RU2782069C2 - Schemes and methods for treatment of multiple sclerosis, using ofatumumab - Google Patents

Abstract

FIELD: medicine; neurology.

SUBSTANCE: group of inventions relates to the field of medicine, namely to neurology; it is intended for the treatment of multiple sclerosis. A method for the treatment of multiple sclerosis includes a) administration of ofatumumab to a patient according to a loading dose scheme at a dose of 20 mg of ofatumumab during 0, 1^st, and 2^nd weeks; and b) administration of ofatumumab to a patient according to a supporting dose scheme at a dose of 20 mg of ofatumumab, starting from the fourth week of the dosing scheme, and then continuing every four weeks. In another embodiment, the use of a method for administration of ofatumumab for the treatment of multiple sclerosis is provided.

EFFECT: use of the group of inventions allows for increase in the efficiency of treatment of multiple sclerosis with a high safety profile.

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Description

FIELD OF TECHNOLOGY

The present invention relates to a dosing regimen for the anti-CD20 monoclonal antibody, ofatumumab, for the treatment of multiple sclerosis (MS). The dosing regimen uses lower doses than previously used for other anti-CD20 monoclonal antibodies, allowing subcutaneous administration of ofatumumab. The dosing schedule also uses a loading dose schedule and then a maintenance dose schedule.

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and destruction of axons/neurons, which ultimately leads to severe disability.

The standard of care for first-line drugs is injectable compounds with poor efficacy, good safety profile, and well-known tolerability problems (interferon-beta and glatiramer acetate). More effective drugs for the treatment of MS are natalizumab and fingolimod. Natalizumab is a monoclonal antibody (mAb) directed against alpha-4 integrins on lymphocytes and has been shown to be effective in patients with RMS (Polman et al. (2006); Rudick et al. (2006)). However, in the vast majority of cases, natalizumab is limited for use as a second-line therapy due to the risk of developing a fatal opportunistic infection (i.e. progressive multifocal leukoencephalopathy or PML). Fingolimod is an oral S1P receptor modulator that has also been shown to be effective in relapsing MS and is approved as first line (eg in the US) or second line therapy (eg in the EU). Fingolimod has been shown to be effective against both placebo and one of the current first-line therapies, interferon beta-1a IM (Kappos et al. (2010); Cohen et al. (2010)). The use of fingolimod is associated with well-known safety risks associated with S1P (eg, bradyarrhythmia after treatment initiation, which requires monitoring of the first dose), macular edema, hypertension, and elevated liver transaminases.

Given that high-potency drugs for the treatment of MS have been associated with risks and first-line therapies with very poor efficacy, there remains a need to identify pharmaceuticals and concomitant dosing regimens that provide high efficacy with a safety profile comparable to or better than compared with first-line drugs.

BRIEF DESCRIPTION OF THE INVENTION

The present invention provides a method for treating, arresting or preventing multiple sclerosis (MS) using an anti-CD20 antibody, ofatumumab, or an antigen-binding fragment thereof, in a patient suffering from the disease, comprising administering to the patient at least one subcutaneous dose of ofatumumab or a fragment of this antibody. .

Disclosed herein are methods of treating MS comprising: a) administering ofatumumab, or an antigen-binding fragment thereof, to a patient in need thereof in a loading dose schedule, wherein the loading dose schedule comprises administering a loading dose of ofatumumab to the patient at least once prior to the first maintenance dose; and b) subsequently administering ofatumumab or an antigen-binding fragment thereof to the patient on a maintenance schedule, wherein the maintenance regimen provides for administering about 3 mg to about 60 mg of ofatumumab or an antigen-binding fragment thereof to the patient at week 4 and every four weeks thereafter.

Disclosed herein are methods of treating MS comprising: a) administering ofatumumab, or an antigen-binding fragment thereof, to a patient in need thereof in a loading dose schedule, wherein the loading dose schedule comprises administering a loading dose of ofatumumab to the patient at least once prior to the first maintenance dose; and b) subsequently administering ofatumumab or an antigen-binding fragment thereof to the patient on a maintenance schedule, wherein the maintenance regimen provides for administering approximately 3 mg, 10 mg, 20 mg, 30 mg, or 60 mg of ofatumumab or an antigen-binding fragment thereof to the patient at week 4 and every four weeks thereafter.

Disclosed herein are methods of treating MS comprising: a) administering ofatumumab, or an antigen-binding fragment thereof, to a patient in need thereof in a loading dose schedule, wherein the loading dose schedule involves administering a loading dose of ofatumumab to the patient at least three times prior to the first maintenance dose; and b) subsequently administering ofatumumab or an antigen-binding fragment thereof to the patient on a maintenance schedule, wherein the maintenance regimen provides for administering approximately 3 mg, 10 mg, 20 mg, 30 mg, or 60 mg of ofatumumab or an antigen-binding fragment thereof to the patient at week 4 and every four weeks thereafter.

This document discloses methods of treating MS, including:

a) administering ofatumumab, or an antigen-binding fragment thereof, to a patient in need of it, on a loading dose schedule, where the loading dose schedule provides for administering to the patient 3-60 mg, or about 3 mg, or about 10 mg, or about 20 mg, or about 30 mg or approximately 60 mg ofatumumab on day 0, day 7 and day 14 prior to the first maintenance dose. Preferably the loading dose is 20 mg ofatumumab; and

b) subsequently administering ofatumumab or an antigen-binding fragment thereof to a patient on a maintenance schedule, wherein the maintenance regimen provides for administering to the patient about 3 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 60 mg of ofatumumab or its antigen-binding fragment per week 4 and every four weeks thereafter. Preferably the maintenance dose is 20 mg ofatumumab.

Disclosed herein are methods of treating MS comprising: a) administering ofatumumab, or an antigen-binding fragment thereof, to a patient in need thereof, on a loading dose schedule, wherein the loading dose schedule involves administering 20 mg ofatumumab to the patient on day 0, day 7, and day 14 prior to administration first maintenance dose; and b) subsequently administering ofatumumab, or an antigen-binding fragment thereof, to the patient on a maintenance schedule, wherein the maintenance regimen includes administering approximately 20 mg of ofatumumab, or an antigen-binding fragment thereof, to the patient at week 4 and every four weeks thereafter.

BRIEF DESCRIPTION OF GRAPHICS

Figure 1 shows the average cumulative volume of new GdE lesions at week 24 versus the number of GdE lesions at baseline and categories based on the average number of CD19 B cells over 4-20 weeks.

Figure 2 shows the mean number of CD19 B cells expressed as a percentage of baseline.

(semilogarithmic scale) (ITT population).

Figure 3 shows the results of simulations predicting CD19 cell depletion as a function of loading dose regimen.

4 shows the results of simulations predicting CD19 cell depletion versus maintenance dosage.

Figure 5 shows the number of new GdE lesions by treatment group over time.

DETAILED DESCRIPTION OF THE INVENTION

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system (CNS) characterized by inflammation, demyelination, and destruction of axons/neurons, which ultimately leads to severe disability.

To date, there is increasing evidence that not only T cells are involved in immune-mediated damage in MS. In particular, the early role of B cells in the development of immune-mediated tissue damage in MS has become better understood (Archelos et al. 2000; Frohman et al. 2006; McFarland 2008). B cells have important functions in regulating the immune response and may contribute to disease pathogenesis by presenting self antigens, acting as cell adjuvants for CD4+ T cell activation (Bouaziz et al. 2007), and by regulating T cell function and inflammation beyond through the production of cytokines (Lund 2008) in addition to the production of autoantibodies. B cells are present in long-standing plaques, areas of demyelination, and in the cerebrospinal fluid of patients with MS (Klaus et al. 2013).

Clinical data from phase 2 studies with rituximab (Hauser et al. 2008) and ocrelizumab (Kappos et al. 2011) demonstrated that B-cell depletion by these agents resulted in a marked reduction in MRI-measured inflammatory activity in patients with relapsing MS. . Recently, the efficacy of ocrelizumab has been confirmed in 3 phase 2 trials in patients with RMS (Hauser et al. 2015; Hauser et al. 2017). These studies showed that ocrelizumab significantly reduced relapse rates, reduced disease activity as assessed by MRI, and delayed the time to worsening disability compared with interferon beta 1a by 2 years.

There may be problems associated with the use of anti-CD20 monoclonal antibodies such as rituximab and ocrelizumab in the treatment of MS. First, rituximab is a chimeric antibody, and chimeric antibodies are more immunogenic than their humanized (ocrelizumab) and fully human (ofatumumab) counterparts. In addition, high-dose regimens, such as those used with rituximab and ocrelizumab, lead to significant depletion of B cells in many compartments. This, in turn, may result in a higher incidence of infections and a concomitant loss of effective control over the effects of B cells compared to a regimen using anti-CD20 monoclonal antibody doses, which result in more precise and reversible B cell depletion. In addition, high doses of rituximab and ocrelizumab are given as intravenous infusions that must be administered in the clinic by a healthcare professional and can lead to a high rate of infusion reactions (Hauser et al. 2008; Hauser et al., 2015). Given the downside of high-dose regimens such as "anti-cancer" and B-cell depleting regimens for MS, it would be beneficial to develop a more convenient and safe anti-CD20 monoclonal antibody regimen for MS with similar or better efficacy.

Accordingly, there is still an unmet need for an improved treatment targeting B-cell pathology with a similar mechanism of action, high efficacy, an acceptable safety profile, and ease of self-administration by the patient.

Ofatumumab is an anti-CD20 human monoclonal antibody (mAb) approved for the treatment of patients with chronic lymphocytic leukemia (Arzerra®). The actions of ofatumumab on B cells are similar to those of rituximab and ocrelizumab. Ofatumumab recognizes a unique epitope located near the cell membrane on 2 extracellular domains of the CD20+ molecule, N-terminally from the epitope for the anti-CD20 monoclonal antibody (mAb), rituximab. Binding of CD20 by ofatumumab induces B cell lysis predominantly through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), rather than through apoptosis (unlike rituximab). Because ofatumumab is a fully human antibody (Ab), it is expected to have a low potential for immunogenicity, as evidenced by the very low incidence of anti-drug antibodies (ADA) directed against ofatumumab observed in clinical trials (<1% of patients in oncology trials; instructions for use of Arzerra® in the USA,

2016).

Ofatumumab targets a new epitope on the CD20 molecule, different from the epitope targeted by rituximab (RTX), a chimeric MAb to CD20. In studies with RTX, high intravenous (IV) doses (two doses of 1000 mg 14 days apart) were used, resulting in very rapid lysis of B cells, resulting in infusion reactions despite premedication with corticosteroids (CS). The first trial involving ofatumumab was a Phase I/II study looking at the low dose subcutaneous (SC) formulation of ofatumumab in rheumatoid arthritis (RA) administered without CS, which potentially provided more controlled B-cell depletion, than observed in studies with RTX. The primary objective was to investigate the safety and tolerability of a single SC dose of ofatumumab in patients with rheumatoid arthritis (RA) while receiving methotrexate (MTX). Secondary goals included investigating the minimum dose to achieve target peripheral B cell depletion, constructing a pharmacodynamic dose-response curve, and investigating the B cell replenishment profile. In this study, in RA patients treated with stable doses of MTX, SC doses containing 30, 60, or 100 mg ofatumumab resulted in significant and prolonged depletion of peripheral B cells. Single doses up to 60 mg were well tolerated and could provide a way to achieve B cell depletion without additional CS premedication. According to the results of this study, the duration of peripheral B-cell depletion is increased with a dose of ofatumumab (ofatumumab), which is an anti-CD20 antibody.

Ofatumumab has also been studied in patients with MS. Ofatumumab was evaluated in 2 phase 2 studies in patients with RRMS (studies OMS115102 and OMS112831/MIRROR). The OMS115102 study was a 48-week (24-week crossover study), double-blind, placebo-controlled study evaluating the effects of IV ofatumumab in 38 patients with RRMS (Soerensen et al. 2014). The study consisted of 3 different dose cohorts (100 mg, 300 mg, 700 mg), each of which randomized 12 patients to receive ofatumumab or placebo in a 2:1 ratio. After 24 weeks, ofatumumab-treated patients were switched to placebo, and placebo-treated patients were switched to the appropriate dose of ofatumumab for their cohort and followed up for 24 weeks (weeks 24-48). The results of the study showed that iv administration of ofatumumab resulted in a significant decrease in the number of circulating B cells and suppression of the activity of lesions observed on MRI (up to 96% reduction in activity of lesions compared with placebo) at each dose level evaluated in both treatment periods (Teeling et al (2004), Blood 104(6):1793-800).

The OMS112831/MIRROR study was a 48-week phase 2b study (24 weeks double-blind treatment phase followed by a 24-week follow-up phase) investigating the efficacy and safety of repeated subcutaneous doses of ofatumumab over a wide dose range in relapsing-remitting multiple sclerosis (RRMS). ) (Bar-Or, 2016). In this study, called MIRROR (MRI study in RRMS: evaluating ofatumumab regimen ( M RI study I n RR MS: evaluating ofatumumab R egimen)), patients received ofatumumab 3 mg, 30 mg, or 60 mg every 12 weeks (q12w ) or ofatumumab 60 mg every 4 weeks (q4w). To evaluate whether higher doses of ofatumumab (30 and 60 mg) could be tolerated by administering an initial, lower, conditioning dose of ofatumumab (which would theoretically result in gradual B cell lysis and potentially reduce cytokine release responses), patients in the treatment groups doses of 30 mg q12w, 60 mg q12w, and 60 mg q4w were randomized (1:1) to receive either placebo or a conditioning dose of ofatumumab 3 mg at week 0.

The primary endpoint was the cumulative number of new gadolinium-enhanced lesions over weeks 0-12 on magnetic resonance imaging (MRI) of the brain. Other endpoints included:

(i) cumulative number of new Gd-enhanced lesions at other time points;

(ii) total volume at weeks 12 and 24 of: a) new Gd-enhanced lesions, b) new/recently increased T2 lesions, and c) hypointense T1 lesions;

(iii) proportion of patients without recurrence;

(iv) Expanded Disability Scoring Scale (EDSS) scores;

(v) Multiple Sclerosis Functional Comprehensive Scale (MSFC) scores and its components;

(vi) Modified Fatigue Impact Scale (MFIS) scores; as well as

(vii) evaluation of the initial conditioning dose of ofatumumab.

Ofatumumab reduced the mean cumulative number of new gadolinium-enhanced lesions by 65% compared with placebo over weeks 0-12 (p<0.001) and ≥90% compared to placebo at weeks 4-12 at post hoc analysis of cumulative doses of ofatumumab ≥30 mg (p<0.001). Ofatumumab reduced cumulative new/recently increased T2 lesions compared with placebo over weeks 0-12 (60-72%;p≤0.002) and depleted CD19 B cells in a dose-dependent manner. During weeks 0-12, 17/164 patients (10%) who received ofatumumab relapsed compared with 9/67 patients (13%) who received placebo. It is important to note that the 3 mg conditioning dose was not beneficial.

Overall, these results indicate that SC-administered ofatumumab can suppress new lesions seen on MRI in the brain at doses significantly lower than those previously studied in MS patients. The results also demonstrated a rapid decrease in B cells in a dose- and dose-frequency dependent manner, with the effect being less pronounced with the 3 mg q12 regimen. Monthly dosing showed no signs of B cell replenishment during the dosing interval. For doses of 30 mg and 60 mg q12, approximately 95% suppression of B-cells in the blood compartment was shown before repeated dosing. After cessation of dosing, all treatments showed a relatively rapid repopulation of B cells within 60 weeks of follow-up compared to i.v. the introduction of antibodies to CD20 in high doses. Inhibition of CD19+ B cells by treatment group is shown in Figure 1. Monthly dosing showed no evidence of B cell recruitment during the dosing interval, and doses of 30 and 60 mg q12 showed approximately 75% suppression of B cells before repeated dosing. On a semi-log scale after dosing is stopped, all treatments show the same rate of B cell repopulation as evidenced by parallel growth curves (FIG. 1). Ofatumumab's sustained suppression of new Gd-boosted and T2 lesions is consistent with the effects shown by other anti-CD20 mAbs at doses that maximize peripheral B-cell depletion (von Budingen et al. 2012; Bleeker et al. 2008).

Overall, ofatumumab was safe and well tolerated by patients with RRMS. The safety profile of ofatumumab was consistent with previous data; no new reported issues.

In the OMS112831/MIRROR study with s.c. Ofatumumab AEs most commonly reported across all dose groups of ofatumumab were injection-related reactions (52% for ofatumumab, 15% for placebo). Injection-related reactions occurred predominantly after the first dose, decreased with subsequent doses, and were mostly mild/moderate in severity (97% of cases). There were no significant differences between treatment groups in the overall incidence of infection-related AE, including urinary tract and respiratory tract infections. Several serious adverse events (SAEs) have been reported. These were mostly injection-related systemic reactions (3 patients), all occurring on day 1 and in the ofatumumab 60 mg dose groups. No cases of opportunistic infections were reported during the study.

The term "comprising" encompasses "comprising" as well as "comprising", for example, a composition containing "X" may consist solely of X, or may include something additional, such as X+Y.

The term "about" in relation to the numerical value of x means +/- 10%, unless the context requires otherwise.

As used herein, the term "immunoglobulin" refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains, and one pair of heavy (H) chains, with all four chains linked by disulfide bonds. The structure of immunoglobulins has been described in detail. See, for example, Fundamental Immunology Ch. 7 (Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)). Briefly, each heavy chain typically consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region, CH, typically consists of three domains, CH1, CH2, and CH3. Each light chain typically consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region typically consists of a single domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability (or hypervariable regions, which may be hypervariable in terms of the sequence and/or shape of structurally defined loops), also called complementarity determining regions (CDRs), which are interspersed with more conservative regions, called frame regions (FR). Each VH and VL typically contains three CDRs and four FRs, arranged from N-terminus to C-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mol Biol 196, 901-917 (1987)). Typically, the numbering of amino acid residues in this region is carried out according to the method described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, Md. (1991) (phrases such as "variable domain residue numbering as in Kabat" or "according to Kabat" herein refer to this numbering system for heavy chain variable domains or light chain variable domains). Using this numbering system, the actual linear amino acid sequence of the peptide may contain fewer amino acids or additional amino acids corresponding to a truncation or insertion in the FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion (e.g., residue 52a according to Kabat) after residue 52 in CDR2 VH and inserted residues (e.g., residues 82a, 82b and 82c, etc. according to Kabat) after residue 82 FR heavy chain. Kabat residue numbering for a given antibody can be determined by aligning regions of antibody sequence homology with a "standard" Kabat numbered sequence.

As used herein, the term "antibody" refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of any of the foregoing, which has the ability to specifically bind to an antigen under typical physiological conditions for a significant period of time, such as at least about 30 minutes, at least at least about 45 minutes, at least about one hour, at least about two hours, at least about four hours, at least about 8 hours, at least about 12 hours, about 24 hours or more, about 48 hours, or more than about 3, 4, 5, 6, 7 or more days, etc., or for any other appropriate functionally defined period (such as time sufficient to induce, stimulate, enhance and/or modulate physiological response associated with antibody-antigen binding, and/or and such as sufficient time for the antibody to engage Fc-mediated effector activity). As used herein, the term "antigen-binding portion" of an antibody refers to antibody fragments that retain the ability to specifically bind to an antigen (eg, CD20). It has been shown that the antigen-binding function of an antibody can be carried out by fragments of a full-length antibody. Examples of binding fragments encompassed by the term "antigen-binding portion" of an antibody include a Fab fragment, a monovalent fragment consisting of V _L , V _H , CL and CH1 domains; F(ab)2 fragment, a bivalent fragment containing two Fab fragments connected by a disulfide bridge in the hinge region; Fd fragment consisting of V _H and CH1 domains; Fv fragment consisting of the V _L and V _H domains of one antibody arm; dAb fragment (Ward et al., 1989 Nature 341: 544-546) which consists of a V _H domain; and dedicated CDR.

The variable regions of the heavy and light chains of an immunoglobulin molecule contain a binding domain that interacts with an antigen. Antibody constant regions can mediate immunoglobulin binding to host tissues or factors, including various cells of the immune system (such as effector cells) and components of the complement system such as C1q, the first component in the classical complement pathway.

As noted above, as used herein, the term "antibody", unless otherwise indicated or clearly contradicted by the context, includes antibody fragments obtained using any known technique, such as enzymatic cleavage, peptide synthesis, and using recombinant techniques that preserve the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be carried out by fragments of a full-length (intact) antibody. Examples of antigen-binding fragments encompassed by the term "antibody" include, without limitation: (i) Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) F(ab)2 and F(ab')2 fragments, bivalent fragments containing two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragment, actually consisting of VH and CH1 domains; (iv) an Fv fragment actually consisting of the VL and VH domains of one arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341, 544-546 (1989)), which actually consists of a VH domain and is also called domain antibody (Holt et al. (November 2003) Trends Biotechnol. 21 (11): 484-90); (vi) camel antibody or nanobody (Revets et al. (January 2005) Expert Opin Biol Ther. 5 (1): 111-24), (vii) a complementarity determining region (CDR) such as CDR3 VH, (viii ) UniBody ^TM , monovalent antibody disclosed in WO 2007/059782, (ix) single chain antibody or single chain Fv (scFv), see, for example, Bird et al., Science 242, 423-426 (1988) and Huston et al. , PNAS USA 85, 5879-5883 (1988)), (x) a diabody (scFv dimer), which can be monospecific or bispecific (see, for example, the description of diabodies in PNAS USA 90(14), 6444-6448 (1993) , EP 404097 or WO 93/11161), triatelo or tetrabody. Although such fragments are generally included in the definition of an antibody, they together and each independently represent unique features of the present invention, demonstrating different biological properties and applicability. These and other useful antibody fragments in the context of the present invention are discussed later in this document.

It should be understood that the term "antibody" generally includes monoclonal antibodies as well as polyclonal antibodies. The antibodies may be human, humanized, chimeric, murine, etc. The resulting antibody may be of any isotype.

As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. Human antibodies of the present invention may include amino acid residues not encoded by human germline immunoglobulin sequences (eg, mutations introduced by in vitro random or site-specific mutagenesis or by in vivo somatic mutation). However, as used herein, the term "human antibody" is intended not to include antibodies in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted into human framework sequences.

As used herein, a human antibody is "derived from" a particular germline sequence if the antibody is produced in a system using human immunoglobulin sequences, for example, by immunizing a transgenic mouse carrying human immunoglobulin genes or by screening a human immunoglobulin gene library, and where selected human antibody by at least 90%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, or such as at least 99% identical in amino acid sequence to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody derived from a particular human germline sequence will have no more than 10 amino acid differences, such as no more than 5, such as no more than 4, 3, 2, or 1 amino acid differences, from the amino acid sequence encoded by the immunoglobulin gene. germline. In the case of VH sequences, antibodies do not include the VH CDR3 domain in this comparison.

The term "chimeric antibody" refers to an antibody that contains one or more regions from one antibody and one or more regions from one or more other antibodies. The term "chimeric antibody" includes monovalent, divalent or polyvalent antibodies. A monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain linked through disulfide bridges to a chimeric L chain. A divalent chimeric antibody is a tetramer (H2L2) formed by two HL dimers linked through at least one disulfide bridge. A polyvalent chimeric antibody can also be generated, for example, using a CH region that assembles into a molecule with 2+ binding sites (eg, from an IgM H chain or mu chain). Generally, a chimeric antibody refers to an antibody in which a portion of the heavy and/or light chain is identical or homologous to the corresponding sequences in antibodies derived from a particular species or belonging to a particular class or subclass of antibodies, while the remainder of the chain(s) are identical. or homologous to the corresponding sequences in antibodies derived from a different species or belonging to a different class or subclass of antibodies, and also refers to fragments of such antibodies, provided that they exhibit the desired biological activity (see, for example, US patent No. 4816567; see. also Morrison et al., PNAS USA 81, 6851-6855 (1984)). Chimeric antibodies are produced by recombinant processes well known in the art (see e.g. Cabilly et al., PNAS USA 81, 3273-3277 (1984), Morrison et al., PNAS USA 81, 6851-6855 (1984) , Boulianne et al., Nature 312, 643-646 (1984), EP125023, Neuberger et al., Nature 314, 268-270 (1985), EP171496, EP173494, WO 86/01533, EP184187, Sahagan et al., J Immunol 137, 1066-1074 (1986), WO 87/02671, Liu et al., PNAS USA 84, 3439-3443 (1987), Sun et al., PNAS USA 84, 214-218 (1987), Better et al., Science 240, 1041-1043 (1988) and Harlow et al., Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (1988)).

The term "humanized antibody" refers to a human antibody that contains minimal sequences derived from a non-human antibody. Typically, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from the hypervariable region of the recipient are replaced by residues from the hypervariable region of a non-human species (donor antibody), such as a mouse, rat, rabbit, or non-human primate, with the desired specificity, affinity and capacity.

In addition, humanized antibodies may contain residues that are not found in the recipient antibody or in the donor antibody. Such modifications are made to further improve the performance of the antibody. In most cases, a humanized antibody will contain substantially all of at least one, and usually two, variable domains, wherein all or substantially all of the hypervariable loops correspond to such regions in a non-human immunoglobulin, and all or substantially all of the FR regions correspond to such regions in the immunoglobulin sequence. person. Optionally, the humanized antibody will also contain at least a portion of a human immunoglobulin constant region. For additional information, see Jones et al., Nature 321, 522-525 (1986), Riechmann et al., Nature 332, 323-329 (1988) and Presta, Curr. Op. Struct. Biol. 2, 593-596 (1992).

The term "CD19" refers to the B-lymphocyte antigen CD19 (CD19=cluster of differentiation 19), which is a protein encoded by the human CD19 gene and found on the surface of B-cells, which is a type of white blood cell. The term "B cells" refers to a type of white blood cell. B cells are also known as B lymphocytes. They function in the humoral immunity component of the adaptive immune system by secreting antibodies. In addition, B cells present antigen (they are also classified as professional antigen presenting cells (APC)) and secrete cytokines. As used herein, "CD19 cells" and "B cells" refer to the same cell type.

The term "patient" refers to a human patient.

As used herein, the terms "monoclonal antibody" or "monoclonal antibody composition" refer to a formulation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single specificity and binding affinity for a particular epitope. Accordingly, the term "human monoclonal antibody" refers to antibodies exhibiting a single binding specificity that have variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by a hybridoma that includes a B cell derived from a transgenic or transchromosomal non-human animal, such as a transgenic mouse, having a genome containing a human heavy chain transgene and a light chain transgene, fused to an immortalized cell.

As used herein, the term "recombinant human antibody" includes all human antibodies that are produced, expressed, generated, or isolated by recombinant methods, such as (a) antibodies isolated from an animal (such as a mouse) that is transgenic or transchromosomal in human immunoglobulin genes, or from a hybridoma derived therefrom (described further elsewhere in this document), (b) antibodies isolated from a host cell transformed to express the antibody, such as from a transfectoma, (c) antibodies isolated from a recombinant combinatorial library of human antibodies, and (d) antibodies produced, expressed, generated or isolated by any other means which involve splicing human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, in the case of an animal transgenic for human Ig sequences, somatic mutagenesis in vivo), and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although derived from or related to human germline VH and VL sequences, may not naturally exist in the in vivo human germline antibody repertoire.

The CD20 molecule (also called human B-lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein of approximately 35 kDa localized on pre-B and mature B-lymphocytes (Valentine et al. (1989) J Biol Chem 264(19):11282-11287 and Einfield et al (1988) EMBO J 7(3):711-717). CD20 is found on the surface of over 90% of B cells from peripheral blood or lymphoid organs and is expressed during early pre-B cell development and persists until differentiation into plasma cells. CD20 is present on both normal B cells and malignant B cells. In particular, CD20 is expressed in more than 90% of B-cell non-Hodgkin's lymphomas (NHL) (Anderson et al. (1984) Blood 63 (6): 1424-1433), but is not found on hematopoietic stem cells, pro-B cells , normal plasma cells, or other normal tissues (Tedder et al. (1985) J. Immunol. 135(2):973-979).

The region of the CD20 protein of 85 amino acids located at the carboxy-terminus is located inside the cytoplasm. The length of this region differs sharply from that of other surface structures specific to B cells, such as the heavy chains of IgM, IgD and IgG or the alpha or beta chains of class II histocompatibility antigens, which have relatively short intracytoplasmic regions of 3, 3, 28 , 15 and 16 amino acids, respectively (Komaromy et al. (1983) NAR 11:6775-6785). Of the last 61 carboxy-terminal amino acids, 21 are acidic, while only 2 are basic, indicating that this region has a strong net negative charge. GenBank access number: NP_690605.

The anti-CD20 antibody, ofatumumab, of the present invention can be administered via any suitable route of administration such as oral, nasal, inhalation, intrabronchial, intraalveolar, topical (including buccal, transdermal and sublingual), rectal, vaginal and/or parenteral route of administration. In one embodiment, the pharmaceutical composition of the present invention is administered subcutaneously (s.c.), typically by injection. In one embodiment, SC administration of a pharmaceutical composition containing ofatumumab is performed using an auto-injector. A non-limiting example of an auto-injector suitable for use in accordance with the present invention is the Sensoready® pen.

As used herein, the phrases "parenteral administration" and "introduced by the parenteral route" means methods of administration other than enteral and topical administration, usually by injection, and they include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural and intrasternal injection and infusion.

In one embodiment of the present invention, the ofatumumab composition is formulated according to conventional procedures into a pharmaceutical composition adapted for intravenous administration to a human. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. If necessary, the composition may also include a solubilizing agent and a local anesthetic such as lignocaine to relieve pain at the injection site. Typically, the ingredients are supplied either singly or mixed together in a unit dosage form, for example, as a dry lyophilized powder or anhydrous concentrate, in a hermetically sealed container such as an ampoule or sachet, indicating the amount of active agent.

If the composition is to be administered by infusion, it may be dispensed in an infusion bottle containing sterile pharmaceutical grade water or physiological saline.

If the composition is administered by injection, an ampoule of sterile water for injection or physiological saline may be provided so that the ingredients can be mixed prior to administration.

In one embodiment, the formulation for ofatumumab may be formulated according to the formulation described in WO/2009/009407.

In one embodiment, ofatumumab is formulated as an antibody formulation wherein ofatumumab is present in an amount of about 20-300 mg/mL, 50-300 mg/mL, 100-300 mg/mL, 150-300 mg/mL, 200-300 mg/ml or 250-300 mg/ml, preferably in an amount of 50 mg/ml.

In one embodiment, ofatumumab is formulated as an antibody formulation, wherein the formulation contains 10-100 mM sodium acetate, 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0.2 mM EDTA, 0.01-0.2% polysorbate 80 and adjusted to pH 5.0-7.0. Preferably, the ofatumumab formulation contains 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, 0.02% polysorbate 80 and adjusted to pH 5.5.

In one embodiment, the ofatumumab formulation is provided as a pre-filled syringe.

In one embodiment, a method for the treatment of multiple sclerosis (MS) is provided, comprising: a) administering ofatumumab to a patient in need thereof on a loading dose schedule; and b) subsequently administering ofatumumab to the patient on a maintenance schedule.

In one embodiment, a method for attenuating or delaying the progression of symptoms of multiple sclerosis is provided, comprising: a) administering ofatumumab to a patient in need thereof on a loading dose schedule; and b) subsequently administering ofatumumab to the patient on a maintenance schedule.

In one embodiment, a method for slowing the progression of multiple sclerosis is provided, comprising: a) administering ofatumumab to a patient in need thereof on a loading dose schedule; and b) subsequently administering ofatumumab to the patient on a maintenance schedule.

In one embodiment, the loading dose is from about 15 mg to about 25 mg of ofatumumab, preferably from about 18 mg to about 22 mg of ofatumumab, most preferably about 20 mg of ofatumumab. In one embodiment, the maintenance dose is from about 15 mg to about 25 mg of ofatumumab, preferably from about 18 mg to about 22 mg of ofatumumab, and preferably about 20 mg of ofatumumab. In one embodiment, both the loading dose and the maintenance dose are from about 15 mg to about 25 mg of ofatumumab, preferably from about 18 mg to about 22 mg of ofatumumab, most preferably about 20 mg of ofatumumab.

In one embodiment, a method for the treatment of multiple sclerosis (MS) is provided, comprising the following schedule: a) ofatumumab is administered to a patient in need thereof,

according to the loading dose scheme providing for s.c. injections of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) ofatumumab is administered to a patient in need of it, according to a maintenance dose regimen comprising s.c. injections of 20 mg ofatumumab starting at week four of the dosing regimen and continuing every four weeks thereafter throughout the treatment protocol.

In one embodiment, a method for attenuating or delaying the progression of symptoms of multiple sclerosis (MS) is provided, comprising the following schedule: a) ofatumumab is administered to a patient in need thereof in a loading dose schedule comprising s.c. injections of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) ofatumumab is administered to a patient in need of it, according to a maintenance dose regimen comprising s.c. injections of 20 mg ofatumumab starting at week four of the dosing regimen and continuing every four weeks thereafter throughout the treatment protocol.

In one embodiment, a method for slowing the progression of multiple sclerosis (MS) is provided, comprising the following schedule: a) ofatumumab is administered to a patient in need thereof in a loading dose schedule comprising s.c. injections of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) ofatumumab is administered to a patient in need of it, according to a maintenance dose regimen comprising s.c. injections of 20 mg ofatumumab starting at week four of the dosing regimen and continuing every four weeks thereafter throughout the treatment protocol.

In one embodiment, ofatumumab is provided for use in a method for the treatment of multiple sclerosis (MS), the method comprising: a) administering ofatumumab to a patient in need thereof on a loading dose schedule; and b) subsequently administering ofatumumab to the patient on a maintenance schedule.

In one embodiment, ofatumumab is provided for use in a method for the treatment of multiple sclerosis (MS), the method comprising the following: a) ofatumumab is administered to a patient in need thereof in a loading dose schedule comprising s.c. injections of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) ofatumumab is administered to a patient in need of it, according to a maintenance dose regimen comprising s.c. injections of 20 mg ofatumumab starting at week four of the dosing regimen and continuing every four weeks thereafter throughout the treatment protocol.

In one embodiment, ofatumumab is provided for the manufacture of a medicament for use in a method of treating multiple sclerosis (MS), the method comprising: a) administering ofatumumab to a patient in need thereof on a loading dose schedule; and b) subsequently administering ofatumumab to the patient on a maintenance schedule.

The details of one or more embodiments of the present invention are set forth in the accompanying description above. Although any methods and materials similar or equivalent to those described in the present invention may be used in the practice or testing of the present invention, the preferred methods and materials are described below. Other features, objects and advantages of the present invention will be apparent from the description and claims. Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as is generally understood by one of ordinary skill in the art to which the present invention pertains. All patents and publications cited in this specification are incorporated herein by reference. The following example is presented in order to more fully illustrate the preferred embodiment of the present invention. This example should in no way be construed as limiting the scope of the disclosed subject matter as defined in the appended claims.

EXAMPLE

Randomized, double-blind, double-blind, parallel-group study comparing the efficacy and safety of ofatumumab with teriflunomide in patients with relapsing multiple sclerosis

The study was designed in conjunction with a parallel second study of identical design to provide data on the efficacy, safety and tolerability of ofatumumab in s.c. administration versus oral teriflunomide (Aubagio®) in patients with relapsing MS.

The primary aim of this study is to demonstrate that ofatumumab 20 mg given subcutaneously (s.c.) once every 4 weeks (q4) is superior to teriflunomide 14 mg given orally once daily in reducing the rate of confirmed relapses as measured by the frequency score. annualized rate of recurrence (ARR) in patients with relapsing MS.

Secondary goals include: (i) time to worsening disability measured as 3-month confirmed worsening (3mCDW) on the Expanded Disability Scoring Scale (EDSS); (ii) time to worsening disability, measured as 6-month confirmed worsening (6mCDW)

EDSS; (iii) time to improvement in disability measured as 6-month confirmed improvement (6mCDI) by EDSS; (iv) the number of Gd-enhanced T1 lesions on the MRI scan; (v) number of new or enlarged T2 lesions on MRI per year (annual rate of T2 lesions); and (vi) a reduction in brain volume (BVL) score based on estimates of percent change in brain volume from baseline.

The safety and tolerability of ofatumumab administered by s.c. at a rate of 20 mg q4 weeks, compared with teriflunomide administered orally at a rate of 14 mg once a day.

Study design

This is a randomized, double-blind, multicentre, parallel-group, double-masked study using the active drug as control and variable duration of treatment in patients with relapsing MS. Patients meeting the inclusion criteria will be randomized to receive either s.c. injections of ofatumumab 20 mg q4 weeks (following an initial loading schedule of three weekly doses of 20 mg for the first 14 days) or teriflunomide 14 mg orally once a day. A double-masked design will be used to blind the different formulations: patients in the active oftumumab treatment group will additionally receive once-daily oral placebo capsules; patients in the active teriflunomide treatment group will additionally receive placebo-containing s.c. injections for q4 weeks (following an initial regimen of three weekly doses for the first 14 days).

The study will include patients with relapsing MS (RRMS or SPMS with disease activity as defined by Lublin et al. 2014) with EDSS scores ranging from 0 to 5.5. Specific criteria for disease activity define a population with active inflammatory disease based on recent relapse within one or two years prior to study entry or one or more Gd-enhanced lesions on MRI one year prior to randomization. The population specified in the trial is typical of relapsing MS.

Loading dose schedule and maintenance dose schedule

The dosing regimen of ofatumumab in this study is a loading dose regimen of 20 mg on day 1, day 7, and day 14 followed by a monthly maintenance regimen of 20 mg administered every 4 weeks starting at week 4. Dose selection is based on clinical the hypothesis that depletion of B cells in lymphatic tissues is an important condition for efficacy (measured by MRI and relapses), and that depletion of parenchymal and meningeal B cells in the brain may be an additional factor in the mechanism of action; while the number of B-cells in the blood is an imperfect, epiphenomenal indicator of the state of tissues. This hypothesis assumes that 2 conditions must be met to achieve the required efficiency:

• a loading dose schedule with a sufficiently high initial PK for lymphatic depletion, and

• a constant maintenance dose that will keep B cell depletion levels below the desired threshold.

Phase 2 study at s.c. The administration of ofatumumab in patients with relapsing MS (the OMS112831/MIRROR study) provided important information regarding the relationship between peripheral B-cell depletion and efficacy as measured by Gd-enhanced lesions in the brain on MRI. This study identified a clear dose-response relationship using a quasi-Poisson regression model that related Gd-enhanced volumes of new lesions, number of lesions at baseline, and treatment group. The dose-response relationship was fully explained by the degree of reduction in the number of CD19+ cells. The model indicates that lower levels of CD19+ cells lead to better control of lesion volumes, and therefore a high level of CD19+ cell depletion (e.g., ≤8 cells/µl) must be maintained throughout the course of treatment to ensure the desired efficacy.

Simulation

It is desirable to achieve maximum MRI efficiency and B cell depletion below 8 cells/µl without any delay (FIG. 1). Exploratory modeling based on data from the phase 2 study, OMS112831/MIRROR, suggested that a single dose of ofatumumab 20 mg in s.c. the introduction is not enough to reduce the level of B-cells to ≤8 cells/μl (see figure 2). As can also be seen in Figures 3 and 4, the simulations predict that a high degree of target depletion can be achieved by administering 20 mg ofatumumab over multiple loading doses, and that subsequent maintenance doses (also 20 mg) either maintain or increase initial depletion. More specifically, based on simulations, the present inventors have determined that a loading dose schedule of 3 separate doses of 20 mg (at weeks 0, 1, and 2) is necessary to achieve target depletion (≤8 cells/µl) in >95% of patients, however, it was suggested that this regimen is more effective than the regimen with a single loading dose of 60 mg. Therefore, we chose this scheme of loading doses.

The OMS112831/MIRROR study investigated the administration of ofatumumab at 3 mg every 12 weeks, 30 mg every 12 weeks, 60 mg every 12 weeks, and 60 mg every 4 weeks. Although the 3 mg dose had a clear effect on MRI, and the 30 mg dose every 12 weeks seemed to be very close to the maximum effect on MRI, a dose of 60 mg every 12 weeks was also investigated to see if the maximum effect on MRI could indeed lead to the maximum clinical effect in terms of relapses and disability. The highest dose level, 60 mg every 4 weeks, resulted in no increase in efficacy compared to a dose of 60 mg every 12 weeks (Figure 5). However, when considering B cell replenishment, the present inventors noted a trend towards B cell replenishment until the next dose after 12 weeks. Since patients treated with a dose of 60 mg every 4 weeks showed no signs of replenishment of B-cells in the interval between injections, the authors of the present invention chose the interval between the introduction of maintenance doses of 4 weeks (once every 4 (q4) weeks) . The simulations evaluated the rate of B cell replenishment as a function of the amount of dose and the frequency of dosing. B-cell recruitment rates in MS patients were assessed according to the MIRROR study. Simulations have shown that for median cases of MS, a maintenance dose of 3 mg is considered adequate to maintain B cell depletion over a 4 week period (see Figure 4, top panel). However, the same modeling showed that for patients with a very high replacement rate (corresponding to the 95th ^percentile as assessed in the MIRROR study), i.e. under "worst case scenarios", neither the 3 mg maintenance dose nor the 10 mg maintenance dose will not be adequate to maintain B cell depletion over a 4 week interval, while 20 mg or higher doses will maintain adequate depletion (see Figure 4, bottom panel). Thus, based on the results of exploratory modeling, it was suggested that a dose of 20 mg ofatumumab is sufficient not only to maintain B-cell depletion, but also or further B-cell depletion in >95% of patients in whom they were previously depleted, and even in patients with a high replenishment rate. Therefore, in order to ensure continued efficacy in maintenance, the present inventors decided to split the tested MIRROR dosing regimen (60 mg every 12 weeks) to switch to 20 mg every 4 weeks.

In terms of safety and tolerability, in the OMS112831/MIRROR study, 60 mg q12 and q4 week dosing regimens were associated with more adverse events (AE) compared with lower dose regimens of 3 or 30 mg q12 weeks. In particular, post-injection systemic reactions reported as SAE on day 1 have only been observed with 60 mg dose regimens. If B cells are present at the first dose, and when B cells have begun to replenish, systemic reactions are expected AEs and their severity appears to be dose and B cell number dependent.

Because relapsing MS is a chronic disease with long-term treatment potential, dose selection should aim to balance efficacy and safety aspects. A subcutaneous loading regimen of 20 mg ofatumumab on day 1, day 7, and day 14 followed by a monthly maintenance regimen of 20 mg given every 4 weeks (starting at week 4) were chosen because they would deplete and subsequently maintain B cells at levels below 8 cells/µl in almost all patients and are expected to have maximum clinical benefit and better tolerability compared to higher dose regimens. Taken together, the strong relationship between MRI lesions and recurrences (Sormani et al. 2009; Sormani et al. 2013), as well as the observed inhibition of lesions at the cumulative doses tested, in combination with maintaining B-cell counts below the cut-off, support the choice proposed dosing regimen.

BIBLIOGRAPHY

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Claims (21)

1. A method for the treatment of multiple sclerosis (MS), including: a) administration of ofatumumab to the patient according to the loading dose schedule at a dose of 20 mg ofatumumab in the 0th, 1st and 2nd weeks; and b) administering ofatumumab to the patient on a maintenance dose schedule of 20 mg of ofatumumab starting on the fourth week of the dosing regimen and continuing every four weeks thereafter. 2. The method according to claim 1, where a) ofatumumab is administered to the patient on a loading dose schedule that includes subcutaneous injections of 20 mg ofatumumab at weeks 0, 1, and 2 of the dosing regimen; and b) ofatumumab is administered to the patient on a maintenance dosing regimen comprising subcutaneous injections of 20 mg ofatumumab starting on the fourth week of the dosing regimen and continuing every four weeks thereafter. 3. The method of claim 2 wherein 20 mg of ofatumumab is administered on a loading dose schedule and a maintenance dose schedule using an auto-injector filled with a formulation containing 50 mg/ml ofatumumab. 4. The method of claim 2 wherein 20 mg ofatumumab is administered on a loading dose schedule and a maintenance dose schedule using a syringe pre-filled with a formulation containing 50 mg/mL ofatumumab. 5. The method of claim 1 or 2, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). 6. The method of claim 1 or 2, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS). 7. The method of claim 1 or 2, wherein the multiple sclerosis is secondary progressive multiple sclerosis (SPMS). 8. The method of claim 1 or 2, wherein ofatumumab is administered to the patient on a loading dose schedule on day 0, day 7, and day 14 of the dosing schedule. 9. The method of claim 1 or 2, wherein ofatumumab is administered to the patient on a loading dose schedule on day 1, day 7, and day 14 of the dosing schedule. 10. Use of a method of administering ofatumumab for the treatment of multiple sclerosis, wherein the method comprises: a) a loading dose schedule with a dose of 20 mg ofatumumab at weeks 0, 1, and 2; and b) a maintenance dosing regimen with a dose of 20 mg ofatumumab starting from the fourth week of the dosing regimen and continuing every four weeks thereafter. 11. Use according to claim 10 wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). 12. Use according to claim 10 wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS). 13. The use of claim 10 wherein the multiple sclerosis is secondary progressive multiple sclerosis (SPMS). 14. Use according to claim 10, wherein ofatumumab is administered to the patient on a loading dose schedule on day 0, day 7, and day 14 of the dosing schedule. 15. Use according to claim 10 wherein ofatumumab is administered to the patient on a loading dose schedule on day 1, day 7 and day 14 of the dosing schedule.

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