and Open Label Extension Period. A schematic of the study design is shown in FIG. 1.
  • Patients will be screened for eligibility for up to 4 weeks during the Screening Period. Approximately 354 eligible adult patients with ALS from North America, Europe, and the Asia Pacific region will be enrolled into the study. Patients who are not taking or who are on a stable regimen of riluzole and/or edaravone at Screening will be considered for participation.
  • Eligible patients will be randomized in a 2: 1 ratio to receive weight-based intravenous (IV) infusion of ravulizumab or matching placebo until Week 50 during the double blind Randomized Controlled Period. Randomization will be stratified based on the site of ALS muscle weakness onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS therapy) (Table 10). The Schedule of Activities for the Screening Period to Week 50 is shown in Table 1 below.
  • the Randomized Controlled Period ends and the Open Label Extension Period starts when the patient has completed the Week 50 visit assessments. Regardless of prior treatment allocation, all patients will receive ravulizumab treatment during the Open Label Extension Period. The Open Label Extension Period will continue for up to 2 years, or until ravulizumab is approved and/or available (in accordance with country specific regulations), whichever occurs first.
  • the Schedule of Activities for Week 50 to Week 116 is shown in Table 2 below. After the end of treatment visit or early discontinuation, patients will be followed for an additional 8 weeks after the last dose of study drug. Treatment allocation will be blinded to patients, study sites, and the Sponsor throughout the Randomized Controlled Period and will remain blinded to patients and study sites until end of the study.
  • the Schedule of Activities for Week 124 to the End of Study is shown in Table 3 below.
  • Table 1 Schedule of Activities: Screening to Week 50
  • Table 1 Schedule of Activities: Screening to Week 50 (Continued)
  • Table 1 Schedule of Activities: Screening to Week 50 (Continued)
  • Table 1 Schedule of Activities: Screening to Week 50 (Continued)
  • ADA antidrug antibody
  • AE adverse event
  • ALSAQ-40 amyotrophic lateral sclerosis assessment questionnaire
  • ALSFRS-R amyotrophic lateral sclerosis functional rating scale-revised
  • CBC complete blood count
  • CSF cerebrospinal fluid
  • C-SSRS Columbia-suicide severity rating scale
  • ECG electrocardiogram
  • ED early discontinuation
  • EQ-5D-5L European Quality of Life Health 5-item questionnaire
  • HHD handheld dynamometry
  • KSS King’s staging system;
  • PK pharmacokinetics
  • RCP Randomized Controlled Period
  • SF-36 short form health survey
  • SVC slow vital capacity
  • TSQM Treatment Satisfaction Questionnaire for Medication
  • W week
  • WOCBP women of childbearing potential.
  • c Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be more than 16 weeks apart. d Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study. When possible, ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HHD should be performed as last assessment prior to dosing. e At the time points specified, or if a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee.
  • H can be performed in clinic, by home visit, or by telephone contact. When performed by telephone, the telephone interview version of the questionnaire should be used, if available. g Most recent CBC and coagulation panel should be reviewed prior to CSF sample collection. Lumbar punctures must be performed after all assessments are completed.
  • Table 2 Schedule of Activities: Week 50 to Week 116
  • Table 2 Schedule of Activities: Week 50 to Week 116 (Continued)
  • ADA antidrug antibody
  • AE adverse event
  • ALSFRS-R revised amyotrophic lateral sclerosis functional rating scale
  • C5 complement component 5
  • C- SSRS Columbia-suicide severity rating scale
  • D day
  • ECG electrocardiogram
  • ED early discontinuation
  • EQ-5D-5L European Quality of Life Health 5-item questionnaire
  • HHD handheld dynamometry
  • PK pharmacokinetics
  • SF-36 short form health survey
  • SVC slow vital capacity
  • W week
  • WOCBP women of childbearing potential.
  • a Ravulizumab dosing is based on the last recorded study visit body weight.
  • weights should be obtained at every dosing visit; consecutive weights must not be more than 16 weeks apart.
  • b Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study. When possible, ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HHD should be performed as last assessment prior to dosing.
  • c If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee. d If this is an ED visit, no dose of study drug is given.
  • Table 3 Schedule of Activities: Week 124 to End of Study
  • Table 3 Schedule of Activities: Week 124 to End of Study (Continued)
  • ADA antidrug antibody
  • AE adverse event
  • ALSFRS-R revised amyotrophic lateral sclerosis functional rating scale
  • C5 complement component 5;
  • C-SSRS Columbia-suicide severity rating scale
  • D day
  • ECG electrocardiogram
  • ED early discontinuation
  • EOS end of study
  • EQ-5D-5L European Quality of Life Health 5-item questionnaire
  • OLE Open-Label Extension
  • PK pharmacokinetics
  • SF-36 short form health survey
  • SVC slow vital capacity
  • TSQM Treatment Satisfaction Questionnaire for Medication
  • W week
  • WOCBP women of childbearing potential.
  • a Follow-up Phone Call will be performed 8 weeks (56 days) ⁇ 5 days following the patient’s last dose of study drug to collect concomitant medications, nonpharmacological therapies and procedures, and AEs.
  • b Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study.
  • ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HF1D should be performed last c If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee.
  • Two interim analyses are planned for the Randomized Controlled Period.
  • An independent data monitoring committee (IDMC) will be established to conduct the unblinded interim analyses and periodic review of accumulating data for patient safety and efficacy during the trial.
  • the first interim analysis for futility will be conducted when approximately 33% of patients have completed the Week 26 (6 months) visit.
  • the second interim analysis will be performed when approximately all patients have completed the Week 26 visit.
  • a futility analysis will be conducted. If the study is not considered futile, an additional analysis will be performed to determine if success criteria are met. If the efficacy analysis meets prespecified criteria for success, the Randomized Controlled Period may be stopped for success and all patients may transition to the Open-Label Extension Period.
  • any patient who is still in the Randomized Controlled Period will transition to the Open-Label Extension Period at their next scheduled dosing visit. Regardless of previous visit number, when the patient returns for the next scheduled dosing visit, the patient will follow the procedures outlined in Visit 13 in the Schedule of Activities and continue all subsequent visits as outlined to the End of Study Visit. For patients who are in the Open-Label Extension Period when the Randomized Controlled Period is stopped for success, there will be no change to the visit schedule.
  • ravulizumab Based on clinical trial experience and cumulative clinical trial safety data of ravulizumab in PNH and aHUS, ravulizumab has been demonstrated to be well tolerated and safe, and exposure to ravulizumab in humans has not raised any unexpected safety concerns.
  • Ravulizumab functions by blocking terminal complement; therefore, patients have increased susceptibility to serious infections, in particular Neisseria meningitidis (Table 4).
  • Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a poor prognosis, rapid progression, and limited treatment options for which discovery of new therapies is important to address unmet medical need.
  • Clinical research provides the best modality to identify effective treatments with the potential to slow disease progression and improve survival which are of critical importance to patients with ALS and their providers.
  • ravulizumab has not been previously studied in patients with ALS, it represents an appropriate candidate for investigation due to its plausible mechanism of action in ALS and reliable pharmacokinetic (PK) and pharmacodynamic (PD) properties as well as the demonstrable functional benefit of complement inhibition in ALS animal models and in the treatment of other neuroinflammatory conditions.
  • PK pharmacokinetic
  • PD pharmacodynamic
  • Neuroinflammation and complement dysregulation are hypothesized to be common pathways in both sporadic and familial ALS. Complement dysregulation may be important to disease progression both early and throughout the course of disease, and thus a broad study population is targeted.
  • the eligible study population fulfils the El Escorial diagnostic criteria of possible, probable, probable laboratory supported, or definite ALS, is within 36 months or less from disease onset, and demonstrates a SVC of 65% predicted or more and not yet requiring respiratory support.
  • ALSFRS-R amyotrophic lateral sclerosis functional rating scale revised
  • a randomized, double-blind, placebo-controlled study design is selected to provide the most robust evidence of the effectiveness of the intervention on disease progression and safety. Randomization minimizes the effects of baseline differences and confounding factors on the study population.
  • the use of a placebo comparator allows for the true treatment effect of the intervention to be established while also allowing for study management, drug administration, and assessments to be conducted similarly between treatment groups, thus minimizing the potential for bias.
  • An unequal randomization scheme was chosen to decrease the number of patients receiving placebo. Patients may continue to receive standard of care treatment for ALS, which may include riluzole and/or edaravone as detailed in the inclusion/exclusion criteria. To reduce the heterogeneity in the study results, a stratification scheme has been implemented. This stratification includes the use of background therapies which are permitted, but not mandated, in accordance with ethical standards.
  • a 50-week primary evaluation period was selected to ensure characterization of effects on multiple functional and survival endpoints. This timeframe allows for a rigorous assessment of ALSFRS R in which potential differences can both be detected and characterized for magnitude and durability of response.
  • the 50 week treatment period also allows the opportunity to characterize potential treatment effects on other important endpoints, such as survival, which may take longer to demonstrate than the ALSFRS-R.
  • a trial design with interim analyses was chosen to allow for early stopping in the case of futility or efficacy.
  • the interim analyses minimize exposing patients to an ineffective therapy or prolonged exposure to placebo in the event of detecting efficacy earlier.
  • An open-label extension period was chosen to ensure that all patients participating in this study have the opportunity to receive active treatment after the completion of the Randomized Controlled Period of the study. This period also allows for further evaluation of longer term safety and efficacy of the study intervention.
  • the ALSFRS-R is a validated instrument and the most widely used instrument to measure physical function in performance of daily living activities across the 4 domains of gross motor activity, fine motor activity, bulbar, and respiratory function in patients with ALS (Cedarbaum, 1999).
  • the scale is composed of 12 items with a maximum score of 48, with lower scores associated with declining function. Changes in ALSFRS R total score have been shown to be reproducible over time and to correlate with survival and other functional measures. It is considered an important efficacy endpoint in clinical trials and clinical practices (Castrillo- Viguera, 2010).
  • VAFS Ventilation Assistance-Free Survival
  • VAFS a composite endpoint accounting for survival and severe respiratory failure. In the absence of uniform guidelines for the initiation of NIV and PAV, this endpoint is defined around dependence based on the continuous or nearly continuous need for ventilation assistance. Therefore, VAFS is defined for this study as the time to the earliest occurrence of one of the following events: all-cause mortality; first use of NIV for > 22 hours per day for > 10 consecutive days; or first use of PAV for > 22 hours per day for > 7 consecutive days.
  • Slow vital capacity is defined as the amount of air expelled from the lungs during a slow, gentle breath, which has been shown to correlate with clinical events such as use of assisted ventilation, tracheostomy, and ultimately, death. Patients with slower decline in SVC could breathe unassisted and survive longer than patients whose SVC declined faster (Andrews, 2018).
  • SVC may be easier to measure in ALS patients as patients with loss of muscle function in the face and mouth are still able to perform the gentler test and it is less subject to the fatigue and bronchospasm that can underestimate lung capacity measured by FVC.
  • Slow vital capacity is considered as a prognostic marker in the clinic and may predict disease progression, respiratory functional decline, and survival.
  • the dosing regimen of ravulizumab was designed to target immediate, complete, and sustained inhibition of terminal complement in patients.
  • the weight-based doses of ravulizumab in the PNH program were based on PK/PD data from early and late clinical development studies in healthy adult volunteers and patients with PNH.
  • the proposed ravulizumab dosage regimen is the approved regimen for the treatment of patients with PNH and aHUS in the Ultomiris USPI, and the same dose regimen is also approved by the European Commission in the EU and the Pharmaceuticals and Medical Devices Agency in Japan for the treatment of PNH.
  • ALS ALS patients and preclinical models, dysregulation of the complement system has been identified prior to the onset of neurodegeneration. Inhibition of terminal complement may therefore diminish neuroinflammatory damage in ALS.
  • the body weight- based dosage regimen for treating adult patients with PNH and aHUS has been selected for this study, and is expected to be beneficial in treating patients with ALS through immediate, complete and sustained inhibition of terminal complement activation.
  • a patient is considered to have completed the study if he/she has completed all phases of the study including the last scheduled procedure shown in the Schedule of Activities.
  • the end of the study is defined as the date the last patient completes the last visit shown in the Schedule of Activities.
  • the primary objective of the study is to evaluate the effect of ravulizumab compared with placebo on ALSFRS-R score in adult patients with ALS.
  • the secondary objectives of this study are: (1) evaluate the effect of ravulizumab compared with placebo on VAFS in adult patients with ALS; (2) to evaluate the effect of ravulizumab compared with placebo on respiratory function in adult patients with ALS; (3) to evaluate the safety of ravulizumab compared with placebo in adult patients with ALS; (4) evaluate the effect of ravulizumab compared with placebo on muscle strength in adult patients with ALS; (5) to evaluate the effect of ravulizumab compared with placebo on neurofilament light chain (NfL) concentrations in adult patients with ALS; (6) to characterize the PK of ravulizumab in adult patients with ALS; (6) to characterize the D of ravulizumab in adult patients with ALS; and (7) to characterize the immunogenicity of ravulizumab in adult patients with ALS.
  • NfL neurofilament light chain
  • Exploratory objectives of this study are: (1) to evaluate the effect of ravulizumab compared with placebo on respiratory function in adult patients with ALS; (2) to evaluate the effect of ravulizumab compared with placebo on overall health related quality of life in adult patients with ALS; (3) to evaluate the safety of ravulizumab compared with placebo in adult patients with ALS; (4) to characterize biomarkers in adult patients with ALS; (5) to evaluate the effect of ravulizumab compared with placebo on ALS-related health quality of life in adult patients with ALS; (5) to characterize the effect of ravulizumab compared to placebo on disease stage in adult patients with ALS; (6) to evaluate the long-term efficacy of ravulizumab in adult patients with ALS; and (7) to evaluate the long-term safety of ravulizumab in adult patients with ALS.
  • the primary efficacy endpoint of the study is change from baseline in ALSFRS-R total score at Week 50.
  • Secondary efficacy endpoints of the study include: (1) time to the earliest occurrence of 1 of the following events during the 50-week Randomized Controlled Period: (a) all-cause mortality; (b) first use of NIV for > 22 hours per day for > 10 consecutive days; and (c) first use of PAV for > 22 hours per day for > 7 consecutive days; (2) change from baseline in percent (%) predicted SVC at Week 50; (3) incidence of TEAEs, TESAEs, and TEAEs leading to study drug discontinuation; (4) percent change in combined muscle megascore from baseline at Week 50 as assessed by HHD; (5) change from baseline in NfL concentrations in serum at Week 50; (6) change in serum ravulizumab concentration over the study duration; (7) change in serum free C5 concentration over the study duration; and (8) presence and titer of antidrug antibodies (AD As).
  • the exploratory endpoints of this study are: (1) time to first instance of SVC ⁇ 50% predicted during the 50-week Randomized Controlled Period; (2) change from baseline in SF-36 at Week 50; (3) change from baseline in EQ 5D 5L at Week 50; (4) shifts from baseline in C- SSRS at Week 50; (5) change from baseline in vital signs, ECG parameters, and clinical laboratory assessments; (6) change from baseline in levels of biomarkers of complement dysregulation, neuroinflammation and neurodegeneration; (7) change from baseline in ALSAQ- 40 score at Week 50; (8) any decline from baseline stage on the King’s staging system at Week 50; (9) change in ALSFRS-R total score, VAFS, SVC, HHD, and patient-reported outcome measures over time in all patients exposed to ravulizumab during the Open-Label Extension Period; and (10) incidence of TEAEs, TESAEs, and TEAEs leading to study drug discontinuation during the Open-Label Extension Period.
  • the objectives and endpoints of the study are
  • Type of Patient and Disease Characteristics A diagnosis of ALS, defined as meeting the possible, laboratory supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria. Patients diagnosed with either sporadic or familial ALS are eligible for enrollment.
  • ALS onset defined as time of onset of first muscle weakness (e.g ., limb weakness, dysarthria, dysphagia, shortness of breath), ⁇ 36 months from the Screening Visit.
  • Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
  • Male patients Male patients must agree to use contraception as detailed in the protocol during the treatment period and for at least 8 months after the last dose of study drug and refrain from donating sperm during this period.
  • a female patient is eligible to participate if she is not pregnant, not breastfeeding, and meets at least one of the following conditions:
  • the Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study drug.
  • a WOCBP must have a negative serum pregnancy test at Screening and a negative urine pregnancy test before the first dose of study drug.
  • the Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
  • HIV infection (evidenced by HIV-1 or HIV-2 antibody titer).
  • Dependence on invasive or non-invasive mechanical ventilation is defined as being unable to lie flat (supine) without it, unable to sleep without it, or daytime use > 6 hours per day for > 3 days per week.
  • Non- invasive ventilation for sleep apnea is allowed subject to discussion with Medical Monitor.
  • IV immunoglobulin IV immunoglobulin
  • DPS diaphragm pacing system
  • Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently randomly assigned to study drug.
  • a minimal set of screen failure information is required to ensure transparent reporting of screen failures to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities.
  • Minimal information includes demography, screen failure details (e.g ., failed eligibility criteria), and any adverse events (AEs), including any serious adverse events (SAEs) and any related concomitant medication, occurring during the screening period.
  • Study drug is defined as any investigational drug(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
  • IMP investigational medicinal product
  • IV intravenous
  • NIMP non-investigational medicinal product
  • q8w every 8 weeks.
  • study drug kits Upon arrival of the study drug at the study site, the study drug kits should be removed from the shipping container and stored in their original cartons under refrigerated conditions at 2°C to 8°C (35°F to 47°F) and protected from light. Study drugs should not be frozen. Study drugs must be stored in a secure, limited-access storage area with temperature monitored daily.
  • Infusions of study drug should be prepared using aseptic technique.
  • Ravulizumab and placebo will be further diluted in a 1:1 ratio with compatible diluent.
  • Ravulizumab and placebo will be filtered with a 0.2 micron filter during infusion.
  • the Investigator, institution, or the head of the medical institution is responsible for study drug accountability, reconciliation, and record maintenance (/. ., receipt, reconciliation, and final disposition records).
  • Patients will be randomly allocated on Day 1 to one of two treatment groups after the Investigator and Medical Monitor have verified that they are eligible. Patients will be stratified by site of muscle weakness onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS therapy) and randomized 2: 1 either to ravulizumab IV infusion or placebo IV infusion. Patients will be centrally randomized using Interactive Response Technology (IRT).
  • IRT Interactive Response Technology
  • patients in the placebo group will receive a blinded loading dose of ravulizumab, and patients in the ravulizumab group will receive a blinded ravulizumab dose of 900 mg.
  • all patients will begin open-label ravulizumab maintenance doses every 8 weeks (q8w).
  • a blinded ravulizumab dose of 900 mg was chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance dose at Week 52.
  • Blind to prior assignment will be maintained for patients and providers (study site) during the Open-Label Extension Period.
  • the Investigator has the sole responsibility for determining if unblinding of a patient’s intervention assignment is warranted. Patient 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 the sponsor prior to unblinding a patient’s intervention assignment unless this could delay emergency treatment of the patient. If a patient’s intervention assignment is unblinded, The Sponsor must be notified within 24 hours after breaking the blind. The date and reason that the blind was broken must be recorded in the source documentation and case report form (CRF), as applicable.
  • CRM source documentation and case report form
  • the infusion of study drug into patients will be under the supervision of the Investigator or their designee to ensure that patients receive the appropriate dose at the appropriate time points during the study.
  • the date and time of each dose administered in the clinic will be recorded in the source documents and CRF.
  • the dose of study drug and study patient identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study drug.
  • riluzole and edaravone There are 2 therapies currently available for treating ALS that may slow disease progression: riluzole and edaravone. Patients who are naive to ALS therapies or have not taken ALS therapies for at least 30 days before screening are allowed to enroll. For a patient who is on one or more ALS-specific therapies at Day 1 of the study, the patient must be on a stable dose regimen of riluzole for at least 30 days and/or on a stable treatment of edaravone for at least 60 days (2 treatment cycles) prior to Day 1 and has no plan to discontinue or change dose during the trial. Temporary discontinuations or dose modifications of riluzole or edaravone are acceptable at the discretion of the Investigator for medical reasons.
  • Vitamin B 12 vitamin E, creatine, coenzyme Q10, and biotin supplements are permitted in this study. Patients who take any or all of these supplements should be on a stable dose beginning 14 days prior to first dose of study drug and remain on a stable dose for the duration of the Randomized Controlled Period of the study unless alteration in dose is deemed medically necessary or reviewed with the Medical Monitor. All other vitamins and supplements are permitted on this study. Patients are encouraged to remain on stable dosing for the duration of the Randomized Controlled Period of the study.
  • PP/PE plasmapheresis/plasma exchange
  • Ravulizumab will not be provided to the patients after the last scheduled dosing. After the end of therapy visit or ED, all patients will be followed for an additional 8 weeks after the last dose of study drug.
  • study drug is permanently discontinued, the patient should complete the ED visit for safety follow-up before discontinuing from the study. See the Schedule of Activities for data to be collected at the time of discontinuation of study drug and follow-up and for any further evaluations that need to be completed.
  • an ED visit corresponding with the period of the study the patient is in should be conducted.
  • the ED visit should be conducted as soon as possible, and no later than 8 weeks after the last dose of study drug, as shown in the Schedule of Activities.
  • a follow-up phone call will be performed at 8 weeks (56 days) ⁇ 5 days following the patient’s last dose of study drug to collect concomitant medications, non- pharmacologic therapies and procedures, and AEs. This phone call can be omitted if it falls within 5 days of the ED visit.
  • the patient will be permanently discontinued both from the study drug and from the study at that time.
  • the patient will be instructed to see his or her local neurologist or physician.
  • the Investigator or designee will contact the local neurologist or physician to obtain as much information as possible about the patient’s medical and neurological condition, and provide clinical guidance, if needed.
  • the study site will obtain relevant medical records as documentation from the local physician’s examination and enter relevant data in the eCRF as appropriate.
  • a patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.
  • the site must attempt to contact the patient and reschedule the missed visit as soon as possible and counsel the patient on the importance of maintaining the assigned visit schedule and ascertain whether or not the patient wishes to and/or should continue in the study.
  • the Principal Investigator or Sub-Investigator will review the patient’s medical history including ALS history and diagnosis. The following will be evaluated and documented at the Screening Visit and/or other visits as specified in the Schedule of Activities:
  • Time of ALS onset (defined as time of onset of first muscle weakness symptom date).
  • Criteria for ALS diagnosis defined as meeting the clinically possible, laboratory supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria (Brooks, 2000).
  • ALS stage will be evaluated using King’s staging system (KSS) (Balendra, 2019) by the Investigator or trained designee. Stage will be assigned based on the number of involved CNS regions and nutritional and respiratory status.
  • KSS King’s staging system
  • ravulizumab increases the patient’s susceptibility to meningococcal infection (N. meningitidis).
  • meningococcal infection N. meningitidis
  • all patients must be vaccinated against meningococcal infections within the 3 years before or at the time of initiating study drug.
  • Patients who initiate study drug less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics from the first day of study drug treatment until 2 weeks after vaccination. Patients must be vaccinated or revaccinated according to current national vaccination guidelines or local practice for vaccination use with complement inhibitors (e.g ., eculizumab, ravulizumab).
  • complement inhibitors e.g ., eculizumab, ravulizumab.
  • Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to prevent common pathogenic meningococcal serotypes. Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given according to official guidance and local practice on the appropriate use of antibacterial agents. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics, if necessary. Inclusion/Exclusion Criteria
  • study drug infusion should be performed after all other tests and procedures have been completed, excluding the post-dose blood sampling for PK and free C5.
  • the ravulizumab dose for each patient will be based on last recorded body weight.
  • the dosing regimen (Table 7) consists of a loading dose followed by maintenance dosing administered q8w. The maintenance dose should be initiated 2 weeks after the loading dose administration.
  • Table 7 Weight-based Doses of Ravulizumab a Dose regimen will be based on the last recorded study visit body weight.
  • b In the event that a patient drops below 40 kg during the course of the study the approved ravulizumab aHUS dosing for patients weighing 30 - 40 kg will be used: a loading dose of 1200 mg and maintenance dose of 2700 mg, and in the event that a patient drops below 30 kg during the course of the study the approved ravulizumab aHUS dosing for patients weighing 20 - 30 kg will be used: a loading dose of 900 mg and maintenance dose of 2100 mg.
  • aHUS atypical hemolytic uremic syndrome.
  • any patient who is still in the Randomized Controlled Period will transition to the Open-Label Extension Period at their next scheduled dosing visit. Regardless of previous visit number, when the patient returns for the next scheduled dosing visit, the patient will follow the procedures outlined in Visit 13 in the Schedule of Activities and continue all subsequent visits as outlined to the End of Study Visit. For patients who are in the Open-Label Extension Period when the Randomized Controlled Period is stopped for success, there will be no change to the visit schedule. For each patient, the entire treatment duration is up to 156 weeks, consisting of a
  • Randomized Controlled Period 50 weeks
  • Open Label Extension Period up to 106 weeks.
  • Study drug administration will end when all patients have completed the 2 year Open Label Extension Period, or ravulizumab is approved and/or available (in accordance with country specific regulations), or anytime during the Open Label Extension Period at the discretion of the Sponsor, whichever occurs first.
  • the Randomized Controlled Period is a double blind, randomized, placebo controlled period. Eligible patients will be randomized 2:1 to receive blinded doses of ravulizumab or placebo during the Randomized Controlled Period (Day 1 through Week 42). Patients in the ravulizumab group will receive a blinded loading dose of ravulizumab on Day 1, followed by a blinded maintenance dose on at Week 2 (Table 1), then once q8w up to Week 42 (inclusive) (Table 1). Patients in the placebo group will receive a blinded matching placebo dose via IV infusion on Day 1, followed by a blinded matching placebo maintenance dose at Week 2, then q8w up to Week 42 (inclusive).
  • ALSFRS-R Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised
  • the ALSFRS-Revised (Cedarbaum, 1999) is a validated instrument for evaluating the levels of the functional status of patients with ALS in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions.
  • the scale includes 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicates greater retention of function.
  • the ALSFRS-R will be performed throughout the study by the Investigator or any designee who has been properly trained for the evaluation. When possible, it is highly recommended that all assessments be performed by the same assessor.
  • the ALSFRS-R will be assessed as indicated in the Schedule of Activities. At the time points specified in the Schedule of Activities, or if a patient is not able to attend the scheduled onsite visit, the ALSFRS R can be assessed via a phone call by the Investigator or trained designee.
  • VAFS Ventilation Assistance-Free Survival
  • VAFS Ventilation Assistance-Free Survival is a composite endpoint of survival and severe and irreversible respiratory decline.
  • the use of VAFS allows for the collection of survival data that is not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which can prolong life without impacting underlying disease progression.
  • the composite endpoint of VAFS (Paganoni, 2014) that will be used as a secondary endpoint for this trial will be defined as the first occurrence of:
  • Slow vital capacity is a spirometry technique that utilizes slow and gradual expulsion of air from the lungs.
  • the full volume of expired air is measured as a proportion of the expected vital capacity of the patient based on biometric features such as height, weight, and sex.
  • Slow vital capacity evaluation will be performed by the Investigator, or any designee who has been properly trained for the evaluation, at screening and time points specified in the Schedule of Activities. When possible, it is highly recommended that all assessments be performed by the same assessor.
  • Handheld dynamometry (Shefner, 2016) is a procedure for quantitative strength testing. This testing will be conducted by the Investigator or any designee who has been properly trained for the quantitative muscle strength evaluation. When possible, it is highly recommended that all assessments be performed by the same assessor. Muscle strength testing will be performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements recorded. Handheld dynamometry will be assessed at screening and time points specified in the Schedule of Activities.
  • the European Quality of Life (EQ-5D-5L) is a self-assessed, standardized instrument to measure health-related quality of life and has been used in a wide range of health conditions, including ALS (Schrag, 2000).
  • the EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS).
  • EQ-5D-5L can be assessed via a phone call.
  • the descriptive system is 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.
  • the EQ-5D-5L VAS is an overall health state scale where the patient selects a number between 0 and 100 to describe the condition of their health, with 100 being ‘The best health state you can imagine’ and 0 being ‘The worst health state you can imagine’.
  • the SF-36 is a 36-item self-report of health-related quality of life (Stewart, 1988; Ware, 1992). It contains 8 subscales measuring different domains of health-related quality of life: 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 SF-36 will be conducted at screening and at timepoints specified per Schedule of Activities.
  • the two (2) summary scores are the physical component summary and the mental component summary. There is no single overall score for the SF-36.
  • Treatment Satisfaction Questionnaire for Medication TQM
  • the Treatment Satisfaction Questionnaire for Medication assesses 3 key dimensions of treatment satisfaction: Effectiveness (3 items); Convenience (3 items); and Global Satisfaction (3 items) (Bharmal, 2009).
  • Effectiveness 3 items
  • Convenience 3 items
  • Global Satisfaction 3 items
  • the instrument has been validated in chronic diseases including ALS (Meyer, 2019).
  • the recall period for the TSQM is the previous 2 to 3 weeks or since last use.
  • the TSQM-9 can be used to estimate total TSQM score, score for effectiveness, and score for convenience.
  • the TSQM-9 will be administered at Day 1 and at timepoints specified in the Schedule of Activities.
  • the planned schedule for all safety assessments is provided in the Schedule of Activities.
  • a complete physical examination will include, at a minimum, assessments of the following organs/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, and musculoskeletal.
  • An abbreviated physical examination will include, at a minimum, a body-system relevant examination based upon Investigator judgment and patient symptoms. Examiners should pay special attention to clinical signs related to previous serious illnesses. For consistency, all efforts should be made to have the physical examination performed by the same qualified study staff at each study visit. Additional physical examinations can be performed as medically indicated during the study at the Investigator’s discretion.
  • a general neurologic examination will be performed by the Investigator, Sub- Investigator, or designee at the scheduled visits.
  • the general neurologic examination includes assessments of the following systems: mental status, cranial nerves, deep tendon reflexes, power/strength, sensation, muscle fasciculations, and muscle atrophy.
  • Body weight will be measured in pounds or kilograms. Height will be measured in inches or centimeters.
  • Oral temperature (°C or °F), pulse rate, respiratory rate, and systolic and diastolic blood pressure (mm Hg) will be assessed.
  • Blood pressure and pulse measurements will be assessed seated with a completely automated device. Manual techniques will be used only if an automated device is not available. Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the patient in a quiet setting without distractions ( e.g ., television, cell phones). Ideally, the same arm for each patient should be used for measurements.
  • ECG electrocardiogram
  • a Patient Safety Card Before the first dose of study drug, a Patient Safety Card will be provided to patients to carry with them at all times.
  • the card is provided to increase patient awareness of the risk of infections, especially meningococcal infection, and to promote quick recognition and disclosure of any potential signs or symptoms of infection experienced by patients during the course of the study and to inform patients on what actions must be taken if they are experiencing signs or symptoms of infection.
  • the study staff At each visit throughout the study, the study staff will ensure that the patient has the Patient Safety Card.
  • Prior medications and/or vaccines including vitamins, herbal preparations, and those discussed in the exclusion criteria
  • procedures any therapeutic drug, such as surgery /biopsy or physical therapy
  • any therapeutic drug such as surgery /biopsy or physical therapy
  • all medications or therapies ever used for treating ALS before the first dose of study drug must be collected.
  • Concomitant medications including any medication, vitamin, herbal preparation or supplement
  • procedures are those received on or after the first study treatment date (Day 1), including those started before Day 1 and continued after Day 1.
  • Day 1 the first study treatment date
  • patients should be questioned about any new medication or non-drug therapies or changes to concomitant medications and nondrug therapies since the last visit.
  • Concomitant medications and non-drug therapies should be recorded in the source documents and the patient’s eCRF.
  • Concomitant medications must be recorded in the patient’s source document/medical chart and eCRF along with:
  • ALS specific treatment including riluzole and edaravone must be collected. Meningococcal vaccination and antibiotics administered for prophylaxis of meningococcal infection (if applicable) will also be recorded.
  • any concomitant medication deemed necessary for the patient’s care during the study, or for the treatment of any AE, along with any other medications, other than those listed as disallowed medications, may be given at the discretion of the Investigator. However, it is the responsibility of the Investigator to ensure that details regarding all medications are recorded in full in the patient’s source document/medical chart and eCRF. The Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy.
  • Table 8 Protocol -Required Laboratory Assessments a FSH to be performed at Screening in selected female patients to confirm postmenopausal status. b Coagulation to be performed at Screening for all patients and at Week 28 and Week 42 for patients in CSF cohort. Additional tests may be performed at any time during the study as determined necessary by the Investigator or required by local regulations. Women of childbearing potential should only be enrolled after a negative serum pregnancy test. Additional urine pregnancy testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC and should be performed per the time points specified in the Schedule of Activities.
  • 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 which are not associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the patient's condition.
  • C-SSRS Columbia-suicide severity rating scale
  • Pregnancy testing must be performed on all WOCBP at protocol-specified time points in the Schedule of Activities. Pregnancy tests (urine or serum) may also be performed at any time during the study at the Investigator’s discretion. A negative pregnancy test is required for WOCBP before study drug administration. Details of all pregnancies in female patients and, if indicated, female partners of male patients will be collected after the start of study drug and until the termination of the pregnancy.
  • Adverse events will be reported to the Investigator by the patient (or, when appropriate, by a caregiver, surrogate, or the patient'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 drug or study procedures, or that caused the patient to discontinue the study drug.
  • All AEs and SAEs will be collected from the signing of the ICF until the last visit specified in the Schedule of Activities. All SAEs will be recorded and reported to The Sponsor or designee immediately and under no circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to The Sponsor within 24 hours of awareness. Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study participation. However, if the Investigator learns of any SAE, including a death, at any time after a patient has been discharged from the study, and he/she considers the event to be reasonably related to the study drug or study participation, the Investigator must promptly notify The Sponsor.
  • Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal obligations and ethical responsibilities towards the safety of patients and the safety of a study drug under clinical investigation are met.
  • the Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study drug under clinical investigation.
  • the Sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
  • Meningococcal infections will be collected as AESIs.
  • any dose of study drug greater than that specified in the protocol will be considered an overdose. If dose cannot be established during the Randomized Controlled Period due to blinding, suspected overdose should be defined by volume administered. Accidental overdose or suspected overdose without any association with laboratory abnormalities or clinical symptoms should not be considered as an AE. Overdose must be reported by the Investigator within 24 hours to the Sponsor regardless of its association with or without an AE.
  • the Sponsor does not recommend specific treatment for an overdose or suspected overdose. In the event of an overdose or suspected overdose, the Investigator should:
  • Blood samples for determination of serum drug concentrations and PD assessments will be collected before and after administration of study drug at the time points specified in the Schedule of Activities.
  • Cerebrospinal fluid (CSF) samples for PK and PD assessments are optional at protocol specified time points and will only be obtained from patients who consent to CSF collection (CSF Cohort).
  • Lumbar punctures will be performed to collect CSF samples and may only be performed on patients who have consented to CSF sample collection.
  • Patients who are on therapeutic doses of anticoagulants will be deemed ineligible for the optional lumbar puncture procedures in this study.
  • patients may be deemed ineligible to undergo lumbar puncture at the discretion of the Investigator after consideration of medical history, physical examination findings, laboratory assessments required as part of the Schedule of Activities or other factors.
  • Baseline and trough PK and PD blood samples will be collected at pre-dose, within 90 minutes before administering study drug at visits specified in the Schedule of Activities.
  • the pre-dose blood sample may be drawn through the venous access created for the dose infusion, prior to administration of the dose.
  • Post-dose PK and PD blood samples will be collected post-dose, within 60 minutes after completing study drug infusion.
  • the post-dose blood samples will be drawn from the patient's opposite, non-infused arm. Blood samples at a non-dosing visit can be collected at any time. In the event of an unscheduled visit, PK and PD blood sample will be collected as soon as possible.
  • CSF samples are optional samples for biomarker research and should only be collected from patients who have consented to CSF sample collection.
  • biomarker CSF sample collection follow the same instructions on lumbar punctures for PK/PD assessments.
  • Biomarkers will be measured and include, but are not limited to, assessments of the following:
  • Markers of neuroinflammation such as levels of proinflammatory cytokines and inflammatory cells
  • Blood samples for DNA and RNA isolation will be collected from patients who have consented to participate in the future genetic analysis component of the study. Future DNA and RNA testing on these samples includes, but is not limited to, specific candidate genes/genome wide analysis. Remaining samples from PK, PD, immunogenicity, and biomarker testing will be stored for future biomarker research. Analyses may be performed on biomarker variants thought to play a role in ALS activity/progression or treatment response to ravulizumab.
  • Samples may also be used to develop methods, assays, prognostics and/or companion diagnostics related to the study drug target, disease process, pathways associated with disease state, other complement-related diseases, and/or mechanism of action of the study drug. Samples may be stored for a maximum duration according to local regulations following the last patient’s last visit for the study at a facility selected by The Sponsor to enable further analyses.
  • Antidrug antibodies (AD As) to study drug will be evaluated in serum samples collected pre-dose (within 5 to 90 minutes prior to the start of infusion of study drug) from all patients according to the Schedule of Activities. Additionally, serum samples should also be collected at the final visit from patients who discontinued study drug or were withdrawn from the study. Serum samples will be screened for antibodies binding to ravulizumab and the titer of confirmed positive samples will be reported. Other analyses may be performed to verify the stability of antibodies to ravulizumab and/or further characterize the immunogenicity of ravulizumab.
  • the detection and characterization of antibodies to ravulizumab will be performed using a validated assay method by or under the supervision of The Sponsor. Samples may be further characterized to determine the titer and the presence of neutralizing antibodies if deemed necessary. Samples may be stored for a maximum duration according to local regulations following the last patient’s last visit for the study at a facility selected by the Sponsor to enable further analysis of immune responses to ravulizumab.
  • SAP Statistical Analysis Plan
  • the SAP will be developed and finalized prior to the database lock for the Randomized Controlled period.
  • the summary statistics for continuous variables will include but not be limited to the number of patients, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented.
  • the baseline value for analysis and reporting will be based on the last non-missing measurement on or prior to the first dose of study drug unless stated otherwise.
  • the treatment groups for analysis and reporting will be based on the conventions outlined in Table 9.
  • a ‘Total’ treatment group will be formed to report demographics, baseline characteristics, and other pre-study information including, medical and ALS history, and prior medications and SAEs captured between screening and first infusion. Details for imputation of efficacy data will be described in the SAP. Missing safety data will not be imputed. Analyses will be performed using the SAS® software Version 9.4 or higher.
  • the primary null hypothesis is that the effect of ravulizumab is no different than placebo in functional decline measured by the change from baseline in ALSFRS-R total score at Week 50.
  • the alternative hypothesis is that ravulizumab will slow the disease progression by reducing the decline from baseline in ALSFRS-R total score at Week 50 compared to placebo.
  • null hypotheses associated with the secondary objectives are that ravulizumab is no different than placebo for the respective endpoints; the alternative hypotheses are described below:
  • Time to VAFS The alternative hypothesis is that treatment with ravulizumab will prolong the time to VAFS compared to placebo.
  • Change in SVC The alternative hypothesis is that treatment with ravulizumab will slow the decline from baseline in SVC at Week 50 compared to placebo.
  • Change in muscle strength (HHD) The alternative hypothesis is that treatment with ravulizumab will slow the decline from baseline in muscle strength at Week 50 compared to placebo.
  • sample size calculations were based on information extracted from the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials, https://nctu.partners.org/ProACT) database consisting of clinical trials data pooled from 23 Phase 2/3 ALS clinical trials. Approximately 354 patients will be randomized to ravulizumab or placebo in a 2: 1 ratio.
  • the mean change in ALSFRS-R total score in the placebo arm at Week 50 is estimated as 14.3 (assuming a monthly linear slope of decline of 1.19 calculated based on the proposed study inclusion criteria). Assuming a 30% relative reduction in monthly slope in the ravulizumab group, which is considered a clinically meaningful treatment effect (Castrillo-Viguera, 2010; Writing Group for Edaravone ALS Study, 2017), the mean change in ALSFRS-R total score at Week 50 is estimated as -10.
  • a common standard deviation of 10.3 was estimated for the change from baseline in ALSFRS-R total score.
  • the total sample size is estimated as 354 after adjusting for a 20% dropout (Cudkowicz, 2013).
  • this sample size will provide at least 90% nominal power based on the primary analysis (CAFS).
  • Amyotrophic lateral sclerosis is a heterogeneous disease the progression of which is impacted by intrinsic disease factors and concomitant ALS medication use. Patients with bulbar onset ALS are well described to have a poorer prognosis than other ALS patients (Swinnen, 2014). To control this heterogeneity the study will be stratified based on known prognostic factors and concomitant ALS medication use.
  • SOC System Organ Class
  • MedDRA Medical Dictionary for Regulatory Activities
  • any medication started prior to first dose of study drug will be considered as prior medication and any medication taken by a patient that overlaps with the intake of study drug will be considered as concomitant medication. All prior and concomitant medications including ALS-specific medications during the study, if any, will be summarized. Efficacy Analyses
  • CAFS joint rank analysis
  • CAFS ranks will be based on an analysis of covariance model.
  • age sex
  • baseline ALSFRS-R total score baseline SVC
  • time from muscle weakness onset time from muscle weakness onset
  • stratification factors A p value less than the adjusted Type I error associated with the higher mean rank in ravulizumab group compared to placebo will indicate a statistically significant treatment benefit.
  • the mixed-effect model for repeated measures (MMRM) analysis will be conducted using all available longitudinal data (either complete or partial).
  • the patient-specific random intercept and slope will be added to the model with an unstructured variance-covariance matrix to model the correlations among repeated measurements within each patient.
  • Other covariance structures will be implemented if a convergence issue occurs (details to be provided in SAP).
  • the Kenward Rogers method will be used to estimate the denominator degrees of freedom.
  • parametric modeling may also be performed (Vonesh, 2006).
  • both the longitudinal changes in the ALSFRS-R total score and the time to death are modeled together assuming a patient specific slope and intercept for ALSFRS-R trajectory.
  • the model also assumes that a patient’s survival time has a Weibull distribution with a hazard that is a function of the patient’s ALSFRS-R trajectory; the treatment effect of ravulizumab on ALSFRS-R and mortality will be estimated separately from this joint model.
  • Time to VAFS The treatment effect on the time to VAFS will be analyzed based on a Cox’s regression model treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
  • VAFS VAFS The components of VAFS will be analyzed separately using similar models.
  • Change in SVC The treatment effect on SVC will be evaluated based on a MMRM with the change from baseline in SVC percent predicted as the dependent variable and following list of independent variables as fixed effects: actual time on study (months), time and treatment interaction, age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
  • the patient-specific random intercept and slope will be added to the model with an unstructured variance-covariance matrix.
  • the Kenward-Rogers method will be used to estimate the denominator degrees of freedom. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
  • HHD Change in muscle strength
  • NfL neurofilament light chain
  • Time to first instance of SVC ⁇ 50% predicted The treatment effect on the time to first instance of SVC ⁇ 50% will be evaluated based on a Cox’s regression model with treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
  • Change in SF-36 The treatment effect on SF-36 physical component score (PCS) will be evaluated based on a MMRM with the change from baseline in SF-36 PCS as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and visit interaction, age, sex, baseline SF-36 PCS, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
  • the Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance- covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
  • MCS mental component score
  • Change in EO-5D-5L index score The treatment effect on EQ-5D-5L index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline EQ-5D-5L index score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor.
  • the Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
  • Change in EO-5D-5L VAS score The treatment effect on EQ-5D-5L VAS score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline EQ-5D-5L VAS score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor.
  • the Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
  • Change in ALSAQ-40 score A single index score is created by adding all of the responses (0, 1, 2, 3, or 4) of 40 items of ALSAQ-40, dividing this total score by the maximal score of 160 and finally multiplying by 100. An index score of 0 indicates perfect health and 100 indicates worst possible health status.
  • the treatment effect on ALSAQ-40 index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline ALSAQ-40 index score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor.
  • the Kenward Rogers method will be used to estimate the denominator degrees of freedom.
  • the safety and tolerability of ravulizumab will be assessed based on AEs, clinical laboratory findings, vital sign findings, and ECG abnormalities. Safety analyses will be performed on the Safety Set and Open-label extension Set based on the study period under consideration.
  • Treatment-emergent AEs including TESAEs defined as an AE with onset on or after first dose of study drug administration in the Randomized Controlled Period.
  • Treatment-emergent AEs and TESAEs will be summarized by MedDRA SOC and Preferred Term and by relationship to the study drug; TEAEs will also be summarized by severity.
  • Patient-years adjusted event rates will be generated to characterize long-term safety profile.
  • Pharmacodynamic analyses will be performed for all patients who receive at least 1 dose of ravulizumab and who have evaluable PD data. Descriptive statistics will be presented for all ravulizumab PD endpoints at each sampling time. The PD effects of ravulizumab will be evaluated by assessing the absolute values and changes and percentage changes from baseline in free C5 serum concentrations over time, as appropriate. Assessments of ravulizumab PK/PD relationships may be explored using data from this study or in combination with data from other studies.
  • Two interim analyses for futility will be conducted by an IDMC to determine if the study is unlikely to meet its objective. If futility criteria are met, the study (both the Randomized Controlled Period and Open-Label Extension Period) may be terminated early, thereby limiting patient exposure. In addition, an interim analysis will also be conducted to determine if ravulizumab has demonstrated early evidence of efficacy. If success criteria are met, the double blind period may be terminated early, permitting all patients in the study to enter the open-label period and access an efficacious treatment.
  • Interim analysis 1 This interim analysis will be conducted by the IDMC when approximately 33% of patients complete the Week 26 visit. Only futility will be assessed at this point. This assessment will be performed using all available ALSFRS-R data. The criteria for futility will be prespecified in the IDMC charter.
  • a second interim analysis will be targeted to occur when approximately all patients complete the Week 26 visit.
  • the second futility assessment will be performed using all available ALSFRS R data.
  • the criteria for futility will be prespecified in the IDMC charter. If the study is not considered futile at interim analysis 2, an analysis for early stopping for efficacy based on ALSFRS-R will also be performed at this time.
  • the prespecified framework will be documented in the IDMC charter.
  • a delayed start analysis will be conducted based on an MMRM approach and by incorporating all data from the Randomized Controlled Period (referred to as early start) and the first 50 weeks of the Open-Label Extension Period (referred to as delayed start).
  • early start the Randomized Controlled Period
  • delayed start the first 50 weeks of the Open-Label Extension Period
  • the patients initially randomized to placebo will be assumed to have different ALSFRS R slopes for the Randomized Controlled Period and the Open-Label Extension Period whereas for the patients randomized to ravulizumab, a slope common to both periods will be assumed.
  • the treatment effects will be quantified by the estimated differences between the groups based on their original treatment arms (ravulizumab vs placebo) for both early and delayed start periods; the estimated difference at the end of the delayed start period will be assessed for noninferiority compared to the estimated difference at the end of the early start period (Liu-Seifert, 2015). Further details will be provided in the SAP.
  • the safety and efficacy data of this study will be monitored by an IDMC appointed by The Sponsor.
  • the IDMC members will include external physicians and a statistician who have expertise in both the field of ALS and clinical trial conduct and with no direct relationship to the study.
  • Each member of the IDMC will be required to sign an agreement, including confidentiality and financial disclosure statements, assuring no conflicts of interest as a condition for membership on the committee.
  • IDMC All statistical analyses presented to the IDMC will be performed by an independent statistical center.
  • the IDMC will independently evaluate safety and efficacy data from the trial periodically and at prespecified enrollment-dependent time points.
  • the IDMC will make recommendations regarding trial modification or continuation based on their review and in accordance with the agreed upon IDMC charter.
  • Recommendations from the IDMC will be relayed to an Executive Representative of the Sponsor who will make a determination about implementing recommendations to modify or discontinue the study. All appropriate regulatory authorities and ethics committees will be notified of significant actions taken as a result of IDMC recommendations.
  • To maintain study integrity and to prevent the potential introduction of bias all study team members will remain blinded until the final analysis of the Randomized Controlled Period is conducted. Details of this process will be documented in the IDMC charter.
  • CAFS Combined Assessment of Function and Survival
  • ALSFRS-R a revised ALS functional rating scale that incorporates assessments of respiratory function. Journal of the Neurological Sciences. 1999; 169(1): 13-21.
  • Orsini M Oliveira AB, Nascimento OJ, et al. Amyotrophic lateral sclerosis: new perpectives and update. Neurol Int. 2015;7(2):5885.
  • Woodruff TM, Lee JD, Noakes PG Role for terminal complement activation in amyotrophic lateral sclerosis disease progression. Proc Natl Acad Sci U S A. 2014; 11 l(l):E3-4. Writing Group for Edaravone ALS Study. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017; 16(7):505-512.

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Abstract

Provided are methods for clinical treatment of amyotrophic lateral sclerosis (ALS) using an anti-C5 antibody or antigen binding fragment thereof.

Description

DOSAGE AND ADMINISTRATION OF ANTI-C5 ANTIBODIES FOR TREATMENT OF
AMYOTROPHIC LATERAL SCLEROSIS
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to, and the benefit of, U.S. Provisional Application No. 63/044,341, filed June 25, 2020, the entire contents of which is incorporated herein by reference.
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a debilitating neurodegenerative disease characterized by progressive degeneration of upper and lower motor neurons leading to severe disability and eventually death. In Europe and North America, the incidence has been estimated as 1-3 per 100,000 (Couratier, 2016; Orsini, 2015). The burden of ALS is substantial with an average life expectancy from symptom onset between 2 and 5 years (Mehta, 2018). Typically, the onset of ALS occurs in the fifth or sixth decade of life and is marked by a progressive loss of motor neurons leading to variable amounts of weakness and spasticity in the limb, bulbar, and respiratory muscles (Swinnen, 2014).
Most patients present with limb onset, also referred to as spinal onset, with asymmetric painless weakness in a limb, but in approximately 20% of patients, weakness may be of bulbar onset manifesting as dysarthria or dysphagia. Bulbar onset patients have a poorer prognosis. Patients develop progressive disability limiting ambulation, communication, nourishment, and independence. Declining respiratory function can lead to respiratory insufficiency and failure which often is the cause for death, unless permanent mechanical ventilation is elected (Paulukonis, 2015).
While the etiology of ALS is largely unknown, neuroinflammation may be a key event in disease pathology (Boillee, 2006; Kjaeldgaard, 2018). Immune dysregulation and neuroinflammation in both the central and peripheral nervous system are common features of familial and sporadic ALS and have negative influences on motor neuron viability in ALS (Beers, 2019). The complement system is a major component of the innate immune system that comprises more than 30 proteins and plays an essential role in pathogen killing, stimulation of phagocytosis, chemoattraction of inflammatory cells, and disposal of self debris (Chen, 2010).
Upregulation of proximal and terminal components of the complement system and its regulators has been identified in the biofluids, neural tissue, and skeletal muscle of patients with ALS and has been corroborated by data from ALS animal models (Parker, 2019). Complement dysregulation likely occurs early in ALS pathogenesis as its deposition has been identified at the neuromuscular junction prior to nerve cell death, making it a potential mediator of the proposed “dying back” effect where motor neuron loss results from axonal damage at the neuromuscular junction (Bahia El Idrissi, 2016; Kjaeldgaard, 2018). Further, quantitative analyses in multiple ALS mouse models show that complement deposition increases over time and correlates with disease progression (Lee, 2017)
Terminal complement, specifically, has been shown to play an important role in the pathology of ALS (Parker, 2019). While plasma levels of proximal complement are similar in ALS patients and normal controls, serum levels of the membrane attack complex, as well as serum and leukocyte levels of C5a, are increased in ALS patients (Mantovani, 2014). Terminal complement is also found to correlate with mediators of neuroinflammation in ALS. Inflammatory Ml macrophages and microglia are associated with disease progression in ALS and these invading cells at the neuromuscular junction express the complement receptor C5aRl (Lee, 2017; Liao, 2012).
Both pharmacologic inhibition and genetic deletion of C5aRl receptor signalling diminishes recruitment of these inflammatory cells to affected tissue and potentially decreases denervation induced by inflammation (Lee, 2017). Inhibition of terminal complement can alter the course of disease in animal models of ALS. When transgenic hSODlG93A mice and rats were treated with an inhibitor of C5aRl, both prior to symptom onset and at an early stage of disease, survival was prolonged. Functional benefit as evidenced by a delay in time to significant loss of hind limb strength was also observed. Similar results were observed in animals with a genetic knockout of the C5aRl receptor, but not when proximal complement components such as C3 were targeted (Lobsiger, 2013; Woodruff, 2014).
The potential for terminal complement inhibition to modify disease progression of ALS is likely dependent on the ability to have a biological effect in the central nervous system (CNS) and neuromuscular junction. As there is no cure for ALS, and standard of care is not effective for all patients, there is a need to provide improved methods for treating these patients.
SUMMARY
Provided herein are compositions and methods for treating ALS. The disclosure also provides ravulizumab for use in the treatment of ALS in a human patient according to any of the embodiments, described above.
Further, the disclosure encompasses any of the above embodiments being used with any other of the above embodiments in any combination.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic depicting the design of a clinical trial in ALS patients.
FIG. 2 is the El Escorial diagnostic criteria of possible, probable, probable laboratory supported, or definite ALS, used in the clinical trial disclosed herein.
FIG. 3 is the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) used to measure physical function in performance of daily living activities in patients with ALS, used in the clinical trial disclosed herein.
FIG. 4 is the Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40) used to measuring quality of life in patients with ALS, used in the clinical trial disclosed herein.
FIG. 5 is the in-clinic version of the European Quality of Life 5 Dimensions (EQ-5D- 5L) standardized instrument to measure health-related quality of life, used in the clinical trial disclosed herein.
FIG. 6 is the phone interview version of the EQ-5D-5L standardized instrument to measure health-related quality of life, used in the clinical trial disclosed herein.
FIG. 7 is the in-clinic version of the Short Form Health Survey (SF-36) health-related quality of life survey, used in the clinical trial disclosed herein.
FIG. 8 is the phone interview version of the SF-36 health-related quality of life survey, used in the clinical trial disclosed herein.
FIG. 9 is the Treatment Satisfaction Questionnaire for Medication (TSQM-9) used to asses three key dimensions of treatment satisfaction, used in the clinical trial disclosed herein.
FIG. 10 is the Columbia-Suicide Severity Rating Scale (C-SSRS) as measured at the patient’s baseline/screening.
FIG. 11 is the C-SSRS as measured since the time of the patient’s last visit. DETAILED DESCRIPTION
As used herein, the term “subject” or “patient” is a human patient (e.g. , a patient having ALS). As used herein, the terms “subject” and “patient” are interchangeable. 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, for example, alleviation of at least one symptom of ALS.
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 anti-C5 antibody or antigen binding fragment thereof useful, e.g., clinically proven, to alleviate at least one symptom of ALS. An effective amount can be administered in one or more administrations.
As used herein, the phrase “randomized controlled period” refers to the first phase of a dosing regimen.
As used herein, the terms “loading dose” refers to the initial dose administered to the patient, e.g., during the randomized control period of a dosing regimen. A loading dose may be, for example, 2400 mg, 2700 mg, or 3000 mg. Loading doses may be fixed or titered based on body weight. In some embodiments, 2400 mg is administered to a patient weighing > 40 to < 60 kg, 2700 mg is administered to a patient weighing > 60 to < 100 kg, and/or 3000 mg is administered to a patient weighing > 100 kg. In some embodiments, the loading dose is administered at day 1 of treatment.
As used herein, the term “maintenance phase” refers to the second phase of a dosing regimen. In some embodiments, treatment is continued as long as clinical benefit is observed or until unmanageable toxicity or disease progression occurs. In some embodiments, the maintenance phase begins on day 15 if treatment. According to some embodiments, the maintenance phase lasts for 50-76, 50-102, 50-128, 50-154, 50-180, 50-206 weeks, or more. In some embodiments, the maintenance phase lasts for greater than 50, 51, 52, 53, 54, 55, 56,
57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 102, 128, 154,
180, or 206 weeks. According to some 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 years, or more. In some embodiments, the maintenance phase lasts for the remainder of the subject's life.
As used herein, the term “maintenance dose” refers to a dose administered to the patient after the loading dose. In some embodiments, the maintenance dose is provided during the maintenance phase. For example, a maintenance dose may be 3000 mg, 3300 mg, or 3600 mg. Maintenance doses may be titered based on body weight. In some embodiments, 3000 mg is administered to a patient weighing > 40 to < 60 kg, 3300 mg is administered to a patient weighing > 60 to < 100 kg, and/or 3600 mg is administered to a patient weighing > 100 kg.
As used herein, the term “serum trough concentration” refers to the lowest concentration at which the agent (e.g, the anti-C5 antibody or antigen binding fragment thereof) or medicine is present in serum. In contrast, a “peak serum level” refers to the highest concentration of the agent in serum. The “average serum concentration” refers to the mean concentration of the agent in serum over time.
In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 100 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 150 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 200 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 250 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 300 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 350 pg/mL or greater. In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of 400 pg/mL or greater.
In some embodiments, the treatment regimens described are sufficient to maintain particular serum trough concentrations of the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, for example, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof, of 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165 170, 175, 180, 185, 190, 200, 205, 210, 215, 220, 225, 230, 240, 245, 250, 255, 260, 265, 270, 280, 290, 300, 305, 310, 315, 320, 325, 330, 335, 340, 345, 350, 355, 360, 365, 370,
375, 380, 385, 390, 395 or 400 mg/mL or greater.
In some embodiments, the treatment maintains a serum trough concentration of the anti-C5 antibody or antigen binding fragment thereof of between 100 pg/mL and 200 pg/mL, 200 pg/mL and 300 pg/mL, or 300 pg/mL and 400 pg/mL. In some embodiments, the treatment described herein reduces free C5 concentration by greater than 90% throughout the treatment period. In some embodiments, the treatment described herein reduces free C5 concentration by greater than 95% throughout the treatment period. In some embodiments, the treatment described herein reduces free C5 concentration by greater than 99% throughout the treatment period. In some embodiments, the treatment reduces free C5 concentration greater than 99.5% throughout the treatment period.
The term “antibody” describes polypeptides comprising at least one antibody derived antigen binding site (e.g., VH/VL region or Fv, or CDR). Antibodies include known forms of antibodies. The antibody can be, for example, a human antibody, a humanized antibody, a bispecific antibody, a chimeric antibody or a camelid antibody. The antibody also can be a Fab, Fab’2, scFv, SMIP, Affibody®, nanobody or a single domain antibody. The antibody also can be of any of the following isotypes: IgGl, IgG2, IgG3, IgG4, IgM, IgAl, IgA2, IgAsec, IgD, and IgE, and hybrid isotypes, e.g., IgG2/4. The antibody may be a naturally occurring antibody or may be an antibody that has been altered by a protein engineering technique (e.g., by mutation, deletion, substitution, conjugation to anon-antibody moiety).
An antibody may include, for example one or more variant amino acids (compared to a naturally occurring antibody), which changes a property (e.g., a functional property) of the antibody. Numerous such alterations are known in the art that affect, e.g., half-life, effector function, and/or immune responses to the antibody in a patient. The term antibody also includes artificial or engineered polypeptide constructs that comprise at least one antibody- derived antigen binding site.
Anti-C5 Antibodies
The anti-C5 antibodies described herein bind to complement component C5 (e.g., human complement C5) and inhibit the cleavage of C5 into fragments C5a and C5b. Anti-C5 antibodies (or VH/VL domains or other antigen binding fragments derived therefrom) suitable for use herein can be generated using methods known in the art. Art-recognized anti- C5 antibodies can also be used. Antibodies that compete with any of these art-recognized antibodies for binding to C5 also can also be used.
Eculizumab (also known as Soliris®) is an anti-C5 antibody comprising heavy and light chains having sequences shown in SEQ ID NO: 10 and 11, respectively, or antigen binding fragments and variants thereof. Eculizumab is described in PCT/US2007/006606, the teachings of which are hereby incorporated by reference. In some embodiments the anti-C5 antibody, comprises the CDR1, CDR2 and CDR3 domains of the VH region of eculizumab having the sequence set forth in SEQ ID NO:7, and the CDR1, CDR2 and CDR3 domains of the VL region of eculizumab having the sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 1, 2 and 3, respectively, and light chain CDR1,
CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 4, 5 and 6, respectively. In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO:7 and SEQ ID NO:8, respectively.
Ravulizumab (also known as BNJ441, ALXN1210, or Ultomiris®) is an anti-C5 antibody comprising heavy and light chains having the sequences shown in SEQ ID NOs: 14 and 11, respectively, or antigen binding fragments and variants thereof. Ravulizumab is described in PCT/US2015/019225 and US Patent No. 9,079,949, the teachings of which are hereby incorporated by reference. Ravulizumab selectively binds to human complement protein C5, inhibiting its cleavage to C5a and C5b during complement activation. This inhibition prevents the release of the proinflammatory mediator C5a and the formation of the cytolytic pore-forming membrane attack complex (MAC) C5b-9 while preserving the proximal or early components of complement activation ( e.g ., C3 and C3b) essential for the opsonization of microorganisms and clearance of immune complexes.
In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of ravulizumab. Accordingly, in some embodiments, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of ravulizumab having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of ravulizumab having the sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
Another exemplary anti-C5 antibody is antibody BNJ421 comprising heavy and light chains having the sequences shown in SEQ ID NOs:20 and 11, respectively, or antigen binding fragments and variants thereof. BNJ421 is described in PCT/US2015/019225 and US Patent No. 9,079,949, the entire teachings of which are hereby incorporated by reference.
In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of BNJ421. Accordingly, in some embodiments, the antibody comprises the CDR1, CDR2 and CDR3 domains of the VH region of BNJ421 having the sequence set forth in SEQ ID NO: 12, and the CDR1, CDR2 and CDR3 domains of the VL region of BNJ421 having the sequence set forth in SEQ ID NO: 8. In some embodiments, the antibody comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:19, 18 and 3, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs:4, 5 and 6, respectively. In some embodiments, the antibody comprises VH and VL regions having the amino acid sequences set forth in SEQ ID NO: 12 and SEQ ID NO: 8, respectively.
The exact boundaries of CDRs have been defined differently according to different methods. In some embodiments, the positions of the CDRs or framework regions within a light or heavy chain variable domain can be as defined by Rabat et al. [(1991) “Sequences of Proteins of Immunological Interest.” NIH Publication No. 91-3242, U.S. Department of Health and Human Services, Bethesda, MD] In such cases, the CDRs can be referred to as “Rabat CDRs” (e.g., “Rabat LCDR2” or “Rabat HCDR1”). In some embodiments, the positions of the CDRs of a light or heavy chain variable region can be as defined by Chothia et al. ( Nature , 342:877-83, 1989). Accordingly, these regions can be referred to as “Chothia CDRs” (e.g., “Chothia LCDR2” or “Chothia HCDR3”). In some embodiments, the positions of the CDRs of the light and heavy chain variable regions can be as defined by a Rabat- Chothia combined definition. In such embodiments, these regions can be referred to as “combined Rabat-Chothia CDRs” (Thomas, T. et aI.,MoI. Immunol., 33:1389-401, 1996).
Another exemplary anti-C5 antibody is the 7086 antibody described in US Patent Nos. 8,241,628 and 8,883,158. In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of the 7086 antibody (see US Patent Nos. 8,241,628 and 8,883,158). In some embodiments, the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 24, 25 and 26, respectively. In some embodiments, the antibody or antigen binding fragment thereof comprises the VH region of the 7086 antibody having the sequence set forth in SEQ ID NO:27, and the VL region of the 7086 antibody having the sequence set forth in SEQ ID NO:28.
Another exemplary anti-C5 antibody is the 8110 antibody also described in US Patent Nos. 8,241,628 and 8,883,158. In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of the 8110 antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 32, 33 and 34, respectively. In some embodiments, the antibody comprises the VH region of the 8110 antibody having the sequence set forth in SEQ ID NO:35, and the VL region of the 8110 antibody having the sequence set forth in SEQ ID NO:36.
Another exemplary anti-C5 antibody is the 305LO5 antibody described in US2016/0176954A1. In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of the 305LO5 antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises heavy chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains having the sequences set forth in SEQ ID NOs: 40, 41 and 42, respectively. In some embodiments, the antibody comprises the VH region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:43, and the VL region of the 305LO5 antibody having the sequence set forth in SEQ ID NO:44.
Another exemplary anti-C5 antibody is the SKY59 antibody (FukuzawaT. et al., Sci. Rep., 7:1080, 2017). In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of the SKY59 antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46.
Another exemplary anti-C5 antibody is the H4H12166PP antibody described in PCT/US2017/037226 and US2017/0355757A1. In some embodiments, the antibody comprises the heavy and light chain CDRs or variable regions of the H4H12166PP antibody. In some embodiments, the antibody or antigen binding fragment thereof comprises the VH region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO:47, and the VL region of the H4H12166PP antibody having the sequence set forth in SEQ ID NO:48. In some embodiments, the antibody or antigen binding fragment thereof comprises a heavy chain comprising SEQ ID NO:49 and a light chain comprising SEQ ID NO: 50.
In some embodiments, a patient is treated with eculizumab and then switched to treatment with the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody, the H4H12166PP antibody or ravulizumab. In some embodiments, the patient is switched from an anti-C5 antibody (e.g., eculizumab, the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody or the H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment.
In some embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR1 comprising or consisting of the following amino acid sequence: GHIFSNYWIQ (SEQ ID NO: 19). In some embodiments, an anti-C5 antibody described herein comprises a heavy chain CDR2 comprising or consisting of the following amino acid sequence: EILPGSGHTEYTENFKD (SEQ ID NO: 18). In some embodiments, an anti-C5 antibody described herein comprises a heavy chain variable region comprising the following amino acid sequence:
QVQLVQSGAEVKKPGASVKVSCKASGHIFSNYWIQWVRQAPGQGLEWMGE ILPGSGHTEYTENFKDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARYF FGSSPNWYFDVWGQGTLVTVSS (SEQ ID NO:12).
In some embodiments, an anti-C5 antibody described herein comprises a light chain variable region comprising the following amino acid sequence:
DIQMTQSPSSLSASVGDRVTITCGASENIYGALNWYQQKPGKAPKLLIY GATNLADGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQNVLNTPLTF GQGTKVEIK (SEQ ID NO:8).
An anti-C5 antibody described herein can, in some embodiments, comprise a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn) with greater affinity than that of the native human Fc constant region from which the variant human Fc constant region was derived. The Fc constant region can comprise, for example, one or more (e.g., two, three, four, five, six, seven or eight or more) amino acid substitutions relative to the native human Fc constant region from which the variant human Fc constant region was derived. The substitutions can increase the binding affinity of an IgG antibody containing the variant Fc constant region to FcRn at pH 6.0, while maintaining the pH dependence of the interaction. Methods for testing whether one or more substitutions in the Fc constant region of an antibody increase the affinity of the Fc constant region for FcRn at pH 6.0 (while maintaining pH dependence of the interaction) are known in the art and exemplified in the working examples (see, e.g., PCT/US2015/019225 and US Patent No. 9,079,949 the disclosures of each of which are incorporated herein by reference in their entirety).
Substitutions that enhance the binding affinity of an antibody Fc constant region for FcRn are known in the art and include, e.g., (1) the M252Y/S254T/T256E triple substitution (Dall’Acqua, W. etal., J. Biol. Chem., 281:23514-24, 2006); (2) M428L or T250Q/M428L substitutions (Hinton, P. et ak, J. Biol. Chem., 279:6213-6, 2004; Hinton, P. et ak, J. Immunol., 176:346-56, 2006); and (3) N434A or T307/E380A/N434A substitutions (Petkova, S. et ak , Int. Immunol., 18:1759-69, 2006). Additional substitution pairings, e.g., P257I/Q311I, P257I/N434H, and D376V/N434H (Datta-Mannan, A. etal, J. Biol. Chem., 282:1709-17, 2007) are also contemplated herein. In some embodiments, the variant constant region has a substitution at EU amino acid residue 255 for valine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 309 for asparagine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 312 for isoleucine. In some embodiments, the variant constant region has a substitution at EU amino acid residue 386.
In some embodiments, the variant Fc constant region comprises no more than 30 (e.g., no more than 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3 or 2) amino acid substitutions, insertions or deletions relative to the native constant region from which it was derived. In some embodiments, the variant Fc constant region comprises one or more amino acid substitutions selected from the group consisting of: M252Y, S254T, T256E, N434S, M428L, V259I, T250I and V308F. In some embodiments, the variant human Fc constant region comprises a methionine at position 428 and an asparagine at position 434, each in EU numbering. In some embodiments, the variant Fc constant region comprises a428L/434S double substitution as described in, e.g., U.S. Patent No. 8,088,376.
In some embodiments the precise location of these mutations may be shifted from the native human Fc constant region position due to antibody engineering. The 428L/434S double substitution when used in a IgG2/4 chimeric Fc, for example, may correspond to 429L and 435S as in the M429L and N435S variants found in BNJ441 (ravulizumab) and described in US Patent Number 9,079,949, the disclosure of which is incorporated herein by reference in its entirety.
In some embodiments, the variant constant region comprises a substitution at amino acid position 237, 238, 239, 248, 250, 252, 254, 255, 256, 257, 258, 265, 270, 286, 289, 297, 298, 303, 305, 307, 308, 309, 311, 312, 314, 315, 317, 325, 332, 334, 360, 376, 380, 382,
384, 385, 386, 387, 389, 424, 428, 433, 434 or 436 (EU numbering) relative to the native human Fc constant region. In some embodiments, the substitution is selected from the group consisting of: methionine for glycine at position 237; alanine for proline at position 238; lysine for serine at position 239; isoleucine for lysine at position 248; alanine, phenylalanine, isoleucine, methionine, glutamine, serine, valine, tryptophan, or tyrosine for threonine at position 250; phenylalanine, tryptophan, or tyrosine for methionine at position 252; threonine for serine at position 254; glutamic acid for arginine at position 255; aspartic acid, glutamic acid, or glutamine for threonine at position 256; alanine, glycine, isoleucine, leucine, methionine, asparagine, serine, threonine, or valine for proline at position 257; histidine for glutamic acid at position 258; alanine for aspartic acid at position 265; phenylalanine for aspartic acid at position 270; alanine, or glutamic acid for asparagine at position 286; histidine for threonine at position 289; alanine for asparagine at position 297; glycine for serine at position 298; alanine for valine at position 303; alanine for valine at position 305; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, arginine, serine, valine, tryptophan, or tyrosine for threonine at position 307; alanine, phenylalanine, isoleucine, leucine, methionine, proline, glutamine, or threonine for valine at position 308; alanine, aspartic acid, glutamic acid, proline, or arginine for leucine or valine at position 309; alanine, histidine, or isoleucine for glutamine at position 311; alanine or histidine for aspartic acid at position 312;lysine or arginine for leucine at position 314; alanine or histidine for asparagine at position 315; alanine for lysine at position 317; glycine for asparagine at position 325; valine for isoleucine at position 332; leucine for lysine at position 334; histidine for lysine at position 360; alanine for aspartic acid at position 376; alanine for glutamic acid at position 380; alanine for glutamic acid at position 382; alanine for asparagine or serine at position 384; aspartic acid or histidine for glycine at position 385; proline for glutamine at position 386; glutamic acid for proline at position 387; alanine or serine for asparagine at position 389; alanine for serine at position 424; alanine, aspartic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, or tyrosine for methionine at position 428; lysine for histidine at position 433; alanine, phenylalanine, histidine, serine, tryptophan, or tyrosine for asparagine at position 434; and histidine for tyrosine or phenylalanine at position 436, all in EU numbering.
Suitable anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and/or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11. Alternatively, the anti-C5 antibodies for use in the methods described herein can comprise a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO:20 and/or a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
In some embodiments, the antibody binds to C5 at pH 7.4 and 25°C (and, otherwise, under physiologic conditions) with an affinity dissociation constant (KD) that is at least 0.1 (e.g., at least 0.15, 0.175, 0.2, 0.25, 0.275, 0.3, 0.325, 0.35, 0.375, 0.4, 0.425, 0.45, 0.475, 0.5, 0.525, 0.55, 0.575, 0.6, 0.625, 0.65, 0.675, 0.7, 0.725, 0.75, 0.775, 0.8, 0.825, 0.85, 0.875,
0.9, 0.925, 0.95 or 0.975) nM. In some embodiments, the KD of the anti-C5 antibody or antigen binding fragment thereof is no greater than 1 (e.g., no greater than 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3 or 0.2) nM. In some embodiments, the [(KD of the antibody for C5 at pH 6.0 at 25°C)/(KD of the antibody for C5 at pH 7.4 at 25°C)] is greater than 21 (e.g., greater than 22, 23, 24, 25, 26, 27, 28, 29, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 130, 140, 150,
160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 350, 400, 450,
500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500 or 8000).
Methods for determining whether an antibody binds to a protein antigen and/or the affinity for an antibody to a protein antigen are known in the art. The binding of an antibody to a protein antigen, for example, can be detected and/or quantified using a variety of techniques such as, but not limited to, Western blot, dot blot, surface plasmon resonance (SPR) method (e.g., BIAcore system; Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.), or enzyme-linked immunosorbent assay (ELISA) (see, e.g., Benny K. C.
Lo (2004) “Antibody Engineering: Methods and Protocols,” Humana Press (ISBN: 1588290921); Johne, B. et al. , J. Immunol. Meth, 160:191-8, 1993; Jonsson, U. et aI.,Ahh. Biol. Clin., 51:19-26, 1993; Jonsson, U. et al, Biotechniques, 11:620-7, 1991). Additional methods for measuring, for example, affinity (e.g., dissociation and association constants) are set forth in the working examples.
As used herein, the term “ka” refers to the rate constant for association of an antibody to an antigen. The term “kd” refers to the rate constant for dissociation of an antibody from the antibody/antigen complex. And the term “KD” refers to the equilibrium dissociation constant of an antibody-antigen interaction. The equilibrium dissociation constant is deduced from the ratio of the kinetic rate constants, KD = ka/kd. Such determinations preferably are measured at 25°C or 37°C. The kinetics of antibody binding to human C5 can be determined, for example, at pH 8.0, 7.4, 7.0, 6.5 and 6.0 via surface plasmon resonance (SPR) on a BIAcore 3000 instrument using an anti-Fc capture method to immobilize the antibody.
Methods for determining whether a particular antibody described herein inhibits C5 cleavage are known in the art. Inhibition of human complement component C5 can reduce the cell-lysing ability of complement in a subject’s body fluids. Such reductions of the cell-lysing ability of complement present in the body fluid(s) can be measured by methods known in the art such as, for example, by a conventional hemolytic assay such as the hemolysis assay described by Kabat and Mayer (eds.), “Experimental Immunochemistry, 2nd Edition,” 135- 240, Springfield, IL, CC Thomas (1961), pages 135-139, or a conventional variation of that assay such as the chicken erythrocyte hemolysis method (Hillmen, P. et al., N. Engl. J. Med., 350:552-9, 2004). Methods for determining whether a candidate compound inhibits the cleavage of human C5 into forms C5a and C5b are known in the art (Evans, M. et al. , Mol. Immunol., 32:1183-95, 1995). The concentration and/or physiologic activity of C5a and C5b in a body fluid can be measured, for example, by methods known in the art. For C5b, hemolytic assays or assays for soluble C5b-9 as discussed herein can be used. Other assays known in the art can also be used. Using these or other suitable assays, candidate agents capable of inhibiting human complement component C5 can be screened.
Immunological techniques such as, but not limited to, ELISA can be used to measure the protein concentration of C5 and/or its split products to determine the ability of an anti-C5 antibody or antigen binding fragment thereof to inhibit conversion of C5 into biologically active products. In some embodiments, C5a generation is measured. In some embodiments, C5b-9 neoepitope-specific antibodies are used to detect the formation of terminal complement.
Hemolytic assays can be used to determine the inhibitory activity of an anti-C5 antibody or antigen binding fragment thereof on complement activation. To determine the effect of an anti-C5 antibody or antigen binding fragment thereof on classical complement pathway-mediated hemolysis in a serum test solution in vitro, for example, sheep erythrocytes coated with hemolysin or chicken erythrocytes sensitized with anti-chicken erythrocyte antibody are used as target cells. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the classical complement pathway is activated by a human IgM antibody, for example, as utilized in the Wieslab® Classical Pathway Complement Kit (Wieslab® COMPL CP310, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or antigen binding fragment thereof in the presence of a human IgM antibody. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the absorbance at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, the test serum is a C5-deficient serum reconstituted with a C5 polypeptide.
To determine the effect of an anti-C5 antibody or antigen binding fragment thereof on alternative pathway-mediated hemolysis, unsensitized rabbit or guinea pig erythrocytes can be used as the target cells. In some embodiments, the serum test solution is a C5-deficient serum reconstituted with a C5 polypeptide. The percentage of lysis is normalized by considering 100% lysis equal to the lysis occurring in the absence of the inhibitor. In some embodiments, the alternative complement pathway is activated by lipopolysaccharide molecules, for example, as utilized in the Wieslab® Alternative Pathway Complement Kit (Wieslab® COMPL AP330, Euro-Diagnostica, Sweden). Briefly, the test serum is incubated with an anti-C5 antibody or antigen binding fragment thereof in the presence of lipopolysaccharide. The amount of C5b-9 that is generated is measured by contacting the mixture with an enzyme conjugated anti-C5b-9 antibody and a fluorogenic substrate and measuring the fluorescence at the appropriate wavelength. As a control, the test serum is incubated in the absence of the anti-C5 antibody or antigen binding fragment thereof.
In some embodiments, C5 activity, or inhibition thereof, is quantified using a CH50eq assay. The CH50eq assay is a method for measuring the total classical complement activity in serum. This test is a lytic assay that uses antibody-sensitized erythrocytes as the activator of the classical complement pathway and various dilutions of the test serum to determine the amount required to give 50% lysis (CH50). The percent hemolysis can be determined, for example, using a spectrophotometer. The CH50eq assay provides an indirect measure of terminal complement complex (TCC) formation, since the TCC themselves are directly responsible for the hemolysis that is measured. Briefly, to activate the classical complement pathway, undiluted serum samples (e.g., reconstituted human serum samples) are added to microassay wells containing the antibody-sensitized erythrocytes to thereby generate TCC. Next, the activated serum samples are diluted in microassay wells, which are coated with a capture reagent (e.g., an antibody that binds to one or more components of the TCC). The TCC present in the activated samples bind to the monoclonal antibodies coating the surface of the microassay wells. The wells are washed and to each well is added a detection reagent that is detectably labeled and recognizes the bound TCC. The detectable label can be, e.g., a fluorescent label or an enzymatic label. The assay results are expressed in CH50 unit equivalents per milliliter (CH50 U Eq/mL).
Inhibition, e.g., as it pertains to terminal complement activity, includes at least a 5 (e.g., at least a 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 or 60) % decrease in the activity of terminal complement in, e.g., a hemolytic assay or CH50eq assay as compared to the effect of a control antibody (or antigen-binding fragment thereol) under similar conditions and at an equimolar concentration. Substantial inhibition, as used herein, refers to inhibition of a given activity (e.g., terminal complement activity) of at least 40 (e.g., at least 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 or greater) %. In some embodiments, an anti-C5 antibody described herein contains one or more amino acid substitutions relative to the CDRs of eculizumab (i.e., SEQ ID NOs:l-6), yet retains at least 30 (e.g., at least 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95) % of the complement inhibitory activity of eculizumab in a hemolytic assay or CH50eq assay.
An anti-C5 antibody described herein has a serum half-life in humans that is at least 20 (e.g., at least 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, 53, 54 or 55) days. In some embodiments, the anti-C5 antibody described herein has a serum half-life in humans that is at least 40 days. In some embodiments, the anti-C5 antibody described herein has a serum half-life in humans that is approximately 43 days. In some embodiments, the anti-C5 antibody described herein has a serum half-life in humans that is between 39-48 days. Methods for measuring the serum half-life of an antibody are known in the art. In some embodiments, an anti-C5 antibody or antigen binding fragment thereof described herein has a serum half-life that is at least 20 (e.g, at least 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 250, 300, 400, 500) % greater than the serum half-life of eculizumab, e.g., as measured in one of the mouse model systems described in the working examples (e.g., the C5- deficient/NOD/scid mouse or hFcRn transgenic mouse model system).
In some embodiments, the antibody competes for binding with, and/or binds to the same epitope on C5 as an antibody described herein. The term “binds to the same epitope” with reference to two or more antibodies means that the antibodies bind to the same segment of amino acid residues, as determined by a given method. Techniques for determining whether antibodies bind to the “same epitope on C5” with the antibodies described herein include, for example, epitope mapping methods, such as, x-ray analyses of crystals of antigen: antibody complexes that provides atomic resolution of the epitope and hydrogen/deuterium exchange mass spectrometry (HDX-MS). Other methods monitor the binding of the antibody to peptide antigen fragments or mutated variations of the antigen where loss of binding due to a modification of an amino acid residue within the antigen sequence is often considered an indication of an epitope component. Computational combinatorial methods for epitope mapping can also be used. These methods rely on the ability of the antibody of interest to affinity isolate specific short peptides from combinatorial phage display peptide libraries. Antibodies having the same VH and VL or the same CDR1, 2 and 3 sequences are expected to bind to the same epitope.
Antibodies that “compete with another antibody for binding to a target” refer to antibodies that inhibit (partially or completely) the binding of the other antibody to the target. Whether two antibodies compete with each other for binding to a target, i.e., whether and to what extent one antibody inhibits the binding of the other antibody to a target, can be determined using known competition experiments. In some embodiments, an antibody competes with and inhibits binding of another antibody to a target by at least 10%, 20%,
30%, 40%, 50%, 60%, 70%, 80%, 90% or 100%. The level of inhibition or competition may be different depending on which antibody is the “blocking antibody” (i.e., the cold antibody that is incubated first with the target). Competing antibodies can bind, for example, to the same epitope, an overlapping epitope or to adjacent epitopes (e.g., as evidenced by steric hindrance).
Anti-C5 antibodies or antigen-binding fragments thereof described herein, used in the methods described herein, can be generated using a variety of art-recognized techniques. Monoclonal antibodies may be obtained by various techniques familiar to those skilled in the art. Briefly, spleen cells from an animal immunized with a desired antigen are immortalized, commonly by fusion with a myeloma cell (Kohler, G. & Milstein, C., Eur. J. Immunol., 6:511-9, 1976). Alternative methods of immortalization include transformation with Epstein Barr Virus, oncogenes, or retroviruses, or other methods well known in the art. Colonies arising from single immortalized cells are screened for production of antibodies of the desired specificity and affinity for the antigen, and yield of the monoclonal antibodies produced by such cells may be enhanced by various techniques, including injection into the peritoneal cavity of a vertebrate host. One can alternatively isolate DNA sequences that encode a monoclonal antibody or a binding fragment thereof by screening a DNA library from human B cells (Huse, W. et ctl, Science, 246:1275-81, 1989).
Compositions
Pharmaceutical compositions comprising ravulizumab, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers are provided. The pharmaceutical compositions comprising ravulizumab provided herein are for use in, for example, diagnosing, detecting or monitoring a disorder, in preventing, treating, managing or ameliorating a disorder or one or more symptoms thereof, and/or in research. Formulations of pharmaceutical compositions, either alone or in combination with prophylactic agents, therapeutic agents, and/or pharmaceutically acceptable carriers, are known in the art.
Also, provided herein are compositions comprising an anti-C5 antibody or antigen binding fragment thereof for use in the treatment methods described herein, wherein a patient is switched from one anti-C5 antibody (e.g., eculizumab) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. The composition can be formulated as a pharmaceutical solution, e.g., for administration to a subject for the treatment or prevention of ALS. The pharmaceutical composition can include a pharmaceutically acceptable carrier. As used herein, a “pharmaceutically acceptable carrier” refers to, and includes, any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. The composition can include a pharmaceutically acceptable salt, e.g., an acid addition salt or a base addition salt, sugars, carbohydrates, polyols and/or tonicity modifiers.
The composition can be formulated according to known methods (Gennaro (2000) “Remington: The Science and Practice of Pharmacy,” 20th Edition, Lippincott, Williams & Wilkins (ISBN: 0683306472); Ansel et al. (1999) “Pharmaceutical Dosage Forms and Drug Delivery Systems,” 7th Edition, Lippincott Williams & Wilkins Publishers (ISBN: 0683305727); and Kibbe (2000) “Handbook of Pharmaceutical Excipients American Pharmaceutical Association,” 3rd Edition (ISBN: 091733096X)). In some embodiments, a composition can be formulated, for example, as a buffered solution at a suitable concentration and suitable for storage at 2-8°C (e.g., 4°C). In some embodiments, a composition can be formulated for storage at a temperature below 0°C (e.g., -20°C or -80°C). In some embodiments, the composition can be formulated for storage for up to 2 years (e.g., 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 1 year, 1 ½ years or 2 years) at 2-8°C (e.g., 4°C). Thus, in some embodiments, the compositions described herein are stable in storage for at least 1 year at 2- 8°C (e.g, 4°C).
The pharmaceutical compositions can be in a variety of forms. These forms include, e.g., liquid, semi-solid and solid dosage forms, such as liquid solutions (e.g., injectable and infusible solutions), dispersions or suspensions, tablets, pills, powders, liposomes and suppositories. The preferred form depends, in part, on the intended mode of administration and therapeutic application. Compositions containing a composition intended for systemic or local delivery can, for example, be in the form of injectable or infusible solutions. The compositions can be formulated for administration by a parenteral mode (e.g., intravenous, subcutaneous, intraperitoneal, or intramuscular injection). “Parenteral administration,” “administered parenterally” and other grammatically equivalent phrases, as used herein, refer to modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intranasal, intraocular, pulmonary, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intrapulmonary, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural, intracerebral, intracranial, intracarotid and intrastemal injection and infusion. In some embodiments, the antibodies are formulated for intravenous administration.
An exemplary, non-limiting range for a therapeutically or prophylactically effective amount of ravulizumab or other anti-C5 antibodies such as eculizumab, BNJ 421, 7086,
8110, SKY59 and H4H12166PP provided herein is 600-5000 mg, for example, 2000-4000 mg. It is to be noted that dosage values may vary with the type and severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens may be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed methods.
Combination Therapy
An anti-C5 antibody provided herein also can be administered with one or more additional medicaments or therapeutic agents useful in the treatment of ALS. The additional agent can be, for example, a therapeutic agent art-recognized as being useful to treat ALS. The combination can also include more than one additional agents, e.g., two or three additional agents. The binding agent in various embodiments is administered with an agent that is a protein, a peptide, a carbohydrate, a drug, a small molecule, or a genetic material (e.g., DNA or RNA).
Methods
Provided herein are methods for treating complement-associated disorder(s) (e.g., ALS) in a human patient, comprising administering to the patient an anti-C5 antibody or antigen binding fragment thereof wherein the anti-C5 antibody or antigen binding fragment thereof is administered (or is for administration) according to a particular clinical dosage regimen (i.e., at a particular dose amount and according to a specific dosing schedule).
In some embodiments, ALS is defined in a subject or patient in accordance with the King’s ALS clinical staging system (Roche, J.C. etal., Brain, 135(Part 3):847-852, 2012). The King’s ALS system categorizes the extent to which ALS has progressed in a patient or subject based upon the occurrence of discrete milestones, defined as the first occurrence of ALS symptoms (e.g., functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one central nervous system region defined as bulbar, upper limb, lower limb, or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, and a need for gastrostomy and non-invasive ventilation. Based upon these observable and measurable events, the King’s system classifies ALS progress according to four stages: Stage 1 - symptom onset with involvement of a first region; Stage 2 A - diagnosis; Stage 2B - involvement of second region; Stage 3 - involvement of third region; Stage 4A - need for gastrostomy; and Stage 4B - need for non-invasive ventilation.
In some embodiments, ALS is defined in a subject or patient as meeting the possible, laboratory-supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria, as described in FIG. 2. In some embodiments, the subject or patient is diagnosed with ALS onset, defined as the time of onset of first muscle weakness (e.g., limb weakness, dysarthria, dysphagia, and/or shortness of breath), no more than 36 months prior to being evaluated for treatment with the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, the subject or patient has an ALSFRS-R progression of 0.3 points per month or worse in the period from disease onset to the time of evaluation for treatment with the anti-C5 antibody or antigen binding fragment thereof. In some embodiments, the subject or patient has an upright slow vital capacity (SVC) of at least 65% at the time of evaluation for treatment with the anti-C5 antibody or antigen binding fragment thereof.
In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered once on Day 1 of the administration cycle, once on Day 15 of the administration cycle, and every eight weeks thereafter. In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered every eight weeks after the administration cycle for an extension period up to two years (e.g., at a dose of 3000 mg, 3300 mg or 3600 mg).
In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered for one or more administration cycles. In some embodiments, the administration cycle is 50 weeks. In some embodiments, the treatment comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 cycles. In some embodiments, the treatment is continued for the lifetime of the human patient.
In some embodiments, a patient switches from receiving one C5 inhibitor to a different C5 inhibitor during the course of treatment. Different anti-C5 antibodies can be administered during separate treatment periods. In some embodiments, for example, a method of treating a human patient having a complement-associated disorder (e.g., ALS) who is being treated with eculizumab is provided, the method comprising discontinuing treatment with eculizumab and switching the patient to treatment with an alternative complement inhibitor. In some embodiments, a method of treating a human patient having a complement- associated disorder who is being treated with ravulizumab is provided, the method comprising discontinuing treatment with ravulizumab and switching the patient to treatment with an alternative complement inhibitor.
Exemplary alternative complement inhibitors include, but are not limited to antibodies or antigen binding fragments thereof, small molecules, polypeptides, polypeptide analogs, peptidomimetics, siRNA and aptamers. In some embodiments, the alternative complement inhibitor inhibits one or more of complement components Cl, C2, C3, C4, C5, C6, C7, C8, C9, Factor D, Factor B, properdin, MBL, MASP-1, MASP-2, or biologically active fragments thereof. In some embodiments, the alternative complement inhibitor inhibits the anaphylatoxic activity associated with C5a and/or the assembly of the membrane attack complex associated with C5b. In some embodiments, the alternative complement inhibitor is selected from the group consisting of CR1, LEX-CR1, MCP, DAF, CD59, Factor H, cobra venom factor, FUT-175, complestatin and K76 COOH.
Exemplary alternative anti-C5 antibodies included, but are not limited to, (i) eculizumab, (ii), an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 21, 22 and 23, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 24, 25 and 26, respectively, (iii) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO:27 and a light chain variable region comprising SEQ ID NO:28, (iv) an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 29, 30 and 31, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 32, 33 and 34, respectively, (v) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO:35 and a light chain variable region comprising SEQ ID NO:36, (vi) an antibody or antigen binding fragment thereof comprising heavy chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 37, 38 and 39, respectively, and light chain CDR1, CDR2 and CDR3 domains comprising SEQ ID NOs: 40, 41 and 42, respectively, (vii) an antibody or antigen binding fragment thereof comprising a heavy chain variable region comprising SEQ ID NO:43 and a light chain variable region comprising SEQ ID NO:44, and (viii) an antibody or antigen binding fragment thereof comprising a heavy chain comprising SEQ ID NO:45 and a light chain comprising SEQ ID NO:46. In some embodiments, the patient is treated with ravulizumab and then switched to treatment with the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody, the H4H12166PP antibody or eculizumab. In some embodiments, the patient is switched from an anti-C5 antibody (e.g., eculizumab, the 7086 antibody, the 8110 antibody, the 305LO5 antibody, the SKY59 antibody or the H4H12166PP antibody) to another anti-C5 antibody (e.g., ravulizumab) during the course of treatment. In some embodiments, the patient is switched from eculizumab to ravulizumab during the course of treatment.
In some embodiments, the anti-C5 antibody is administered (or is for administration) according to a particular clinical dosage regimen (e.g., at a particular dose amount and/or according to a specific dosing schedule). In some embodiments, the anti-C5 antibody is administered at a fixed dose that is fixed irrespective of the weight of the patient. As used herein, the terms “fixed dose,” “flat dose” and “flat-fixed dose” are used interchangeably and refer to a dose that is administered to a patient without regard for the weight or body surface area (BSA) of the patient. The fixed or flat dose is therefore, not provided as a mg/kg dose, but rather as an absolute amount of the anti-C5 antibody or antigen binding fragment thereof.
In some embodiments, the anti-C5 antibody is administered at a fixed dose of 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg,
275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg,
800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg,
1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg,
2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg,
3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg,
3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg,
4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg,
5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg,
6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg,
7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg,
8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg,
9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg,
10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg, without regard to the patient’s weight.
In some embodiments, the dose of the anti-C5 antibody is based on the weight of the patient. In some embodiments, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg,
450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg,
725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg,
1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg of the anti-C5 antibody or antigen binding fragment thereof is administered to a patient weighing > 40 to < 60 kg.
In some embodiments, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg,
450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg,
725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg,
1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg of the anti-C5 antibody or antigen binding fragment thereof is administered to a patient weighing > 60 to < 100 kg.
In some embodiments, 10 mg, 20 mg, 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 825 mg, 850 mg, 875 mg, 900 mg, 925 mg, 950 mg, 975 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, 2000 mg, 2100 mg, 2200 mg, 2300 mg, 2400 mg, 2500 mg, 2600 mg, 2700 mg, 2800 mg, 2900 mg, 3000 mg, 3100 mg, 3200 mg, 3300 mg, 3400 mg, 3500 mg, 3600 mg, 3700 mg, 3800 mg, 3900 mg, 4000 mg, 4100 mg, 4200 mg, 4300 mg, 4400 mg, 4500 mg, 4600 mg, 4700 mg, 4800 mg, 4900 mg, 5000 mg, 5100 mg, 5200 mg, 5300 mg, 5400 mg, 5500 mg, 5600 mg, 5700 mg, 5800 mg, 5900 mg, 6000 mg, 6100 mg, 6200 mg, 6300 mg, 6400 mg, 6500 mg, 6600 mg, 6700 mg, 6800 mg, 6900 mg, 7000 mg, 7100 mg, 7200 mg, 7300 mg, 7400 mg, 7500 mg, 7600 mg, 7700 mg, 7800 mg, 7900 mg, 8000 mg, 8100 mg, 8200 mg, 8300 mg, 8400 mg, 8500 mg, 8600 mg, 8700 mg, 8800 mg, 8900 mg, 9000 mg, 9100 mg, 9200 mg, 9300 mg, 9400 mg, 9500 mg, 9600 mg, 9700 mg, 9800 mg, 9900 mg, 10000 mg, 10100 mg, 10200 mg, 10300 mg, 10400 mg, 10500 mg, 10600 mg, 10700 mg, 10800 mg, 10900 mg or 11000 mg is administered to a patient weighing > 100 kg. In some embodiments, dosage regimens are adjusted to provide the optimum desired response (e.g., an effective response).
In some embodiments, the anti-C5 antibody is administered at a milligram per kilogram (mg/kg) dose. In some embodiments, the anti-C5 antibody or antigen binding fragment thereof is administered at a dose of 0.1 mg/kg, 0.25 mg/kg, 0.5 mg/kg, 0.75 mg/kg, 1.0 mg/kg, 1.25 mg/kg,
1.50 mg/kg, 1.75 mg/kg, 2.0 mg/kg, 2.25 mg/kg, 2.50 mg/kg, 2.75 mg/kg, 3.0 mg/kg, 3.25 mg/kg,
3.50 mg/kg, 3.75 mg/kg, 4.0 mg/kg, 4.25 mg/kg, 4.50 mg/kg, 4.75 mg/kg, 5.0 mg/kg, 5.25 mg/kg,
5.50 mg/kg, 5.75 mg/kg, 6.0 mg/kg, 6.25 mg/kg, 6.50 mg/kg, 6.75 mg/kg, 7.0 mg/kg, 7.25 mg/kg,
7.50 mg/kg, 7.75 mg/kg, 8.0 mg/kg, 8.25 mg/kg, 8.50 mg/kg, 8.75 mg/kg, 9.0 mg/kg, 9.25 mg/kg,
9.50 mg/kg, 9.75 mg/kg, 10.0 mg/kg, 11.25 mg/kg, 11.50 mg/kg, 11.75 mg/kg, 12.0 mg/kg,
12.25 mg/kg, 12.50 mg/kg, 12.75 mg/kg, 13.0 mg/kg, 13.25 mg/kg, 13.50 mg/kg, 13.75 mg/kg, 14.0 mg/kg, 14.25 mg/kg, 14.50 mg/kg, 14.75 mg/kg, 15.0 mg/kg, 15.25 mg/kg, 15.50 mg/kg,
15.75 mg/kg, 16.0 mg/kg, 16.25 mg/kg, 16.50 mg/kg, 16.75 mg/kg, 17.0 mg/kg, 17.25 mg/kg,
17.50 mg/kg, 17.75 mg/kg, 18.0 mg/kg, 18.25 mg/kg, 18.50 mg/kg, 18.75 mg/kg, 19.0 mg/kg,
19.25 mg/kg, 19.50 mg/kg, 19.75 mg/kg, 20.0 mg/kg, 20.25 mg/kg, 20.50 mg/kg, 20.75 mg/kg, 21.0 mg/kg, 21.25 mg/kg, 21.50 mg/kg, 21.75 mg/kg, 22.0 mg/kg, 22.25 mg/kg, 22.50 mg/kg,
22.75 mg/kg, 23.0 mg/kg, 23.25 mg/kg, 23.50 mg/kg, 23.75 mg/kg, 24.0 mg/kg, 24.25 mg/kg,
24.50 mg/kg, 24.75 mg/kg or 25.0 mg/kg.
In some embodiments, the anti-C5 antibody 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 some embodiments, the anti-C5 antibody is administered twice daily. In some embodiments, the anti-C5 antibody 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 some embodiments, the anti-C5 antibody is administered at a loading dose on Day 1, followed by a different maintenance dose on Day 15 and every eight weeks thereafter.
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 some embodiments, 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 some embodiments, 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 ALS includes the amelioration or improvement of one or more symptoms associated with ALS. Symptoms associated with ALS include a progressive loss of motor neurons leading to variable amounts of weakness and spasticity in the limb, bulbar, and respiratory muscles.
In some embodiments, treatment of ALS includes an improvement of a clinical marker for ALS progression. Nonlimiting examples of clinical markers for ALS progression include:
• change from baseline in ALSFRS-R total score;
• change from baseline in percent predicted SVC at Week 50;
• percent change in combined muscle megascore from baseline at Week 50 as assessed by handheld dynamometry (HHD);
• time to the earliest occurrence of one of the following Ventilation Assistance-Free Survival (VAFS) events during the 50-week Randomized Controlled Period: all-cause mortality; first use of non-invasive ventilation (NIV) for > 22 hours per day for > 10 consecutive days; and first use of permanent assisted ventilation (PAV) for > 22 hours per day for > 7 consecutive days;
• change from baseline in ALSAQ-40 score at Week 50;
• change from baseline in European Quality of Life Health 5-item questionnaire (EQ 5D 5L) at Week 50; • change from baseline in Short Form Health Survey (SF 36) at Week 50;
• change from baseline in total Treatment Satisfaction Questionnaire for Medication (TSQM) score;
• change from baseline in neurofilament light chain (NfL) concentrations in serum at Week 50;
• shifts from baseline in Columbia-suicide severity rating scale (C-SSRS) at Week 50;
• change from baseline in vital signs, electrocardiogram (ECG) parameters, and clinical laboratory assessments;
• change from baseline in levels of biomarkers of complement dysregulation, neuroinflammation, and neurodegeneration;
• any decline from baseline stage on the King’s staging system at Week 50;
• change in ALSFRS-R total score, VAFS, SVC, HHD, and patient-reported outcome measures over time in all patients exposed to ravulizumab during the Open-Label Extension Period; and
• incidence of treatment emergent adverse events (TEAEs), treatment emergent serious adverse events (TESAEs), and TEAEs leading to study drug discontinuation during the Open-Label Extension Period.
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
The ALSFRS-Revised (Cedarbaum, 1999) is a validated instrument for evaluating the levels of the functional status of patients with ALS in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions (FIG. 3). The scale includes 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicates greater retention of function. The ALSFRS-R will be assessed as indicated in the Schedule of Activities. The endpoint for this primary measurement of efficacy is change from baseline in ALSFRS-R total score at Week 50.
Ventilation Assistance-Free Survival (VAFS)
Ventilation Assistance-Free Survival is a composite endpoint of survival and severe and irreversible respiratory decline. The use of VAFS allows for the collection of survival data that is not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which can prolong life without impacting underlying disease progression. The composite endpoint of VAFS (Paganoni, 2014) that will be used as a secondary endpoint for this trial will be defined as the first occurrence of: all-cause mortality; first use of NIV for > 22 hours per day for > 10 consecutive days; or first use of PAV for > 22 hours per day for > 7 consecutive days.
Slow Vital Capacity (SVC)
Slow vital capacity is a spirometry technique that utilizes slow and gradual expulsion of air from the lungs. The full volume of expired air is measured as a proportion of the expected vital capacity of the patient based on biometric features such as height, weight, and sex. The endpoint for this secondary measurement of efficacy is change from baseline in percent (%) predicted SVC at Week 50.
Handheld Dvnamometrv (HHD)
Handheld dynamometry (HHD) (Shefner, 2016) is a procedure for quantitative strength testing. Muscle strength testing will be performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements recorded. Handheld dynamometry will be assessed at screening and time points specified in the Schedule of Activities. The endpoint for this secondary measurement of efficacy is percent change in combined muscle megascore from baseline at Week 50 as assessed by HHD.
Additional secondary measurements of efficacy for this clinical study are, e.g., serum Nil concentration, PK/PD measurements, serum free C5 concentration, the presence of anti drug antibodies (ADSs), and the incidence of TEAEs, TESAEs, and TEAEs leading to study drug discontinuation, are described in Table 5.
Change in ALSAQ-40 score
A single index score is created by adding all of the responses (0, 1, 2, 3, or 4) of 40 items of ALSAQ-40, dividing this total score by the maximal score of 160 and finally multiplying by 100 (FIG. 4). An index score of 0 indicates perfect health and 100 indicates worst possible health status. The treatment effect on ALSAQ-40 index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline ALSAQ-40 index score, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor. The Kenward Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR. The endpoint for this exploratory measurement of efficacy is change from baseline in ALSAQ-40 score at Week 50. EuroQoL 5 Dimensions (EQ-5D-5L)
The European Quality of Life (EQ-5D-5L) is a self-assessed, standardized instrument to measure health-related quality of life and has been used in a wide range of health conditions, including ALS (Schrag, 2000). The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS) (FIG. 5 and FIG. 6). At time points specified in the Schedule of Activities, or if a patient is not able to attend the scheduled onsite visit, EQ-5D-5L can be assessed via a phone call. The EQ-5D-5L descriptive system is 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. The EQ-5D-5L Visual Analog Scale (VAS) is an overall health state scale where the patient selects a number between 0 and 100 to describe the condition of their health, with 100 being ‘The best health state you can imagine’ and 0 being ‘The worst health state you can imagine’. This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Previously published studies by EuroQol Group members showed preliminary evidence of the instrument’s feasibility, reliability, and validity. The endpoint for this exploratory measurement of efficacy is change from baseline in EQ 5D 5L at Week 50.
Short Form Health Survey (SF-36)
The SF-36 is a 36-item self-report of health-related quality of life (Stewart, 1988; Ware, 1992). It contains 8 subscales measuring different domains of health-related quality of life: 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 (FIG. 7 and FIG. 8). The SF-36 will be conducted at screening and at timepoints specified per Schedule of Activities. The two (2) summary scores are the physical component summary and the mental component summary. There is no single overall score for the SF-36. The endpoint for this exploratory measurement of efficacy is change from baseline in SF-36 at Week 50
Treatment Satisfaction Questionnaire for Medication (TSQM)
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) assesses 3 key dimensions of treatment satisfaction: Effectiveness (3 items); Convenience (3 items); and Global Satisfaction (3 items) (Bharmal, 2009) (FIG. 9). The instrument has been validated in chronic diseases including ALS (Meyer, 2019). The recall period for the TSQM is the previous 2 to 3 weeks or since last use. The TSQM-9 can be used to estimate total TSQM score, score for effectiveness, and score for convenience. The TSQM-9 will be administered at Day 1 and at timepoints specified in the Schedule of Activities.
Columbia-Suicide Severity Rating Scale (C-SSRS)
Baseline assessment of suicidal ideation and behavior as well as intervention- emergent suicidal ideation and behavior will be monitored during this study using the Columbia-suicide severity rating scale (C-SSRS). There are 2 types of C-SSRS assessments that will be conducted during the study as an exploratory measurement of efficacy: C-SSRS at Baseline/Screening (FIG. 10) and C-SSRS-Since Last Visit (FIG. 11).
According to some embodiments, the course of treatment with ravulizumab lasts for 50 weeks. According to some embodiments, the course of treatment lasts for 50-76, 50- 102, 50-128, 50-154, 50-180, 50-206 weeks, or more. In some embodiments, the course of treatment lasts for 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 102, 128, 154, 180, or 206 weeks, or more. According to some 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 years, or more. In some embodiments, the maintenance phase 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 ALS improves during the course of treatment and is maintained at the improved level throughout treatment. ALS can improve, for example, after 50 weeks of treatment with a therapeutic antibody that specifically binds C5 and then remain at the improved level for the remaining duration of the treatment with a therapeutic antibody that specifically binds C5. One example of a therapeutic antibody that binds C5 is ravulizumab.
In some embodiments, the first sign of improvement occurs by 50 weeks of treatment with a therapeutic antibody that specifically binds C5. According to some embodiments, the first sign of improvement occurs between weeks 50-76, 76-102, 102- 128, 128-154, 154-180, 180-206 weeks of treatment with a therapeutic antibody that specifically binds C5. 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, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,
76, 102, 128, 154, 180, or 206.
Kits and Unit Dosage Forms
Also provided herein are kits that include a pharmaceutical composition containing an anti-C5 antibody or antigen binding fragment thereof, such as ravulizumab, 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 ALS. 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 anti-C5 antibody or antigen binding fragment thereof 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 anti-C5 antibody or antigen binding fragment thereof.
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
EXAMPLE 1: A PHASE 3, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED, PARALLEL GROUP, MULTICENTER STUDY TO EVALUATE THE EFFICACY AND SAFETY OF RAVULIZUMAB IN ADULT PATIENTS WITH ALS.
This study is a Phase 3, double-blind, randomized, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of ravulizumab in adult patients with ALS. There are 3 periods in this study: Screening Period, Randomized Controlled Period, and Open Label Extension Period. A schematic of the study design is shown in FIG. 1.
Patients will be screened for eligibility for up to 4 weeks during the Screening Period. Approximately 354 eligible adult patients with ALS from North America, Europe, and the Asia Pacific region will be enrolled into the study. Patients who are not taking or who are on a stable regimen of riluzole and/or edaravone at Screening will be considered for participation.
Eligible patients will be randomized in a 2: 1 ratio to receive weight-based intravenous (IV) infusion of ravulizumab or matching placebo until Week 50 during the double blind Randomized Controlled Period. Randomization will be stratified based on the site of ALS muscle weakness onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS therapy) (Table 10). The Schedule of Activities for the Screening Period to Week 50 is shown in Table 1 below.
For each patient, the Randomized Controlled Period ends and the Open Label Extension Period starts when the patient has completed the Week 50 visit assessments. Regardless of prior treatment allocation, all patients will receive ravulizumab treatment during the Open Label Extension Period. The Open Label Extension Period will continue for up to 2 years, or until ravulizumab is approved and/or available (in accordance with country specific regulations), whichever occurs first. The Schedule of Activities for Week 50 to Week 116 is shown in Table 2 below. After the end of treatment visit or early discontinuation, patients will be followed for an additional 8 weeks after the last dose of study drug. Treatment allocation will be blinded to patients, study sites, and the Sponsor throughout the Randomized Controlled Period and will remain blinded to patients and study sites until end of the study. The Schedule of Activities for Week 124 to the End of Study is shown in Table 3 below.
Table 1: Schedule of Activities: Screening to Week 50
Figure imgf000034_0001
Table 1 : Schedule of Activities: Screening to Week 50 (Continued)
Figure imgf000035_0001
Table 1 : Schedule of Activities: Screening to Week 50 (Continued)
Figure imgf000036_0001
Table 1 : Schedule of Activities: Screening to Week 50 (Continued)
Figure imgf000037_0001
Note: B = baseline (Day 1); P = post-dose; T = trough (pre-dose); X = anytime.
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSAQ-40 = amyotrophic lateral sclerosis assessment questionnaire; ALSFRS-R = amyotrophic lateral sclerosis functional rating scale-revised; CBC = complete blood count; CSF = cerebrospinal fluid; C-SSRS = Columbia-suicide severity rating scale; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L = European Quality of Life Health 5-item questionnaire; HHD = handheld dynamometry; KSS = King’s staging system;
PK = pharmacokinetics; RCP = Randomized Controlled Period; SF-36 = short form health survey; SVC = slow vital capacity; TSQM = Treatment Satisfaction Questionnaire for Medication; W = week; WOCBP = women of childbearing potential. a This visit is optional. It should be completed only by patients who consent to optional CSF collection. b For patients who discontinue the study prior to the end of the Randomized Controlled Period, the ED in RCP visit should be completed as soon as possible. In addition, a Followup Phone Call will be performed 8 weeks (56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant medications, nonpharmacological therapies and procedures, and AEs. c Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be more than 16 weeks apart. d Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study. When possible, ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HHD should be performed as last assessment prior to dosing. e At the time points specified, or if a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee. f Assessments denoted by H can be performed in clinic, by home visit, or by telephone contact. When performed by telephone, the telephone interview version of the questionnaire should be used, if available. g Most recent CBC and coagulation panel should be reviewed prior to CSF sample collection. Lumbar punctures must be performed after all assessments are completed.
Table 2: Schedule of Activities: Week 50 to Week 116
Figure imgf000038_0001
Table 2: Schedule of Activities: Week 50 to Week 116 (Continued)
Figure imgf000039_0001
Note: P = postdose; T = trough (pre-dose); X = anytime.
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSFRS-R = revised amyotrophic lateral sclerosis functional rating scale; C5 = complement component 5; C- SSRS = Columbia-suicide severity rating scale; D = day; ECG = electrocardiogram; ED = early discontinuation; EQ-5D-5L = European Quality of Life Health 5-item questionnaire; HHD = handheld dynamometry; PK = pharmacokinetics; SF-36 = short form health survey; SVC = slow vital capacity; W = week; WOCBP = women of childbearing potential. a Ravulizumab dosing is based on the last recorded study visit body weight. When possible, weights should be obtained at every dosing visit; consecutive weights must not be more than 16 weeks apart. b Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study. When possible, ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HHD should be performed as last assessment prior to dosing. c If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee. d If this is an ED visit, no dose of study drug is given.
Table 3 : Schedule of Activities: Week 124 to End of Study
Figure imgf000040_0001
Table 3: Schedule of Activities: Week 124 to End of Study (Continued)
Figure imgf000041_0001
Note: P = postdose; T = trough (pre-dose); X = anytime.
Abbreviations: ADA = antidrug antibody; AE = adverse event; ALSFRS-R = revised amyotrophic lateral sclerosis functional rating scale; C5 = complement component 5;
C-SSRS = Columbia-suicide severity rating scale; D = day; ECG = electrocardiogram; ED = early discontinuation; EOS = end of study; EQ-5D-5L = European Quality of Life Health 5-item questionnaire; OLE = Open-Label Extension; PK = pharmacokinetics; SF-36 = short form health survey; SVC = slow vital capacity; TSQM= Treatment Satisfaction Questionnaire for Medication; W = week; WOCBP = women of childbearing potential. a Patients who discontinue the study during the open-label extension period, the ED in OLE visit should be completed as soon as possible. In addition, a Follow-up Phone Call will be performed 8 weeks (56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant medications, nonpharmacological therapies and procedures, and AEs. b Performed by the Investigator or any designee who has been properly trained for the evaluation, preferably the same Investigator or designee, throughout the study. When possible, ALSFRS-R and SVC should be performed prior to other efficacy assessments, and HF1D should be performed last c If a patient is not able to attend the scheduled onsite visit, the ALSFRS-R and EQ-5D-5L can be assessed via a phone call by the Investigator or trained designee.
Two interim analyses are planned for the Randomized Controlled Period. An independent data monitoring committee (IDMC) will be established to conduct the unblinded interim analyses and periodic review of accumulating data for patient safety and efficacy during the trial. The first interim analysis for futility will be conducted when approximately 33% of patients have completed the Week 26 (6 months) visit. The second interim analysis will be performed when approximately all patients have completed the Week 26 visit. At this time, a futility analysis will be conducted. If the study is not considered futile, an additional analysis will be performed to determine if success criteria are met. If the efficacy analysis meets prespecified criteria for success, the Randomized Controlled Period may be stopped for success and all patients may transition to the Open-Label Extension Period.
In the event that the Randomized Controlled Period is stopped for success, any patient who is still in the Randomized Controlled Period will transition to the Open-Label Extension Period at their next scheduled dosing visit. Regardless of previous visit number, when the patient returns for the next scheduled dosing visit, the patient will follow the procedures outlined in Visit 13 in the Schedule of Activities and continue all subsequent visits as outlined to the End of Study Visit. For patients who are in the Open-Label Extension Period when the Randomized Controlled Period is stopped for success, there will be no change to the visit schedule.
1. RISK BENEFIT ASSESSMENT
Risk Assessment
Based on clinical trial experience and cumulative clinical trial safety data of ravulizumab in PNH and aHUS, ravulizumab has been demonstrated to be well tolerated and safe, and exposure to ravulizumab in humans has not raised any unexpected safety concerns. Ravulizumab functions by blocking terminal complement; therefore, patients have increased susceptibility to serious infections, in particular Neisseria meningitidis (Table 4).
As with any therapeutic protein, administration of ravulizumab may lead to the development of antidrug antibodies (AD As). Monitoring of immunogenicity is planned. Administration of any investigational product may result in infusion reactions. Management of potential infusion reactions is described herein. Table 4: Ravulizumab Identified and Potential Risks
Figure imgf000043_0001
Benefit Assessment
Amyotrophic lateral sclerosis is a devastating neurodegenerative disease with a poor prognosis, rapid progression, and limited treatment options for which discovery of new therapies is important to address unmet medical need. Clinical research provides the best modality to identify effective treatments with the potential to slow disease progression and improve survival which are of critical importance to patients with ALS and their providers. Although the efficacy of ravulizumab has not been previously studied in patients with ALS, it represents an appropriate candidate for investigation due to its plausible mechanism of action in ALS and reliable pharmacokinetic (PK) and pharmacodynamic (PD) properties as well as the demonstrable functional benefit of complement inhibition in ALS animal models and in the treatment of other neuroinflammatory conditions. The scientific and therapeutic hypothesis for the potential benefit in ALS. Given the severity of ALS, collective consideration of the unmet medical need and plausible mechanism of action with the expected safety profile and mitigation measures in place provides support for initiation of a Phase 3 clinical trial with ravulizumab.
2. SCIENTIFIC RATIONALE
Study Population and Treatment Duration
Neuroinflammation and complement dysregulation are hypothesized to be common pathways in both sporadic and familial ALS. Complement dysregulation may be important to disease progression both early and throughout the course of disease, and thus a broad study population is targeted. The eligible study population fulfils the El Escorial diagnostic criteria of possible, probable, probable laboratory supported, or definite ALS, is within 36 months or less from disease onset, and demonstrates a SVC of 65% predicted or more and not yet requiring respiratory support.
Given that the typical time from onset of muscle weakness to diagnosis is approximately 1 year, these characteristics will likely permit enrolment of patients in the early to mid-stages with mild to moderate manifestations of the disease. Given the heterogenous nature of ALS, including rates of disease progression across patients, a minimal pre-study progression criteria of 0.3 points per month or worse on the amyotrophic lateral sclerosis functional rating scale revised (ALSFRS-R), calculated as (48 - ALSFRS R at Screening)/(months from onset to Screening) will be used to enrich for patients more likely to demonstrate disease progression in the course of the study. The selected population is hypothesized to better allow for the potential detection of a treatment benefit.
A randomized, double-blind, placebo-controlled study design is selected to provide the most robust evidence of the effectiveness of the intervention on disease progression and safety. Randomization minimizes the effects of baseline differences and confounding factors on the study population. The use of a placebo comparator allows for the true treatment effect of the intervention to be established while also allowing for study management, drug administration, and assessments to be conducted similarly between treatment groups, thus minimizing the potential for bias. An unequal randomization scheme was chosen to decrease the number of patients receiving placebo. Patients may continue to receive standard of care treatment for ALS, which may include riluzole and/or edaravone as detailed in the inclusion/exclusion criteria. To reduce the heterogeneity in the study results, a stratification scheme has been implemented. This stratification includes the use of background therapies which are permitted, but not mandated, in accordance with ethical standards.
A 50-week primary evaluation period was selected to ensure characterization of effects on multiple functional and survival endpoints. This timeframe allows for a rigorous assessment of ALSFRS R in which potential differences can both be detected and characterized for magnitude and durability of response. The 50 week treatment period also allows the opportunity to characterize potential treatment effects on other important endpoints, such as survival, which may take longer to demonstrate than the ALSFRS-R.
A trial design with interim analyses was chosen to allow for early stopping in the case of futility or efficacy. The interim analyses minimize exposing patients to an ineffective therapy or prolonged exposure to placebo in the event of detecting efficacy earlier. An open-label extension period was chosen to ensure that all patients participating in this study have the opportunity to receive active treatment after the completion of the Randomized Controlled Period of the study. This period also allows for further evaluation of longer term safety and efficacy of the study intervention.
Rationale for Primary Endpoint: ALSFRS-R
The ALSFRS-R is a validated instrument and the most widely used instrument to measure physical function in performance of daily living activities across the 4 domains of gross motor activity, fine motor activity, bulbar, and respiratory function in patients with ALS (Cedarbaum, 1999). The scale is composed of 12 items with a maximum score of 48, with lower scores associated with declining function. Changes in ALSFRS R total score have been shown to be reproducible over time and to correlate with survival and other functional measures. It is considered an important efficacy endpoint in clinical trials and clinical practices (Castrillo- Viguera, 2010).
Rationale for Secondary Endpoints Included in the Multiplicity Adjustment
Ventilation Assistance-Free Survival (VAFS)
Survival is accepted as a clinically relevant outcome measure in ALS clinical trials. However, overall survival in ALS can be significantly influenced by the use of NIV or PAV which can prolong overall survival without altering the underlying disease pathology. To account for the prolongation of survival in the absence of disease modification, VAFS, a composite endpoint accounting for survival and severe respiratory failure, is defined. In the absence of uniform guidelines for the initiation of NIV and PAV, this endpoint is defined around dependence based on the continuous or nearly continuous need for ventilation assistance. Therefore, VAFS is defined for this study as the time to the earliest occurrence of one of the following events: all-cause mortality; first use of NIV for > 22 hours per day for > 10 consecutive days; or first use of PAV for > 22 hours per day for > 7 consecutive days.
Slow Vital Capacity (SVC)
Slow vital capacity is defined as the amount of air expelled from the lungs during a slow, gentle breath, which has been shown to correlate with clinical events such as use of assisted ventilation, tracheostomy, and ultimately, death. Patients with slower decline in SVC could breathe unassisted and survive longer than patients whose SVC declined faster (Andrews, 2018).
Compared with forced vital capacity (FVC), SVC may be easier to measure in ALS patients as patients with loss of muscle function in the face and mouth are still able to perform the gentler test and it is less subject to the fatigue and bronchospasm that can underestimate lung capacity measured by FVC. Slow vital capacity is considered as a prognostic marker in the clinic and may predict disease progression, respiratory functional decline, and survival.
3. JUSTIFICATION FOR DOSE
The dosing regimen of ravulizumab was designed to target immediate, complete, and sustained inhibition of terminal complement in patients. The weight-based doses of ravulizumab in the PNH program were based on PK/PD data from early and late clinical development studies in healthy adult volunteers and patients with PNH. The proposed ravulizumab dosage regimen is the approved regimen for the treatment of patients with PNH and aHUS in the Ultomiris USPI, and the same dose regimen is also approved by the European Commission in the EU and the Pharmaceuticals and Medical Devices Agency in Japan for the treatment of PNH.
In ALS patients and preclinical models, dysregulation of the complement system has been identified prior to the onset of neurodegeneration. Inhibition of terminal complement may therefore diminish neuroinflammatory damage in ALS. Based on this and the PK, PD, ADA, efficacy, and safety data generated in the ravulizumab development program, the body weight- based dosage regimen for treating adult patients with PNH and aHUS has been selected for this study, and is expected to be beneficial in treating patients with ALS through immediate, complete and sustained inhibition of terminal complement activation.
4. END OF STUDY DEFINITION
A patient is considered to have completed the study if he/she has completed all phases of the study including the last scheduled procedure shown in the Schedule of Activities. The end of the study is defined as the date the last patient completes the last visit shown in the Schedule of Activities.
5. OBJECTIVES
The primary objective of the study is to evaluate the effect of ravulizumab compared with placebo on ALSFRS-R score in adult patients with ALS.
The secondary objectives of this study are: (1) evaluate the effect of ravulizumab compared with placebo on VAFS in adult patients with ALS; (2) to evaluate the effect of ravulizumab compared with placebo on respiratory function in adult patients with ALS; (3) to evaluate the safety of ravulizumab compared with placebo in adult patients with ALS; (4) evaluate the effect of ravulizumab compared with placebo on muscle strength in adult patients with ALS; (5) to evaluate the effect of ravulizumab compared with placebo on neurofilament light chain (NfL) concentrations in adult patients with ALS; (6) to characterize the PK of ravulizumab in adult patients with ALS; (6) to characterize the D of ravulizumab in adult patients with ALS; and (7) to characterize the immunogenicity of ravulizumab in adult patients with ALS.
Exploratory objectives of this study are: (1) to evaluate the effect of ravulizumab compared with placebo on respiratory function in adult patients with ALS; (2) to evaluate the effect of ravulizumab compared with placebo on overall health related quality of life in adult patients with ALS; (3) to evaluate the safety of ravulizumab compared with placebo in adult patients with ALS; (4) to characterize biomarkers in adult patients with ALS; (5) to evaluate the effect of ravulizumab compared with placebo on ALS-related health quality of life in adult patients with ALS; (5) to characterize the effect of ravulizumab compared to placebo on disease stage in adult patients with ALS; (6) to evaluate the long-term efficacy of ravulizumab in adult patients with ALS; and (7) to evaluate the long-term safety of ravulizumab in adult patients with ALS.
6. ENDPOINTS
The primary efficacy endpoint of the study is change from baseline in ALSFRS-R total score at Week 50.
Secondary efficacy endpoints of the study include: (1) time to the earliest occurrence of 1 of the following events during the 50-week Randomized Controlled Period: (a) all-cause mortality; (b) first use of NIV for > 22 hours per day for > 10 consecutive days; and (c) first use of PAV for > 22 hours per day for > 7 consecutive days; (2) change from baseline in percent (%) predicted SVC at Week 50; (3) incidence of TEAEs, TESAEs, and TEAEs leading to study drug discontinuation; (4) percent change in combined muscle megascore from baseline at Week 50 as assessed by HHD; (5) change from baseline in NfL concentrations in serum at Week 50; (6) change in serum ravulizumab concentration over the study duration; (7) change in serum free C5 concentration over the study duration; and (8) presence and titer of antidrug antibodies (AD As).
The exploratory endpoints of this study are: (1) time to first instance of SVC < 50% predicted during the 50-week Randomized Controlled Period; (2) change from baseline in SF-36 at Week 50; (3) change from baseline in EQ 5D 5L at Week 50; (4) shifts from baseline in C- SSRS at Week 50; (5) change from baseline in vital signs, ECG parameters, and clinical laboratory assessments; (6) change from baseline in levels of biomarkers of complement dysregulation, neuroinflammation and neurodegeneration; (7) change from baseline in ALSAQ- 40 score at Week 50; (8) any decline from baseline stage on the King’s staging system at Week 50; (9) change in ALSFRS-R total score, VAFS, SVC, HHD, and patient-reported outcome measures over time in all patients exposed to ravulizumab during the Open-Label Extension Period; and (10) incidence of TEAEs, TESAEs, and TEAEs leading to study drug discontinuation during the Open-Label Extension Period. The objectives and endpoints of the study are summarized in Table 5 below.
TABLE 5: Study ALXN1210-ALS-308 objectives and endpoints
Figure imgf000049_0001
Figure imgf000050_0001
7. STUDY POPULATION
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as protocol waivers are not allowed. Inclusion Criteria
Patients are eligible to be included in the study only if all of the following criteria apply: Age
1. Male and female patients are aged > 18 years of age at the time of signing the informed consent
Type of Patient and Disease Characteristics 2. A diagnosis of ALS, defined as meeting the possible, laboratory supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria. Patients diagnosed with either sporadic or familial ALS are eligible for enrollment.
3. ALS onset, defined as time of onset of first muscle weakness ( e.g ., limb weakness, dysarthria, dysphagia, shortness of breath), < 36 months from the Screening Visit.
4. Pre-study ALSFRS-R progression between disease onset and screening of -0.3 points per month or worse (calculated by ALSFRS-R total score decline from 48 divided by the months since onset of ALS symptoms).
5. Upright SVC > 65% predicted at Screening.
6. Vaccinated against N. meningitidis within 3 years prior to, or at the time of, initiating ravulizumab. Patients who initiate study drug treatment less than 2 weeks after receiving a meningococcal vaccine must receive appropriate prophylactic antibiotics until 2 weeks after the vaccination.
7. Patients who enter the trial receiving standard of care for ALS (i.e., riluzole and/or edaravone), either in combination or monotherapy, must be on a stable dosing regimen of adequate duration prior to screening with no plan to discontinue or to change the dose during the study period as follows:
■ If a patient who enters the study is receiving riluzole, the patient must have been on a stable dose of riluzole for > 30 days prior to Day 1.
■ If a patient who enters the study is receiving edaravone, the patient must have initiated edaravone > 60 days (2 treatment cycles) prior to Day 1.
■ Note: Patients not on riluzole and/or edaravone at the time of screening are permitted in the study.
Weight
8. Body weight > 40 kg at Screening.
Sex
9. Male and/or female
Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
• Male patients: Male patients must agree to use contraception as detailed in the protocol during the treatment period and for at least 8 months after the last dose of study drug and refrain from donating sperm during this period.
• Female patients:
A female patient is eligible to participate if she is not pregnant, not breastfeeding, and meets at least one of the following conditions:
Not a woman of childbearing potential (WOCBP); or
Is a WOCBP and using a highly effective or acceptable contraceptive method during the treatment period and for a minimum of 8 months after the last dose of study drug.
The Investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study drug. A WOCBP must have a negative serum pregnancy test at Screening and a negative urine pregnancy test before the first dose of study drug. The Investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
Informed Consent
10. Capable of giving written or verbal informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
Exclusion Criteria
Patients are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of N. meningitidis infection.
2. Human immunodeficiency virus (HIV) infection (evidenced by HIV-1 or HIV-2 antibody titer).
3. History of unexplained infections.
4. Active systemic bacterial, viral, or fungal infection within 14 days prior to study drug administration on Day 1. 5. Presence of fever > 38°C (100.4°F) within 7 days prior to study drug administration on Day 1.
6. Hypersensitivity to murine proteins or to 1 of the excipients of ravulizumab.
7. Dependence on invasive or non-invasive mechanical ventilation. Dependence on mechanical ventilation is defined as being unable to lie flat (supine) without it, unable to sleep without it, or daytime use > 6 hours per day for > 3 days per week. Non- invasive ventilation for sleep apnea is allowed subject to discussion with Medical Monitor.
8. Any medical condition that, in the opinion of the Investigator, might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient.
9. The presence of unstable psychiatric disease or dementia that might interfere with the patient’s participation in the trial, poses any added risk for the patient, or confounds the assessment of the patient.
10. History of drug and/or alcohol abuse (according to Diagnostic and Statistical Manual of Mental Disorders) within 1 year of screening that would limit patient participation in the study as determined by the Investigator.
11. History of Parkinson’s disease, myasthenia gravis, multiple sclerosis, or any other neurological disorder that may confound the diagnosis or assessment of the patient as determined by the Investigator.
Prior/Concomitant Therapy
12. Previously or currently treated with a complement inhibitor.
13. Use of IV immunoglobulin (IVIg) within 3 weeks prior to screening.
14. Has a diaphragm pacing system (DPS) at study entry or anticipate DPS placement during the course of the study.
Prior/Concurrent Clinical Study Experience
15. Participation in any other investigational product study or exposure to an investigational drug or device within 30 days of screening or 5 half-lives of the study drug, whichever is greater or any prior exposure to gene therapy.
Other Exclusions
16. Pregnant, breastfeeding, or intending to conceive during the course of the study. Lifestyle Considerations
There is no lifestyle restriction for this study.
Screen Failures
Screen failures are defined as patients who consent to participate in the clinical study but are not subsequently randomly assigned to study drug. A minimal set of screen failure information is required to ensure transparent reporting of screen failures to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from regulatory authorities. Minimal information includes demography, screen failure details ( e.g ., failed eligibility criteria), and any adverse events (AEs), including any serious adverse events (SAEs) and any related concomitant medication, occurring during the screening period.
Individuals who do not meet the criteria for participation in this study (screen failure) due to a reason that is expected to resolve or has resolved may be rescreened based on discussion and agreement between the Investigator and the Medical Monitor. 8. STUDY DRUG
Study drug is defined as any investigational drug(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol.
Study Drug(s) Administered In this study, patients will be randomized 2: 1 to receive blinded ravulizumab or placebo treatment during the Randomized Controlled Period; during the Open-Label Extension period, all patients will receive open-label ravulizumab treatment (Table 6).
Table 6: Study Drugs
Figure imgf000055_0001
Abbreviations: IMP = investigational medicinal product; IV = intravenous; NIMP = non-investigational medicinal product; q8w = every 8 weeks.
Preparation/Handling/Storage/ Accountability
Upon arrival of the study drug at the study site, the study drug kits should be removed from the shipping container and stored in their original cartons under refrigerated conditions at 2°C to 8°C (35°F to 47°F) and protected from light. Study drugs should not be frozen. Study drugs must be stored in a secure, limited-access storage area with temperature monitored daily.
Infusions of study drug should be prepared using aseptic technique. Ravulizumab and placebo will be further diluted in a 1:1 ratio with compatible diluent. Ravulizumab and placebo will be filtered with a 0.2 micron filter during infusion.
• The Investigator or designee must confirm appropriate temperature conditions have been maintained during transit for all study drug received and any discrepancies are reported and resolved before use of the study drug.
• Only patients enrolled in the study may receive the study drug and only authorized site staff may supply or administer the study drug. All study drug must be stored in a secure, environmentally controlled, and monitored (manual or automated) area in accordance with the labeled storage conditions with access limited to the Investigator and authorized site staff.
• The Investigator, institution, or the head of the medical institution (where applicable) is responsible for study drug accountability, reconciliation, and record maintenance (/. ., receipt, reconciliation, and final disposition records).
• Further guidance and information for the final disposition of unused study drugs are provided in the Pharmacy Manual.
Measures to Minimize Bias: Randomization and Blinding
Randomization
Patients will be randomly allocated on Day 1 to one of two treatment groups after the Investigator and Medical Monitor have verified that they are eligible. Patients will be stratified by site of muscle weakness onset (bulbar vs other) and background ALS treatment (riluzole and/or edaravone vs neither ALS therapy) and randomized 2: 1 either to ravulizumab IV infusion or placebo IV infusion. Patients will be centrally randomized using Interactive Response Technology (IRT). Blinding
Patients, all investigative site personnel and any Sponsor employee or delegate directly associated with the conduct of the study will be blinded to patient treatment assignments. The blinding will be maintained by using identical study drug kits and labels for ravulizumab and placebo. The placebo will have an identical appearance to that of ravulizumab. The randomization code will be maintained by the IRT provider. Patients who elect to continue treatment after completion of the Randomized Controlled Period enter the Open-Label Extension Period at the end of the Week 50 visit after completing all scheduled assessments and before receiving ravulizumab.
To maintain blinding to the patient’s treatment assignment during the Randomized Controlled Period, patients in the placebo group will receive a blinded loading dose of ravulizumab, and patients in the ravulizumab group will receive a blinded ravulizumab dose of 900 mg. Starting at Week 52, all patients will begin open-label ravulizumab maintenance doses every 8 weeks (q8w). For patients in the ravulizumab group, a blinded ravulizumab dose of 900 mg was chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance dose at Week 52. Blind to prior assignment will be maintained for patients and providers (study site) during the Open-Label Extension Period.
In case of an emergency, the Investigator has the sole responsibility for determining if unblinding of a patient’s intervention assignment is warranted. Patient 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 the sponsor prior to unblinding a patient’s intervention assignment unless this could delay emergency treatment of the patient. If a patient’s intervention assignment is unblinded, The Sponsor must be notified within 24 hours after breaking the blind. The date and reason that the blind was broken must be recorded in the source documentation and case report form (CRF), as applicable.
When unblinding is the result of an AE which is unexpected or related and serious, the blind will be broken for that specific patient only. The blind with regard to treatment allocation for that specific patient will be maintained for all persons responsible for the ongoing conduct of the study (such as the management, monitors, Investigators, etc.) and those responsible for data analysis and interpretation of results at the conclusion of the study, such as biometrics personnel. Unblinded information will only be accessible to those who need to be involved in the safety reporting to Health Authorities, Independent Ethics Committees (IECs), Institutional Review Boards (IRBs), and/or IDMC.
Any patient who is unblinded during the Randomized Controlled Period will be discontinued from the study.
Study Drug Compliance
The infusion of study drug into patients will be under the supervision of the Investigator or their designee to ensure that patients receive the appropriate dose at the appropriate time points during the study. The date and time of each dose administered in the clinic will be recorded in the source documents and CRF. The dose of study drug and study patient identification will be confirmed at the time of dosing by a member of the study site staff other than the person administering the study drug.
Concomitant Therapy
Allowed Medications and Therapies
Palliative and Supportive Care
Palliative and supportive care is permitted during the course of the trial for underlying conditions.
ALS Specific Therapies
There are 2 therapies currently available for treating ALS that may slow disease progression: riluzole and edaravone. Patients who are naive to ALS therapies or have not taken ALS therapies for at least 30 days before screening are allowed to enroll. For a patient who is on one or more ALS-specific therapies at Day 1 of the study, the patient must be on a stable dose regimen of riluzole for at least 30 days and/or on a stable treatment of edaravone for at least 60 days (2 treatment cycles) prior to Day 1 and has no plan to discontinue or change dose during the trial. Temporary discontinuations or dose modifications of riluzole or edaravone are acceptable at the discretion of the Investigator for medical reasons. Patients receiving edaravone should not receive edaravone infusions on days when study drug is to be administered. Patients who do not enter the study on riluzole and/or edaravone will not be permitted to start treatment with either drug during the Randomized Controlled Period. Initiation of riluzole and/or edaravone is permitted during the Open-Label Extension Period. Other Allowed Therapies
Vitamin B 12, vitamin E, creatine, coenzyme Q10, and biotin supplements are permitted in this study. Patients who take any or all of these supplements should be on a stable dose beginning 14 days prior to first dose of study drug and remain on a stable dose for the duration of the Randomized Controlled Period of the study unless alteration in dose is deemed medically necessary or reviewed with the Medical Monitor. All other vitamins and supplements are permitted on this study. Patients are encouraged to remain on stable dosing for the duration of the Randomized Controlled Period of the study.
Disallowed Medications and Therapies
The following medications and therapies are prohibited during the study:
• Chronic treatment with IVIg for ALS disease management during the trial is prohibited, Note: If IVIg is deemed necessary for treatment of an acute condition for which IVIg is an indicated therapy, acute treatment with IVIg may be considered on a case by case basis in consultation with the Medical Monitor.
• Chronic use of plasmapheresis/plasma exchange (PP/PE) is prohibited during the study. However, if it is deemed necessary by the Investigator for treatment of an acute condition for which PP/PE is indicated, acute treatment of PP/PE may be considered on a case by case basis in consultation with the Medical Monitor. No more than 1 treatment cycle of PP/PE will be allowed.
• Eculizumab or other complement inhibitory agent is prohibited.
• Chronic systemic use of immunosuppressive therapies, defined as using any systemic immunosuppressive agent for > 14 days, is prohibited during the trial.
Note: Topical and inhaled immunosuppressive agents are permitted.
• Rituximab and other biologic or immunomodulatory therapies are prohibited during the study.
• Any off-label usage of an approved product currently under investigational use for the treatment of ALS during the study is prohibited.
Dose Modification
Dose modification is not permitted for this study. Intervention after the End of the Study
Ravulizumab will not be provided to the patients after the last scheduled dosing. After the end of therapy visit or ED, all patients will be followed for an additional 8 weeks after the last dose of study drug.
9. DISCONTINUATION OF STUDY DRUG AND PATIENT DISCONTINUATION OR WITHDRAWAL
Discontinuation of Study Drug
In rare instances, it may be necessary for a patient to permanently discontinue study drug.
If study drug is permanently discontinued, the patient should complete the ED visit for safety follow-up before discontinuing from the study. See the Schedule of Activities for data to be collected at the time of discontinuation of study drug and follow-up and for any further evaluations that need to be completed.
Patients should be considered for discontinuation from study drug if any of the following occur during the study:
• Serious hypersensitivity reaction;
• Severe uncontrolled infection;
• Use of disallowed medication;
• Pregnancy or planned pregnancy; or
Sponsor or the Investigator deems it is in the best interest of the patient.
Patient Discontinuation/Withdrawal from the Study
All efforts should be made to ensure patients are willing to comply with study participation prior to conducting the screening procedures. The study staff should notify the Sponsor and their site monitor of all trial withdrawals as soon as possible. The reason for patient discontinuation must be recorded in the source documents and electronic CRF (eCRF). A patient 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.
At the time of discontinuing from the study, if possible, an ED visit corresponding with the period of the study the patient is in should be conducted. The ED visit should be conducted as soon as possible, and no later than 8 weeks after the last dose of study drug, as shown in the Schedule of Activities. A follow-up phone call will be performed at 8 weeks (56 days) ± 5 days following the patient’s last dose of study drug to collect concomitant medications, non- pharmacologic therapies and procedures, and AEs. This phone call can be omitted if it falls within 5 days of the ED visit. The patient will be permanently discontinued both from the study drug and from the study at that time.
Lost to Follow up
If a patient fails to return, or is otherwise unavailable, for a scheduled visit within the acceptable visit window, the site study staff must make a reasonable attempt to contact the patient to determine the reason for missing the appointment. As it is vital to obtain any patient’s missing visit information to ensure the missed appointment was not due to an AE, every effort must be made to undertake protocol-specified safety follow-up procedures.
In the exceptional circumstance where a patient cannot or does not come to the study site for examination, the patient will be instructed to see his or her local neurologist or physician. In this event, if possible, the Investigator or designee will contact the local neurologist or physician to obtain as much information as possible about the patient’s medical and neurological condition, and provide clinical guidance, if needed. The study site will obtain relevant medical records as documentation from the local physician’s examination and enter relevant data in the eCRF as appropriate.
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled visits and is unable to be contacted by the study site.
The following actions must be taken if a patient fails to return to the clinic for a required study visit:
• The site must attempt to contact the patient and reschedule the missed visit as soon as possible and counsel the patient on the importance of maintaining the assigned visit schedule and ascertain whether or not the patient wishes to and/or should continue in the study.
• Before a patient is deemed lost to follow-up, the Investigator or designee must make every effort to regain contact with the patient (where possible, 3 telephone calls and, if necessary, a certified letter to the patient’s last known mailing address or local equivalent methods). These contact attempts should be documented in the patient’s medical record.
• Should the patient continue to be unreachable, he/she will be considered as lost to follow-up. 10. STUDY ASSESSMENTS AND PROCEDURES
General Assessments
Medical History and ALS History and Diagnosis
The Principal Investigator or Sub-Investigator will review the patient’s medical history including ALS history and diagnosis. The following will be evaluated and documented at the Screening Visit and/or other visits as specified in the Schedule of Activities:
• Time of ALS onset (defined as time of onset of first muscle weakness symptom date).
• Date of ALS diagnosis.
• Criteria for ALS diagnosis, defined as meeting the clinically possible, laboratory supported probable, probable, or definite criteria for a diagnosis of ALS according to the revised World Federation of Neurology El Escorial criteria (Brooks, 2000).
• ALS stage will be evaluated using King’s staging system (KSS) (Balendra, 2019) by the Investigator or trained designee. Stage will be assigned based on the number of involved CNS regions and nutritional and respiratory status.
Vaccine and Antibiotic Prophylaxis
As with any terminal complement antagonist, the use of ravulizumab increases the patient’s susceptibility to meningococcal infection (N. meningitidis). To reduce the risk of meningococcal infection, all patients must be vaccinated against meningococcal infections within the 3 years before or at the time of initiating study drug.
Patients who initiate study drug less than 2 weeks after receiving a meningococcal vaccine must receive treatment with appropriate prophylactic antibiotics from the first day of study drug treatment until 2 weeks after vaccination. Patients must be vaccinated or revaccinated according to current national vaccination guidelines or local practice for vaccination use with complement inhibitors ( e.g ., eculizumab, ravulizumab).
Vaccines against serotypes A, C, Y, W135, and B, where available, are recommended to prevent common pathogenic meningococcal serotypes. Vaccination may not be sufficient to prevent meningococcal infection. Consideration should be given according to official guidance and local practice on the appropriate use of antibacterial agents. All patients should be monitored for early signs of meningococcal infection, evaluated immediately if infection is suspected, and treated with appropriate antibiotics, if necessary. Inclusion/Exclusion Criteria
All inclusion and exclusion (criteria must be reviewed by the Investigator or qualified designee to ensure the patient qualifies for study participation. Both the Investigator and Sponsor must approve patient eligibility before enrollment. Study Drug Administration
At the scheduled dosing visits, study drug infusion should be performed after all other tests and procedures have been completed, excluding the post-dose blood sampling for PK and free C5. The ravulizumab dose for each patient will be based on last recorded body weight. The dosing regimen (Table 7) consists of a loading dose followed by maintenance dosing administered q8w. The maintenance dose should be initiated 2 weeks after the loading dose administration.
Table 7: Weight-based Doses of Ravulizumab
Figure imgf000063_0001
a Dose regimen will be based on the last recorded study visit body weight. b In the event that a patient drops below 40 kg during the course of the study the approved ravulizumab aHUS dosing for patients weighing 30 - 40 kg will be used: a loading dose of 1200 mg and maintenance dose of 2700 mg, and in the event that a patient drops below 30 kg during the course of the study the approved ravulizumab aHUS dosing for patients weighing 20 - 30 kg will be used: a loading dose of 900 mg and maintenance dose of 2100 mg. Abbreviation: aHUS = atypical hemolytic uremic syndrome.
In the event that the Randomized Controlled Period is stopped for success, any patient who is still in the Randomized Controlled Period will transition to the Open-Label Extension Period at their next scheduled dosing visit. Regardless of previous visit number, when the patient returns for the next scheduled dosing visit, the patient will follow the procedures outlined in Visit 13 in the Schedule of Activities and continue all subsequent visits as outlined to the End of Study Visit. For patients who are in the Open-Label Extension Period when the Randomized Controlled Period is stopped for success, there will be no change to the visit schedule. For each patient, the entire treatment duration is up to 156 weeks, consisting of a
Randomized Controlled Period (50 weeks) and an Open Label Extension Period (up to 106 weeks). Study drug administration will end when all patients have completed the 2 year Open Label Extension Period, or ravulizumab is approved and/or available (in accordance with country specific regulations), or anytime during the Open Label Extension Period at the discretion of the Sponsor, whichever occurs first.
Randomized Controlled Period
The Randomized Controlled Period is a double blind, randomized, placebo controlled period. Eligible patients will be randomized 2:1 to receive blinded doses of ravulizumab or placebo during the Randomized Controlled Period (Day 1 through Week 42). Patients in the ravulizumab group will receive a blinded loading dose of ravulizumab on Day 1, followed by a blinded maintenance dose on at Week 2 (Table 1), then once q8w up to Week 42 (inclusive) (Table 1). Patients in the placebo group will receive a blinded matching placebo dose via IV infusion on Day 1, followed by a blinded matching placebo maintenance dose at Week 2, then q8w up to Week 42 (inclusive).
Open-Label Extension Period
Patients who elect to continue treatment after completion of the Randomized Controlled Period enter the Open-Label Extension Period at the completion of all scheduled pre-dose assessments for the Week 50 visit and before receiving ravulizumab. Patients in the placebo group will switch to receive a blinded loading dose of ravulizumab at Week 50 (Table 2). To ensure treatment allocation remains blinded to patients, Investigators, and site staff, as well as Sponsor staff or delegates, patients in the ravulizumab group will receive a blinded ravulizumab dose of 900 mg at Week 50. The 900 mg dose at Week 50 is chosen to ensure maintenance of complete C5 inhibition until the next scheduled maintenance dose. Starting at Week 52, all patients will receive open-label ravulizumab maintenance doses q8w (Table 2) until the end of the Open-Label Extension Period when all patients have completed 2 years of ravulizumab or ravulizumab is approved and/or available (in accordance with country specific regulations).
Efficacy Assessments
Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R)
The ALSFRS-Revised (Cedarbaum, 1999) is a validated instrument for evaluating the levels of the functional status of patients with ALS in 4 areas, including bulbar, gross motor activity, fine motor activity, and respiratory functions. The scale includes 12 functional items and each item is rated on a 0 to 4 scale, with a maximum total score of 48. A higher score indicates greater retention of function. In this trial, the ALSFRS-R will be performed throughout the study by the Investigator or any designee who has been properly trained for the evaluation. When possible, it is highly recommended that all assessments be performed by the same assessor. The ALSFRS-R will be assessed as indicated in the Schedule of Activities. At the time points specified in the Schedule of Activities, or if a patient is not able to attend the scheduled onsite visit, the ALSFRS R can be assessed via a phone call by the Investigator or trained designee.
Ventilation Assistance-Free Survival (VAFS)
Ventilation Assistance-Free Survival is a composite endpoint of survival and severe and irreversible respiratory decline. The use of VAFS allows for the collection of survival data that is not impacted by survival prolongation from noninvasive or permanent ventilatory interventions which can prolong life without impacting underlying disease progression. The composite endpoint of VAFS (Paganoni, 2014) that will be used as a secondary endpoint for this trial will be defined as the first occurrence of:
• All-cause mortality
• First use of NIV for > 22 hours per day for > 10 consecutive days
• First use of PAV for > 22 hours per day for > 7 consecutive days
Information on the components of VAFS will be assessed at every dosing visit by the
Investigator or designee using the ventilator assistance utilization form. Attempts will be made to obtain information about survival even after the patient has discontinued therapy.
Slow Vital Capacity (SVC)
Slow vital capacity is a spirometry technique that utilizes slow and gradual expulsion of air from the lungs. The full volume of expired air is measured as a proportion of the expected vital capacity of the patient based on biometric features such as height, weight, and sex. Slow vital capacity evaluation will be performed by the Investigator, or any designee who has been properly trained for the evaluation, at screening and time points specified in the Schedule of Activities. When possible, it is highly recommended that all assessments be performed by the same assessor.
Handheld Dynamometry (HHD)
Handheld dynamometry (Shefner, 2016) is a procedure for quantitative strength testing. This testing will be conducted by the Investigator or any designee who has been properly trained for the quantitative muscle strength evaluation. When possible, it is highly recommended that all assessments be performed by the same assessor. Muscle strength testing will be performed on prespecified muscles in the upper and lower extremities bilaterally and the force measurements recorded. Handheld dynamometry will be assessed at screening and time points specified in the Schedule of Activities.
EuroQoL 5 Dimensions (EO-5D-5L)
The European Quality of Life (EQ-5D-5L) is a self-assessed, standardized instrument to measure health-related quality of life and has been used in a wide range of health conditions, including ALS (Schrag, 2000). The EQ-5D-5L consists of 2 pages: the EQ-5D-5L descriptive system and the EQ visual analogue scale (EQ VAS). At time points specified in the Schedule of Activities, or if a patient is not able to attend the scheduled onsite visit, EQ-5D-5L can be assessed via a phone call.
EQ-5D-5L Descriptive System
The descriptive system is 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.
EQ Visual Analogue Scale
The EQ-5D-5L VAS is an overall health state scale where the patient selects a number between 0 and 100 to describe the condition of their health, with 100 being ‘The best health state you can imagine’ and 0 being ‘The worst health state you can imagine’.
This information can be used as a quantitative measure of health outcome as judged by the individual respondents. Previously published studies by EuroQol Group members showed preliminary evidence of the instrument’s feasibility, reliability, and validity.
Short Form Health Survey (SF-36)
The SF-36 is a 36-item self-report of health-related quality of life (Stewart, 1988; Ware, 1992). It contains 8 subscales measuring different domains of health-related quality of life: 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 SF-36 will be conducted at screening and at timepoints specified per Schedule of Activities. The two (2) summary scores are the physical component summary and the mental component summary. There is no single overall score for the SF-36. Treatment Satisfaction Questionnaire for Medication (TSQM)
The Treatment Satisfaction Questionnaire for Medication (TSQM-9) assesses 3 key dimensions of treatment satisfaction: Effectiveness (3 items); Convenience (3 items); and Global Satisfaction (3 items) (Bharmal, 2009). The instrument has been validated in chronic diseases including ALS (Meyer, 2019). The recall period for the TSQM is the previous 2 to 3 weeks or since last use. The TSQM-9 can be used to estimate total TSQM score, score for effectiveness, and score for convenience. The TSQM-9 will be administered at Day 1 and at timepoints specified in the Schedule of Activities.
Safety Assessments
The planned schedule for all safety assessments is provided in the Schedule of Activities.
Physical Examinations
A complete physical examination will include, at a minimum, assessments of the following organs/body systems: skin, head, ears, eyes, nose, throat, neck, lymph nodes, chest, heart, abdomen, extremities, and musculoskeletal. An abbreviated physical examination will include, at a minimum, a body-system relevant examination based upon Investigator judgment and patient symptoms. Examiners should pay special attention to clinical signs related to previous serious illnesses. For consistency, all efforts should be made to have the physical examination performed by the same qualified study staff at each study visit. Additional physical examinations can be performed as medically indicated during the study at the Investigator’s discretion.
Neurologic Examination
A general neurologic examination will be performed by the Investigator, Sub- Investigator, or designee at the scheduled visits. The general neurologic examination includes assessments of the following systems: mental status, cranial nerves, deep tendon reflexes, power/strength, sensation, muscle fasciculations, and muscle atrophy.
Hei ht and Wei ht
Body weight will be measured in pounds or kilograms. Height will be measured in inches or centimeters.
Vital Signs
Oral temperature (°C or °F), pulse rate, respiratory rate, and systolic and diastolic blood pressure (mm Hg) will be assessed. Blood pressure and pulse measurements will be assessed seated with a completely automated device. Manual techniques will be used only if an automated device is not available. Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the patient in a quiet setting without distractions ( e.g ., television, cell phones). Ideally, the same arm for each patient should be used for measurements.
Electrocardiograms
Single 12-lead electrocardiogram (ECG) will be performed at protocol specified visits in the Schedule of Activities using an ECG machine to obtain heart rate and measures of PR, QRS, QT, and corrected QT intervals. Patients must be supine for approximately 5 to 10 minutes before ECG collection and remain supine but awake during ECG collection. The Investigator or Sub-Investigator will be responsible for reviewing the ECG to assess whether the ECG is within normal limits and determine the clinical significance of the results. These assessments will be recorded in the source documents and the eCRF.
Patient Safety Card
Before the first dose of study drug, a Patient Safety Card will be provided to patients to carry with them at all times. The card is provided to increase patient awareness of the risk of infections, especially meningococcal infection, and to promote quick recognition and disclosure of any potential signs or symptoms of infection experienced by patients during the course of the study and to inform patients on what actions must be taken if they are experiencing signs or symptoms of infection. At each visit throughout the study, the study staff will ensure that the patient has the Patient Safety Card.
Prior and Concomitant Medication Review
It is important for Investigators or a designee to review each medication the patient is taking before starting the study and at each visit.
Prior Medications
Prior medications and/or vaccines (including vitamins, herbal preparations, and those discussed in the exclusion criteria) and procedures (any therapeutic drug, such as surgery /biopsy or physical therapy) that the patient takes or undergoes within 30 days before the start of screening or during the Screening Period before the first dose of study drug, as well as any meningococcal vaccine administered within the last 3 years, will be recorded in the patient’s eCRF. Additionally, all medications or therapies ever used for treating ALS before the first dose of study drug must be collected. Concomitant Medications
Concomitant medications (including any medication, vitamin, herbal preparation or supplement) and procedures are those received on or after the first study treatment date (Day 1), including those started before Day 1 and continued after Day 1. At each study visit, patients should be questioned about any new medication or non-drug therapies or changes to concomitant medications and nondrug therapies since the last visit. Concomitant medications and non-drug therapies should be recorded in the source documents and the patient’s eCRF. Concomitant medications must be recorded in the patient’s source document/medical chart and eCRF along with:
• Reason for use
• Dates of administration including start and end dates
• Dosage information including dose and frequency
Information regarding the use of ALS specific treatment including riluzole and edaravone must be collected. Meningococcal vaccination and antibiotics administered for prophylaxis of meningococcal infection (if applicable) will also be recorded.
Any concomitant medication deemed necessary for the patient’s care during the study, or for the treatment of any AE, along with any other medications, other than those listed as disallowed medications, may be given at the discretion of the Investigator. However, it is the responsibility of the Investigator to ensure that details regarding all medications are recorded in full in the patient’s source document/medical chart and eCRF. The Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy.
Clinical Safety Laboratory Assessments
The tests detailed in Table 8 will be performed by a central laboratory. Local laboratory results are only required in the event that the central laboratory results are not available in time for either study drug administration and/or 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 drug decision or response evaluation, the results must be entered into the CRF. Table 8: Protocol -Required Laboratory Assessments
Figure imgf000070_0001
a FSH to be performed at Screening in selected female patients to confirm postmenopausal status. b Coagulation to be performed at Screening for all patients and at Week 28 and Week 42 for patients in CSF cohort. Additional tests may be performed at any time during the study as determined necessary by the Investigator or required by local regulations. Women of childbearing potential should only be enrolled after a negative serum pregnancy test. Additional urine pregnancy testing will be standard for the protocol unless serum testing is required by local regulation or IRB/IEC and should be performed per the time points specified in the Schedule of Activities.
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 which are not associated with the underlying disease, unless judged by the Investigator to be more severe than expected for the patient's condition.
All laboratory tests with values considered clinically significantly abnormal during participation in the study or within 8 weeks after the last dose of study drug 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 The Sponsor notified. All protocol -required laboratory assessments, as defined in, must be conducted in accordance with the Laboratory Manual and the Schedule of Activities. If laboratory values from non-protocol specified laboratory assessments performed at the institution’s local laboratory require a change in patient management or are considered clinically significant by the Investigator ( e.g ., serious adverse event (SAE) or AE or dose modification), then the results must be recorded in the CRF.
Suicidal Ideation and Behavior Risk Evaluation
Patients being treated with a study drug for a neurologic indication should be evaluated prospectively for suicidal ideation or behavior during the study. Baseline assessment of suicidal ideation and behavior as well as intervention-emergent suicidal ideation and behavior will be monitored during this study using the Columbia-suicide severity rating scale (C-SSRS). There are 2 types of C-SSRS assessments that will be conducted during the study: C-SSRS at Baseline/Screening and C-SSRS-Since Last Visit. The C-SSRS will be performed by the Investigator or an appropriately trained designee at visits specified in the Schedule of Activities to ensure that patients who are experiencing suicidal thoughts or behavior are properly recognized and adequately managed or referred for further evaluation. Additional C SSRS assessments are permitted as needed.
Pregnancy
Pregnancy testing must be performed on all WOCBP at protocol-specified time points in the Schedule of Activities. Pregnancy tests (urine or serum) may also be performed at any time during the study at the Investigator’s discretion. A negative pregnancy test is required for WOCBP before study drug administration. Details of all pregnancies in female patients and, if indicated, female partners of male patients will be collected after the start of study drug and until the termination of the pregnancy.
If a pregnancy is reported, the Investigator should inform The Sponsor within 24 hours of learning of the pregnancy and should follow the established procedures outlined. Abnormal pregnancy outcomes ( e.g ., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered SAEs. Pregnancy alone is not considered an AE. If a patient becomes pregnant, the study drug must be immediately discontinued, and The Sponsor must be notified. Each pregnancy will be followed to term and The Sponsor notified regarding the outcome.
Adverse Events and Serious Adverse Events
Adverse events will be reported to the Investigator by the patient (or, when appropriate, by a caregiver, surrogate, or the patient'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 drug or study procedures, or that caused the patient to discontinue the study drug.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs will be collected from the signing of the ICF until the last visit specified in the Schedule of Activities. All SAEs will be recorded and reported to The Sponsor or designee immediately and under no circumstance should this exceed 24 hours. The Investigator will submit any updated SAE data to The Sponsor within 24 hours of awareness. Investigators are not obligated to actively seek AEs or SAEs after conclusion of the study participation. However, if the Investigator learns of any SAE, including a death, at any time after a patient has been discharged from the study, and he/she considers the event to be reasonably related to the study drug or study participation, the Investigator must promptly notify The Sponsor.
Method of Detecting AEs and SAEs
The method of recording, evaluating, and assessing causality of AEs and SAEs and the procedures for completing and transmitting SAE reports are provided herein. Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and non-leading verbal questioning of the patient is the preferred method to inquire about AE occurrences.
Follow-up of AEs and SAEs
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at subsequent visits/contacts. All SAEs and AEs of special interest (AESI) will be followed until resolution, stabilization, the event is otherwise explained, or the patient is lost to follow-up. Every effort will be made to undertake protocol-specified safety follow-up procedures.
Regulatory Reporting Requirements for SAEs
Prompt notification by the Investigator to the Sponsor of a SAE is essential so that legal obligations and ethical responsibilities towards the safety of patients and the safety of a study drug under clinical investigation are met. The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory agencies about the safety of a study drug under clinical investigation. The Sponsor will comply with country-specific regulatory requirements relating to safety reporting to the regulatory authority, IRB/IEC, and Investigators.
Suspected unexpected serious adverse reactions must be reported according to local regulatory requirements and Sponsor policy and forwarded to Investigators as necessary. An Investigator who receives an Investigator safety report describing a SAE or other specific safety information ( e.g ., summary or listing of SAEs) from The Sponsor will review and then file it along with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local requirements.
Adverse Events of Special Interest
Meningococcal infections will be collected as AESIs.
Treatment of Overdose
For this study, any dose of study drug greater than that specified in the protocol will be considered an overdose. If dose cannot be established during the Randomized Controlled Period due to blinding, suspected overdose should be defined by volume administered. Accidental overdose or suspected overdose without any association with laboratory abnormalities or clinical symptoms should not be considered as an AE. Overdose must be reported by the Investigator within 24 hours to the Sponsor regardless of its association with or without an AE.
The Sponsor does not recommend specific treatment for an overdose or suspected overdose. In the event of an overdose or suspected overdose, the Investigator should:
• Contact the Medical Monitor immediately.
• Closely monitor the patient for any AE/SAE
• Obtain a plasma sample for PK analysis if requested by the Medical Monitor (determined on a case-by-case basis).
• For unblinded patients, document the quantity of the excess dose as well as the timing of the overdose in the CRF.
Decisions regarding dose interruptions will be made by the Investigator in consultation with the Medical Monitor based on the clinical evaluation of the patient.
Pharmacokinetics and Pharmacodynamics
Blood samples for determination of serum drug concentrations and PD assessments will be collected before and after administration of study drug at the time points specified in the Schedule of Activities. Cerebrospinal fluid (CSF) samples for PK and PD assessments are optional at protocol specified time points and will only be obtained from patients who consent to CSF collection (CSF Cohort). Lumbar punctures will be performed to collect CSF samples and may only be performed on patients who have consented to CSF sample collection. Patients who are on therapeutic doses of anticoagulants will be deemed ineligible for the optional lumbar puncture procedures in this study. In addition, patients may be deemed ineligible to undergo lumbar puncture at the discretion of the Investigator after consideration of medical history, physical examination findings, laboratory assessments required as part of the Schedule of Activities or other factors.
Instructions for the collection and handling of biological samples will be provided by the Sponsor. The actual date and time (24-hour clock time) of each sample will be recorded on the eCRF and the central laboratory requisition form. Baseline and trough PK and PD blood samples will be collected at pre-dose, within 90 minutes before administering study drug at visits specified in the Schedule of Activities. The pre-dose blood sample may be drawn through the venous access created for the dose infusion, prior to administration of the dose.
Post-dose PK and PD blood samples will be collected post-dose, within 60 minutes after completing study drug infusion. The post-dose blood samples will be drawn from the patient's opposite, non-infused arm. Blood samples at a non-dosing visit can be collected at any time. In the event of an unscheduled visit, PK and PD blood sample will be collected as soon as possible.
Genetics
There are no prespecified genetic analyses in this study.
Biomarkers
Biomarker Research
Blood and urine samples for biomarker research will be collected from all patients at the time points specified in the Schedule of Activities. CSF samples are optional samples for biomarker research and should only be collected from patients who have consented to CSF sample collection. For biomarker CSF sample collection, follow the same instructions on lumbar punctures for PK/PD assessments.
Biomarkers will be measured and include, but are not limited to, assessments of the following:
• Markers of neurodegeneration, such as NfL
• Complement proteins
• Markers of neuroinflammation, such as levels of proinflammatory cytokines and inflammatory cells
Future Biomarker Research
Blood samples for DNA and RNA isolation will be collected from patients who have consented to participate in the future genetic analysis component of the study. Future DNA and RNA testing on these samples includes, but is not limited to, specific candidate genes/genome wide analysis. Remaining samples from PK, PD, immunogenicity, and biomarker testing will be stored for future biomarker research. Analyses may be performed on biomarker variants thought to play a role in ALS activity/progression or treatment response to ravulizumab.
These samples may also be used to develop methods, assays, prognostics and/or companion diagnostics related to the study drug target, disease process, pathways associated with disease state, other complement-related diseases, and/or mechanism of action of the study drug. Samples may be stored for a maximum duration according to local regulations following the last patient’s last visit for the study at a facility selected by The Sponsor to enable further analyses.
Immunogenicitv Assessments
Antidrug antibodies (AD As) to study drug will be evaluated in serum samples collected pre-dose (within 5 to 90 minutes prior to the start of infusion of study drug) from all patients according to the Schedule of Activities. Additionally, serum samples should also be collected at the final visit from patients who discontinued study drug or were withdrawn from the study. Serum samples will be screened for antibodies binding to ravulizumab and the titer of confirmed positive samples will be reported. Other analyses may be performed to verify the stability of antibodies to ravulizumab and/or further characterize the immunogenicity of ravulizumab.
The detection and characterization of antibodies to ravulizumab will be performed using a validated assay method by or under the supervision of The Sponsor. Samples may be further characterized to determine the titer and the presence of neutralizing antibodies if deemed necessary. Samples may be stored for a maximum duration according to local regulations following the last patient’s last visit for the study at a facility selected by the Sponsor to enable further analysis of immune responses to ravulizumab.
Medical Resource Utilization and Health Economics
Medical resource utilization and health economics data associated with medical encounters will be collected in study eCRFs by the Investigator and study-site personnel for all patients throughout the study. Protocol-mandated procedures, tests, and encounters are excluded. The data collected, which may be used to conduct exploratory economic analyses, include the following:
• Number of surgeries, and other selected procedures (inpatient and outpatient)
• Number and duration of hospitalizations
• Use of ventilator use and duration of use
• Use of wheelchair
• Use of feeding tube
11. STATISTICAL CONSIDERATIONS
Statistical methods described in this section will be further detailed in a separate Statistical Analysis Plan (SAP). The SAP will be developed and finalized prior to the database lock for the Randomized Controlled period. Statistical analyses will include tabulations of summary data, inferential analyses, by-patient listings and figures. Inference from efficacy analyses will be based on a 2-sided Type I error (a) = 5% unless stated otherwise. The summary statistics for continuous variables will include but not be limited to the number of patients, mean, standard deviation, minimum, median, and maximum. For categorical variables, frequencies and percentages will be presented. The baseline value for analysis and reporting will be based on the last non-missing measurement on or prior to the first dose of study drug unless stated otherwise. The treatment groups for analysis and reporting will be based on the conventions outlined in Table 9. A ‘Total’ treatment group will be formed to report demographics, baseline characteristics, and other pre-study information including, medical and ALS history, and prior medications and SAEs captured between screening and first infusion. Details for imputation of efficacy data will be described in the SAP. Missing safety data will not be imputed. Analyses will be performed using the SAS® software Version 9.4 or higher.
Table 9: Analysis Sets
Figure imgf000078_0001
Statistical Hypotheses
Primary Hypothesis The primary null hypothesis is that the effect of ravulizumab is no different than placebo in functional decline measured by the change from baseline in ALSFRS-R total score at Week 50. The alternative hypothesis is that ravulizumab will slow the disease progression by reducing the decline from baseline in ALSFRS-R total score at Week 50 compared to placebo.
Secondary Hypotheses The null hypotheses associated with the secondary objectives are that ravulizumab is no different than placebo for the respective endpoints; the alternative hypotheses are described below:
1. Time to VAFS: The alternative hypothesis is that treatment with ravulizumab will prolong the time to VAFS compared to placebo. 2. Change in SVC: The alternative hypothesis is that treatment with ravulizumab will slow the decline from baseline in SVC at Week 50 compared to placebo. 3. Change in muscle strength (HHD): The alternative hypothesis is that treatment with ravulizumab will slow the decline from baseline in muscle strength at Week 50 compared to placebo.
4. Change in ALSAQ-40 score: The alternative hypothesis is that treatment with ravulizumab will show improvement in the change from baseline in ALSAQ-40 at Week 50 compared to placebo.
Sample Size Determination
The sample size calculations were based on information extracted from the PRO-ACT (Pooled Resource Open-Access ALS Clinical Trials, https://nctu.partners.org/ProACT) database consisting of clinical trials data pooled from 23 Phase 2/3 ALS clinical trials. Approximately 354 patients will be randomized to ravulizumab or placebo in a 2: 1 ratio.
The mean change in ALSFRS-R total score in the placebo arm at Week 50 is estimated as 14.3 (assuming a monthly linear slope of decline of 1.19 calculated based on the proposed study inclusion criteria). Assuming a 30% relative reduction in monthly slope in the ravulizumab group, which is considered a clinically meaningful treatment effect (Castrillo-Viguera, 2010; Writing Group for Edaravone ALS Study, 2017), the mean change in ALSFRS-R total score at Week 50 is estimated as -10.
A common standard deviation of 10.3 was estimated for the change from baseline in ALSFRS-R total score. A total of 282 patients will be required to ensure at least 90% nominal power based on a 2-sided t-test (Type I error = 0.05) for detecting a non-zero treatment effect for ALSFRS-R (defined as the difference between ravulizumab and placebo in the mean change from baseline in ALSFRS R total score at Week 50). The total sample size is estimated as 354 after adjusting for a 20% dropout (Cudkowicz, 2013). Furthermore, assuming approximately 82% 1-year survival rate for placebo group and 50% relative reduction in hazard ratio for mortality due to treatment with ravulizumab, this sample size will provide at least 90% nominal power based on the primary analysis (CAFS).
Stratification
Amyotrophic lateral sclerosis is a heterogeneous disease the progression of which is impacted by intrinsic disease factors and concomitant ALS medication use. Patients with bulbar onset ALS are well described to have a poorer prognosis than other ALS patients (Swinnen, 2014). To control this heterogeneity the study will be stratified based on known prognostic factors and concomitant ALS medication use.
The site of muscle weakness onset (bulbar vs other) and riluzole use at study entry will be used as stratification factors (Cudkowicz, 2013). In addition, patients on stable edaravone will also be employed in the stratification scheme. It is anticipated that a relatively low percentage of patients will be on edaravone without concomitant riluzole use; the stratification scheme based on this assumption is provided in Table 10.
Table 10: Stratification Scheme
Figure imgf000080_0001
Populations for Analyses
Analysis sets are defined in Table 11.
Table 11: Analysis Sets
Figure imgf000080_0002
Figure imgf000081_0001
Statistical Analyses
Enrollment and Disposition
The number of patients screened, screen failures, and randomized patients will be presented. Enrollment information will be presented by stratification factor and treatment group. Number of patients discontinued and reasons for discontinuation from the Randomized Controlled Period, Open Label Extension Period, and the overall study will be summarized.
Demographics. Baseline Characteristics. Inclusion and Exclusion Criteria and Protocol Deviations
All demographic information and baseline characteristics will be reported by treatment group and overall. No statistical test will be performed for homogeneity among treatment groups. The number and percentage of patients not meeting specific inclusion or exclusion criterion will be summarized. Similar summary will be provided for major protocol deviations based on prespecified categories.
Medical/Surgical History. Physical Examination and Amyotrophic Lateral Sclerosis
History
The medical and surgical history will be summarized by System Organ Class (SOC) and Preferred Term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 20.1 or higher. Amyotrophic lateral sclerosis history and abnormal physical examination will also be summarized.
Prior and Concomitant Medications
For analysis and reporting purpose, any medication started prior to first dose of study drug will be considered as prior medication and any medication taken by a patient that overlaps with the intake of study drug will be considered as concomitant medication. All prior and concomitant medications including ALS-specific medications during the study, if any, will be summarized. Efficacy Analyses
Analyses of Primary Efficacy Endpoint
Primary Analysis
The analysis of the primary endpoint will be conducted based on the Full Analysis Set. For patients who do not survive until Week 50, ALSFRS-R total scores will be missing which, if not adequately accounted for, may bias the evaluation of clinical benefit. A joint rank analysis (CAFS) recommended in the Food and Drug Administration guidance document on ALS (Sep 2019) that combines deaths and ALSFRS-R will be performed as the primary analysis. The CAFS is an analysis that evaluates function while accounting for missing data due to deaths in ALS where CAFS ranks patients’ clinical outcomes based on survival time and change in the ALSFRS-R total score (Berry, 2013). Each patient will be ranked either based on their last available change from baseline in ALSFRS-R total score within Week 50 or the time to death.
The analysis of CAFS ranks will be based on an analysis of covariance model. The model will include the CAFS ranks as the dependent variable and following list of independent variables: treatment indicator (0 = placebo, 1 = ravulizumab), age, sex, baseline ALSFRS-R total score, baseline SVC, time from muscle weakness onset, and the stratification factors. A p value less than the adjusted Type I error associated with the higher mean rank in ravulizumab group compared to placebo will indicate a statistically significant treatment benefit.
Sensitivity Analyses
To establish the robustness of the primary analysis and to quantify the treatment effect magnitude, the following sensitivity analyses will be conducted.
Mixed-Effect Model for Repeated Measures (MMRM) Sensitivity Analysis
The mixed-effect model for repeated measures (MMRM) analysis will be conducted using all available longitudinal data (either complete or partial). The model will include the change from baseline in ALSFRS-R total score at each nominal visit as the dependent variable and the following list of independent variables as fixed effects: actual time on study (months), the interaction between time and treatment (0 = placebo, 1 = ravulizumab), age, sex, baseline ALSFRS-R total score, baseline SVC, time from muscle weakness onset, and the stratification factors. In addition, the patient-specific random intercept and slope will be added to the model with an unstructured variance-covariance matrix to model the correlations among repeated measurements within each patient. Other covariance structures will be implemented if a convergence issue occurs (details to be provided in SAP). The Kenward Rogers method will be used to estimate the denominator degrees of freedom.
No imputation for the missing data will be performed after discontinuation from the study assuming the data are missing at random (MAR). The treatment effect will be evaluated via the estimated treatment-by-visit interaction term at Week 50.
MMRM Sensitivity Analysis With Placebo-based Imputation
To examine the deviation from MAR assumption, another MMRM analysis will be considered based on the Missing Not At Random mechanism for the missing data. The missing ALSFRS-R total scores after discontinuation of ravulizumab during the Randomized Controlled Period will be imputed based on the assumption that those patients will follow the trajectory of outcomes similar to the placebo arm. Patients who prematurely discontinue from the placebo arm will be assumed to have unobserved outcomes similar to that of placebo patients who remain on their randomized treatment. Missing data due to deaths will not be imputed.
Vonesh Shared Parameter Model
In addition, parametric modeling (Vonesh shared parameter model) may also be performed (Vonesh, 2006). In this model, both the longitudinal changes in the ALSFRS-R total score and the time to death are modeled together assuming a patient specific slope and intercept for ALSFRS-R trajectory. The model also assumes that a patient’s survival time has a Weibull distribution with a hazard that is a function of the patient’s ALSFRS-R trajectory; the treatment effect of ravulizumab on ALSFRS-R and mortality will be estimated separately from this joint model.
Analyses of Secondary Efficacy Endpoint! s)
Analysis of the secondary endpoints will be performed as follows:
Time to VAFS: The treatment effect on the time to VAFS will be analyzed based on a Cox’s regression model treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
The components of VAFS will be analyzed separately using similar models.
Change in SVC: The treatment effect on SVC will be evaluated based on a MMRM with the change from baseline in SVC percent predicted as the dependent variable and following list of independent variables as fixed effects: actual time on study (months), time and treatment interaction, age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor. In addition, the patient-specific random intercept and slope will be added to the model with an unstructured variance-covariance matrix. The Kenward-Rogers method will be used to estimate the denominator degrees of freedom. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
Change in muscle strength (HHD): For each patient, a megascore will be calculated at each visit by summing scores from all muscles. The scores will be normalized by the baseline megascore multiplied by 100 (hence the baseline score is always 100%). The change from the baseline score of 100% will be used for analysis. The treatment effect on HHD will be evaluated based on a MMRM with the change from baseline in HHD as the dependent variable and following list of independent variables as fixed effects: actual time on study (months), time and treatment interaction, age, sex, baseline HHD megascore, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor. In addition, the patient-specific random intercept and slope will be added to the model with an unstructured variance covariance matrix. The Kenward Rogers method will be used to estimate the denominator degrees of freedom. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
Change in neurofilament light chain (NfL) concentration: The treatment effect of ravulizumab on NfL vs placebo will be evaluated based on a MMRM with log(NfL) as the response variable and with adjustments for treatment, age, and log(baseline NfL). The model will further include a visit-by-treatment interaction. An unstructured covariance matrix will be used.
Analyses of Exploratory Endpoint(s)
Time to first instance of SVC < 50% predicted: The treatment effect on the time to first instance of SVC < 50% will be evaluated based on a Cox’s regression model with treatment as a fixed effect adjusting for age, sex, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor.
Change in SF-36: The treatment effect on SF-36 physical component score (PCS) will be evaluated based on a MMRM with the change from baseline in SF-36 PCS as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and visit interaction, age, sex, baseline SF-36 PCS, baseline ALSFRS-R total score, baseline SVC, disease duration, and the stratification factor. The Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance- covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
Similar analysis will be based on SF-36 mental component score (MCS).
Change in EO-5D-5L index score: The treatment effect on EQ-5D-5L index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline EQ-5D-5L index score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor. The Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
Change in EO-5D-5L VAS score: The treatment effect on EQ-5D-5L VAS score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline EQ-5D-5L VAS score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor. The Kenward-Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR.
Change in ALSAQ-40 score: A single index score is created by adding all of the responses (0, 1, 2, 3, or 4) of 40 items of ALSAQ-40, dividing this total score by the maximal score of 160 and finally multiplying by 100. An index score of 0 indicates perfect health and 100 indicates worst possible health status. The treatment effect on ALSAQ-40 index score will be evaluated based on a MMRM with the change from baseline in the index score as the dependent variable and following list of independent variables as fixed effects: categorical visits, treatment and treatment and visit interaction, age, sex, baseline ALSAQ-40 index score, baseline ALSFRS- R total score, baseline SVC, disease duration, and the stratification factor. The Kenward Rogers method will be used to estimate the denominator degrees of freedom. An unstructured within subject variance-covariance matrix will be used. No imputation for the missing data will be performed after discontinuation assuming the data are MAR. Decline in KSS: The proportion of patients with any decline from the baseline KSS at Week 50 will be compared between ravulizumab and placebo. A logistic regression analysis will be conducted with treatment indicator as the fixed effect adjusting for the baseline KSS. Estimate of odds ratio and 95% confidence interval will be generated.
Multiplicity Adjustment
If the primary analysis is statistically significant, the study wise Type I error will be controlled using Hochberg method for multiplicity adjustment of the p-values corresponding to the two secondary endpoints (VAFS and change in SVC).
Safety Analyses
The safety and tolerability of ravulizumab will be assessed based on AEs, clinical laboratory findings, vital sign findings, and ECG abnormalities. Safety analyses will be performed on the Safety Set and Open-label extension Set based on the study period under consideration.
Analysis of Adverse Events
Analysis and reporting for AEs will be based on treatment-emergent AEs, including TESAEs defined as an AE with onset on or after first dose of study drug administration in the Randomized Controlled Period. Treatment-emergent AEs and TESAEs will be summarized by MedDRA SOC and Preferred Term and by relationship to the study drug; TEAEs will also be summarized by severity. Patient-years adjusted event rates will be generated to characterize long-term safety profile.
Analysis of Clinical Laboratory Parameters. Vital Sign Measurements. Weight and Electrocardiogram Parameters
Laboratory measurements as well as their changes from baseline at each visit and shift from baseline, if applicable, will be summarized descriptively. Weight, ECG, and vital signs will also be summarized using descriptive analyses.
Other Safety Analyses
The number and percentage of patients in each of the C-SSRS categories and shift analyses will be presented. Results from pregnancy tests will be summarized. Number and percentage of patients in each category of the neurologic assessments will be summarized. Analysis of Pharmacokinetics and Pharmacodynamics and Anti drug Antibody Analyses
Individual serum concentration data for all patients who receive at least 1 dose of the study drug and have at least 1 post-dose PK sample will be used to derive PK parameters for ravulizumab. Graphs of mean serum concentration-time profiles will be constructed. Graphs of serum concentration-time profiles for individual patients may also be provided. Actual dose administration and sampling times will be used for all calculations. Descriptive statistics will be calculated for serum concentration data at each sampling time, as appropriate. Assessment of population-PK may be considered using data from this study or in combination with data from other studies.
Pharmacodynamic analyses will be performed for all patients who receive at least 1 dose of ravulizumab and who have evaluable PD data. Descriptive statistics will be presented for all ravulizumab PD endpoints at each sampling time. The PD effects of ravulizumab will be evaluated by assessing the absolute values and changes and percentage changes from baseline in free C5 serum concentrations over time, as appropriate. Assessments of ravulizumab PK/PD relationships may be explored using data from this study or in combination with data from other studies.
For assessment of immunogenicity, the presence of confirmed positive AD As will be summarized. Additionally, following confirmation of positive AD As, samples will be assessed for ADA titer and presence of neutralizing antibodies.
Analysis of Exploratory Biomarkers
Analyses of exploratory biomarkers will be described in the SAP.
Interim Analyses
Two interim analyses for futility will be conducted by an IDMC to determine if the study is unlikely to meet its objective. If futility criteria are met, the study (both the Randomized Controlled Period and Open-Label Extension Period) may be terminated early, thereby limiting patient exposure. In addition, an interim analysis will also be conducted to determine if ravulizumab has demonstrated early evidence of efficacy. If success criteria are met, the double blind period may be terminated early, permitting all patients in the study to enter the open-label period and access an efficacious treatment.
Interim analysis 1 : This interim analysis will be conducted by the IDMC when approximately 33% of patients complete the Week 26 visit. Only futility will be assessed at this point. This assessment will be performed using all available ALSFRS-R data. The criteria for futility will be prespecified in the IDMC charter.
Interim analysis 2:
Provided the study was not stopped due to futility at interim analysis 1, a second interim analysis will be targeted to occur when approximately all patients complete the Week 26 visit. The second futility assessment will be performed using all available ALSFRS R data. The criteria for futility will be prespecified in the IDMC charter. If the study is not considered futile at interim analysis 2, an analysis for early stopping for efficacy based on ALSFRS-R will also be performed at this time. The prespecified framework will be documented in the IDMC charter.
Delaved-Start Analysis of Long-term ALSFRS-R
To provide additional evidence of a disease modifying effect of treatment with ravulizumab on disease progression, a delayed start analysis will be conducted based on an MMRM approach and by incorporating all data from the Randomized Controlled Period (referred to as early start) and the first 50 weeks of the Open-Label Extension Period (referred to as delayed start). In this model, the patients initially randomized to placebo will be assumed to have different ALSFRS R slopes for the Randomized Controlled Period and the Open-Label Extension Period whereas for the patients randomized to ravulizumab, a slope common to both periods will be assumed. The treatment effects will be quantified by the estimated differences between the groups based on their original treatment arms (ravulizumab vs placebo) for both early and delayed start periods; the estimated difference at the end of the delayed start period will be assessed for noninferiority compared to the estimated difference at the end of the early start period (Liu-Seifert, 2015). Further details will be provided in the SAP.
Data Monitoring Committee
The safety and efficacy data of this study will be monitored by an IDMC appointed by The Sponsor. Minimally, the IDMC members will include external physicians and a statistician who have expertise in both the field of ALS and clinical trial conduct and with no direct relationship to the study. Each member of the IDMC will be required to sign an agreement, including confidentiality and financial disclosure statements, assuring no conflicts of interest as a condition for membership on the committee.
All statistical analyses presented to the IDMC will be performed by an independent statistical center. The IDMC will independently evaluate safety and efficacy data from the trial periodically and at prespecified enrollment-dependent time points. The IDMC will make recommendations regarding trial modification or continuation based on their review and in accordance with the agreed upon IDMC charter. Recommendations from the IDMC will be relayed to an Executive Representative of the Sponsor who will make a determination about implementing recommendations to modify or discontinue the study. All appropriate regulatory authorities and ethics committees will be notified of significant actions taken as a result of IDMC recommendations. To maintain study integrity and to prevent the potential introduction of bias, all study team members will remain blinded until the final analysis of the Randomized Controlled Period is conducted. Details of this process will be documented in the IDMC charter. Abbreviations
Abbreviations used in the clinical trial disclosed herein are listed in Table 12 below.
Table 12: Abbreviations
Figure imgf000089_0001
Figure imgf000090_0001
Table 13: Sequence Summary
Figure imgf000091_0001
Figure imgf000092_0001
Figure imgf000093_0001
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
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Claims

1. A composition for use in a method of treating amyotrophic lateral sclerosis (ALS) in a human patient, the treatment comprising administering to the patient an effective amount of the composition, wherein the composition comprises an antibody or an antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively.
2. The composition for use according to claim 1, wherein the antibody or the antigen binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
3. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof is administered:
(a) once on Day 1 of the administration cycle at a loading dose of: i. 2400 mg to a patient weighing > 40 to < 60 kg, ii. 2700 mg to a patient weighing > 60 to < 100 kg, or iii. 3000 mg to a patient weighing > 100 kg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. 3000 mg to a patient weighing > 40 to < 60 kg, ii. 3300 mg to a patient weighing > 60 to < 100 kg, or iii 3600 mg to a patient weighing > 100 kg.
4. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof comprises the heavy chain variable region of SEQ ID NO: 12 and the light chain variable region of SEQ ID NO:8.
5. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof further comprises the heavy chain constant region of SEQ ID NO: 13.
6. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and the light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
7. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM.
8. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof, binds to human C5 at pH 6.0 and 25°C with a KD < 10 nM.
9. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 40 to < 60 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 2400 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3000 mg.
10. The composition for use according to any one of claims 1-8, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 60 to < 100 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 2700 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3300 mg.
11. The composition for use according to any one of claims 1 -8, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 100 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 3000 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3600 mg.
12. The composition for use according to any one of the preceding claims, wherein the treatment maintains a serum trough concentration of the antibody or the antigen binding fragment thereof of 100 pg/mL or greater during the administration cycle.
13. The composition for use according to any one of the preceding claims, wherein the treatment maintains a serum trough concentration of the antibody or the antigen binding fragment thereof of 200 pg/mL or greater during the administration cycle.
14. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof is administered at a dose of 3000 mg, 3300 mg, or 3600 mg every eight weeks after the administration cycle for up to two years.
15. The composition for use according to any one of the preceding claims, wherein the antibody or the antigen binding fragment thereof is formulated for intravenous administration.
16. The composition for use according to any one of the preceding claims, wherein the further comprises administering a therapeutically effective amount of one or more compositions selected from the group consisting of riluzole and edaravone.
17. The composition for use according to any one of the preceding claims, wherein the patient has a Revised Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) score progression of 0.3 points per month or worse in the period from disease onset to the time of evaluation for treatment.
18. The composition for use according to any one of the preceding claims, wherein the patient has an upright slow vital capacity (SVC) of at least 65% at the time of evaluation for treatment.
19. The composition for use according to any one of the preceding claims, wherein the administration cycle is a total of 50 weeks of treatment.
20. The composition for use according to any one of the preceding claims, wherein the treatment results in terminal complement inhibition.
21. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing a clinically meaningful improvement from baseline in an ALSFRS-R total score by Week 50 of treatment.
22. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing a clinically meaningful improvement in Ventilation Assistance-Free Survival (VAFS) by Week 50 of treatment.
23. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing a clinically meaningful improvement in a predicted percent change from baseline in SVC by Week 50 of treatment.
24. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing a clinically meaningful improvement in percent change in combined muscle megascore from baseline by Week 50 of treatment as assessed by Handheld Dynamometry (HHD).
25. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing an improvement in change from baseline in serum neurofilament light chain (NfL) concentrations by Week 50 of treatment.
26. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing an improvement one or more health or quality of life assessments by Week 50 of treatment, wherein the health or quality of life assessments are selected from the group consisting of: Amyotrophic Lateral Sclerosis Assessment Questionnaire (ALSAQ-40); EuroQoL 5 Dimensions (EQ-5D-5L); EQ Visual Analogue Scale (EQ-5D-5L VAS); and Short Form Health Survey (SF-36).
27. The composition for use according to any one of the preceding claims, wherein the treatment results in the patient experiencing an improvement in Treatment Satisfaction Questionnaire for Medication (TSQM) score by Week 50 of treatment.
28. A kit for treating amyotrophic lateral sclerosis (ALS) in a human patient, the kit comprising:
(a) a dose of an antibody or an antigen binding fragment thereof comprising CDR1,
CDR2 and CDR3 domains of a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of a light chain variable region comprising the amino acid sequence of SEQ ID NO:8; and (b) instructions for using the antibody or the antigen binding fragment thereof according to any one of the preceding claims.
29. The kit according to claim 28, wherein the antibody or the antigen binding fragment thereof comprises a variant human Fc constant region that specifically binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
30. The kit according to claim 28, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 40 to < 60 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 2400 mg; and
(b) on Day 15 of the administration cycles and every eight weeks thereafter at a maintenance does of 3000 mg.
31. The kit according to claim 28, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 60 to < 100 kg:
(a) once on Day 1 of the administration cycle at a dose of 2700 mg; and
(b) on Day 15 of the administration cycles and every eight weeks thereafter at a maintenance does of 3300 mg.
32. The kit of claim 28, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 100 kg:
(a) once on Day 1 of the administration cycle at a dose of 3000 mg; and
(b) on Day 15 of the administration cycles and every eight weeks thereafter at a maintenance does of 3600 mg.
33. An antibody for use in a method of administration in a treatment cycle, wherein the antibody comprises CDR1, CDR2 and CDR3 domains of the heavy chain variable region having the sequence set forth in SEQ ID NO: 12, and CDR1, CDR2 and CDR3 domains of the light chain variable region having the sequence set forth in SEQ ID NO:8.
34. The antibody for use according to claim 33, wherein the antibody or the antigen binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
35. The antibody for use according to claim 33 or claim 34, wherein the antibody is administered:
(a) once on Day 1 of the administration cycle at a loading dose of: i. 2400 mg to a patient weighing > 40 to < 60 kg, ii. 2700 mg to a patient weighing > 60 to < 100 kg, or iii. 3000 mg to a patient weighing > 100 kg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. 3000 mg to a patient weighing > 40 to < 60 kg, ii. 3300 mg to a patient weighing > 60 to < 100 kg, or iii. 3600 mg to a patient weighing > 100 kg.
36. The antibody for use according to claim 33, wherein the antibody is determined to be safe, tolerable, efficacious and sufficiently non-immunogenic after multiple IV doses for use in ALS patients.
37. A method of treating a human patient with ALS, the method comprising administering to the patient an effective amount of an antibody or an antigen binding fragment thereof comprising CDR1, CDR2 and CDR3 heavy chain sequences as set forth in SEQ ID NOs:19, 18 and 3, respectively, and CDR1, CDR2 and CDR3 light chain sequences as set forth in SEQ ID NOs:4, 5 and 6, respectively.
38. The method according to claim 37, wherein the antibody or the antigen binding fragment thereof comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429- Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
39. The method according to claim 37 or claim 38, wherein the antibody or the antigen binding fragment thereof is administered:
(a) once on Day 1 of the administration cycle at a loading dose of: i. 2400 mg to a patient weighing > 40 to < 60 kg, ii. 2700 mg to a patient weighing > 60 to < 100 kg, or iii. 3000 mg to a patient weighing > 100 kg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of: i. 3000 mg to a patient weighing > 40 to < 60 kg, ii. 3300 mg to a patient weighing > 60 to < 100 kg, o iii 3600 mg to a patient weighing > 100 kg.
40. The method according to any one of claims 37-39, wherein the antibody or the antigen binding fragment thereof comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 8.
41. The method according to any one of claims 37-39, wherein the antibody or the antigen binding fragment thereof further comprises a heavy chain constant region comprising the amino acid sequence of SEQ ID NO: 13.
42. The method according to any one of claims 37-41, wherein the antibody or the antigen binding fragment thereof comprises a heavy chain polypeptide comprising the amino acid sequence of SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence of SEQ ID NO: 11.
43. The method according to any one of claims 37-42, wherein the antibody or the antigen binding fragment thereof binds to human C5 at pH 7.4 and 25°C with an affinity dissociation constant (KD) that is in the range 0.1 nM < KD < 1 nM.
44. The method according to any one of claims 37-43, wherein the antibody or the antigen binding fragment thereof, binds to human C5 at pH 6.0 and 25°C with a KD < 10 nM.
45. The method according to any one of claims 37-44, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 40 to < 60 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 2400 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3000 mg.
46. The method according to any one of claims 37-44, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 60 to < 100 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 2700 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3300 mg.
47. The method according to any one of claims 37-44, wherein the antibody or the antigen binding fragment thereof is administered to a patient weighing > 100 kg:
(a) once on Day 1 of the administration cycle at a loading dose of 3000 mg; and
(b) on Day 15 of the administration cycle and every eight weeks thereafter at a maintenance dose of 3600 mg.
48. The method according to any one of claims 37-47, wherein the treatment maintains a serum trough concentration of the antibody or the antigen binding fragment thereof of 100 pg/mL or greater during the administration cycle.
49. The method according to any one of claims 37-48, wherein the treatment maintains a serum trough concentration of the antibody or the antigen binding fragment thereof of 200 pg/mL or greater during the administration cycle.
50. The method according to any one of claims 37-49, wherein the antibody or the antigen binding fragment thereof is administered at a dose of 3000 mg, 3300 mg or 3600 mg every eight weeks after the administration cycle for up to two years.
51. The method according to any one of claims 37-50, wherein the patient has a ALSFRS-R score progression of 0.3 points per month or worse in the period from disease onset to the time of evaluation for treatment.
52. The composition for use according to any one of claims 37-51, wherein the patient has an upright SVC of at least 65% at the time of evaluation for treatment.
53. The method according to any one of claims 37-52, wherein the antibody or the antigen binding fragment thereof is formulated for intravenous administration.
54. The method according to any one of claims 37-53, wherein the patient has not previously been treated with one or more composition selected from the group consisting of riluzole and edaravone.
55. The method according to any one of claims 37-54, wherein the administration cycle is a total of 50 weeks of treatment.
56. The method according to any one of claims 37-55, wherein the treatment results in terminal complement inhibition.
57. The method according to any one of claims 37-56, wherein the treatment results in the patient experiencing a clinically meaningful improvement from baseline in an ALSFRS- R total score by Week 50 of treatment.
58. The method according to any one of claims 37-57, wherein the treatment results in the patient experiencing a clinically meaningful improvement in VATS by Week 50 of treatment.
59. The method according to any one of claims 37-58, wherein the treatment results in the patient experiencing a clinically meaningful improvement in a predicted percent change from baseline in SVC by Week 50 of treatment.
60. The method according to any one of claims 37-59, wherein the treatment results in the patient experiencing a clinically meaningful improvement in percent change in combined muscle megascore from baseline by Week 50 of treatment as assessed by HHD.
61. The method according to any one of claims 37-60, wherein the treatment results in the patient experiencing an improvement in change from baseline in serum NfL concentrations by Week 50 of treatment.
62. The method according to any one of claims 37-61, wherein the treatment results in the patient experiencing an improvement one or more health or quality of life assessments by Week 50 of treatment, wherein the health or quality of life assessments are selected from the group consisting of: ALSAQ-40; EQ-5D-5L; EQ-5D-5L VAS; and SF-36.
63. The method according to any one of claims 37-62, wherein the treatment results in the patient experiencing an improvement in Treatment Satisfaction Questionnaire for Medication (TSQM) score by Week 50 of treatment.
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