Regidums and methods for treating multiple sclerosis using ofalimumab

Abstract

The present disclosure relates to therapeutic regimens for treating multiple sclerosis (MS). These methods utilize the administration to a patient of Ofalimumab as an anti-CD20 monoclonal antibody during a load dose regimen and maintenance regimen.

Description

[0001] This application is a divisional application of a Chinese patent application with the application number 201780049932.7, the filing date of August 11, 2017, and the invention title of "Regimens and Methods for Treating Multiple Sclerosis with Ofatumumab". The original application is a national stage application of an international application with the international application number PCT / IB2017 / 054909. This international application claims the priority of a US provisional patent application with the filing date of August 15, 2016 and the application number 62 / 374,986. Technical Field

[0002] This disclosure relates to a dosing regimen of the anti-CD20 monoclonal antibody ofatumumab for treating multiple sclerosis (MS). This dosing regimen uses lower doses compared to the doses of other anti-CD20 monoclonal antibodies used previously, and this dosing regimen allows for subcutaneous administration of ofatumumab. This dosing regimen also uses a loading dose regimen followed by a maintenance dose regimen. Background Art

[0003] Multiple sclerosis (MS) is an immune-mediated chronic central nervous system disease characterized by inflammation, demyelination, and axonal / neuronal damage, ultimately leading to severe disability.

[0004] Standard first-line care therapies include injectable compounds (interferon-β and glatiramer acetate) with moderate efficacy, good safety profiles, and well-known tolerance issues. More effective drugs for treating MS are natalizumab and fingolimod. Natalizumab is a monoclonal antibody (mAb) against α-4 integrin on lymphocytes and has shown efficacy in RMS patients (Polman et al. (2006); Rudick et al. (2006)). However, due to the risk of fatal opportunistic infections (i.e., progressive multifocal leukoencephalopathy or PML), natalizumab is mainly limited to use as a second-line therapy. Fingolimod is an oral S1P receptor modulator that has also shown efficacy in relapsing MS and is approved as a first-line (e.g., in the US) or second-line (e.g., in the EU) therapy. Fingolimod is associated with well-known S1P-related safety risks (e.g., bradyarrhythmia at the start of treatment that requires first-dose monitoring), macular edema, hypertension, and elevated liver transaminases.

[0005] Given the associated risks of the highly effective drugs for treating MS, while the first-line therapies only have moderate efficacy, there is a need to identify a drug and an accompanying dosing regimen that provide high efficacy and safety profiles comparable to or better than those of the first-line therapies. Summary of the Invention

[0006] The present invention provides a method for treating, arresting or preventing multiple sclerosis (MS) in a patient with the anti-CD20 antibody ofatumumab or an antigen-binding fragment thereof, the method comprising administering to the patient at least one subcutaneous dose of ofatumumab or an antibody fragment thereof.

[0007] Disclosed herein is a method for treating MS, which comprises: a) administering to a patient in need thereof ofatumumab or an antigen-binding fragment thereof during a loading dose regimen, wherein the loading dose regimen comprises administering to the patient at least one loading dose of ofatumumab before administering a first maintenance dose; and b) subsequently administering to the patient ofatumumab or an antigen-binding fragment thereof during a maintenance regimen, wherein the maintenance regimen comprises administering to the patient from about 3 mg to about 60 mg of ofatumumab or an antigen-binding fragment thereof at week 4 and every four weeks thereafter.

[0008] Disclosed herein is a method for treating MS, which comprises: a) administering to a patient in need thereof ofatumumab or an antigen-binding fragment thereof during a loading dose regimen, wherein the loading dose regimen comprises administering to the patient at least one loading dose of ofatumumab before administering a first maintenance dose; and b) subsequently administering to the patient ofatumumab or an antigen-binding fragment thereof during a maintenance regimen, wherein the maintenance regimen comprises administering to the patient 3 mg, 10 mg, 20 mg, 30 mg or 60 mg of ofatumumab or an antigen-binding fragment thereof at week 4 and every four weeks thereafter.

[0009] Disclosed herein is a method for treating MS, which comprises: a) administering to a patient in need thereof ofatumumab or an antigen-binding fragment thereof during a loading dose regimen, wherein the loading dose regimen comprises administering to the patient at least three loading doses of ofatumumab before administering a first maintenance dose; and b) subsequently administering to the patient ofatumumab or an antigen-binding fragment thereof during a maintenance regimen, wherein the maintenance regimen comprises administering to the patient 3 mg, 10 mg, 20 mg, 30 mg or 60 mg of ofatumumab or an antigen-binding fragment thereof at week 4 and every four weeks thereafter.

[0010] Disclosed herein is a method for treating MS, which comprises:

[0011] a) administering to a patient in need thereof ofatumumab or an antigen-binding fragment thereof during a loading dose regimen, wherein the loading dose regimen comprises administering to the patient 3 - 60 mg, or about 3 mg, or about 10 mg, or about 20 mg, or about 30 mg, or about 60 mg of ofatumumab at day 0, day 7 and day 14 before administering a first maintenance dose. Preferably, the loading dose is 20 mg of ofatumumab; and

[0012] b) Thereafter, ofatumumab or an antigen-binding fragment thereof is administered to the patient during a maintenance regimen, wherein the maintenance regimen comprises 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 an antigen-binding fragment thereof at 4 weeks and every four weeks thereafter. Preferably, the maintenance dose is 20 mg of ofatumumab.

[0013] Disclosed herein are methods of treating MS that comprise a) administering ofatumumab or an antigen-binding fragment thereof to a patient in need thereof during a loading dose regimen, wherein the loading dose regimen comprises administering 20 mg of ofatumumab to the patient on days 0, 7, and 14 before administration of the first maintenance dose; and b) thereafter, administering ofatumumab or an antigen-binding fragment thereof to the patient during a maintenance regimen, wherein the maintenance regimen comprises administering about 20 mg of ofatumumab or an antigen-binding fragment thereof to the patient at 4 weeks and every four weeks thereafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shows the mean cumulative new GdE lesion volume at week 24, the number of GdE lesions at baseline, and the mean CD19 B cell count categories across weeks 4 - 20.

[0015] Figure 2 Shows the mean CD19 B cell count, expressed as a percentage of baseline (semi-log scale) (ITT population).

[0016] Figure 3 Shows the results of a modeling study predicting CD19 cell depletion with the loading dose regimen.

[0017] Figure 4 Shows the results of a modeling study predicting CD19 cell depletion with the maintenance dose.

[0018] Figure 5 Shows the time course of the number of new GdE lesions in the treatment group. DETAILED DESCRIPTION

[0019] Multiple sclerosis (MS) is an immune-mediated chronic central nervous system (CNS) disease characterized by inflammation, demyelination, and axonal / neuronal damage, ultimately leading to severe disability.

[0020] There is growing evidence that immune-mediated damage in MS involves more than just T cells. Specifically, the early role of B cells in the immunemediated histopathology of MS (Archelos et al. 2000; Frohman et al. 2006; McFarland 2008) has become clearer. B cells have important functions in regulating immune responses and can contribute to disease pathogenesis by antigen presentation on their own, as cellular adjuvants for CD4+ T cell activation (Bouaziz et al., 2007), and by modulating T cell function and inflammation via cytokine production (Lund 2008) (in addition to autoantibody production). B cells are present in the chronic plaques, demyelinated regions, and cerebrospinal fluid of MS patients (Klaus et al., 2013).

[0021] Clinical evidence from phase 2 studies of rituximab (Hauser et al., 2008) and ocrelizumab (Kappos et al., 2011) has shown that B cell depletion induced by these agents results in a significant reduction in inflammatory activity measured by MRI in patients with relapsing MS. More recently, the efficacy of ocrelizumab has been confirmed in three phase 2 trials in RMS patients (Hauser et al., 2015; Hauser et al., 2017). These studies have shown that ocrelizumab significantly reduces the relapse rate, reduces MRI disease activity, and delays the time to disability progression (compared to interferon β1a, which led to disability progression over 2 years).

[0022] Treatment of MS with anti-CD20 monoclonal antibodies such as rituximab and ocrelizumab may have problems. 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) result in severe depletion of B cells in many compartments. This can in turn lead to a higher incidence of infections and a concomitant loss of effective management of B cell effector functions compared to regimens using anti-CD20 monoclonal antibody doses that can produce more precise and reversible B cell depletion. In addition, high doses of rituximab and ocrelizumab are administered as intravenous infusions, which must be given by healthcare professionals in a clinic and can result in a high incidence of infusion reactions (Hauser et al. 2008; Hauser et al., 2015). Given the drawbacks of using "cancer-like" high-dose B cell depletion regimens to treat MS, it would be beneficial to find a more convenient and safer regimen to treat MS with anti-CD20 monoclonal antibodies with the same or better efficacy.

[0023] Therefore, there remains an unmet need for advanced therapies that target B cell pathology with a similar mechanism of action, have high efficacy, an acceptable safety profile, and convenience for self-administration.

[0024] Ofatumumab is a human anti-CD20 monoclonal antibody (mAb) approved for the treatment of chronic lymphocytic leukemia patients. Ofatumumab acts on B cells similarly to rituximab and ocrelizumab. Ofatumumab recognizes a unique epitope near the cell membrane on two extracellular domains of the CD20+ molecule, i.e., the N-proximal of the epitope of the anti-CD20 monoclonal antibody (mAb) rituximab. CD20 binding of ofatumumab induces B cell lysis mainly through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), rather than inducing B cell lysis through apoptosis (different from rituximab). As a fully human antibody (Ab), ofatumumab is predicted to have a lower immunogenic potential, as confirmed by the very low incidence of anti-drug antibodies (ADA) against ofatumumab observed in clinical studies (<1% of patients in oncology studies; US prescribing information, 2016).

[0025] Ofatumumab targets a new epitope on the CD20 molecule (different from rituximab (RTX) - a chimeric anti-CD20 mAb). RTX studies have utilized high intravenous (IV) doses (two 1000 mg doses 14 days apart) resulting in very rapid B cell lysis, leading to infusion reactions despite the use of IV corticosteroid (CS) premedication. The first study involving ofatumumab was an I / II phase study to investigate whether the use of a low-dose subcutaneous (SC) ofatumumab formulation (administered without CS) in rheumatoid arthritis (RA) might provide more controlled B cell depletion than that observed in RTX studies. The primary objective was to study the safety and tolerability of a single SC dose of ofatumumab in patients with rheumatoid arthritis (RA) on background methotrexate (MTX). Secondary objectives included studying the minimum dose to achieve target peripheral B cell depletion, the pharmacodynamic dose-response curve, and the B cell recovery curve. In this study of RA patients on a stable MTX dose, SC ofatumumab doses of 30 mg, 60 mg, or 100 mg resulted in severe and sustained peripheral B cell depletion. Single doses up to 60 mg could be tolerated and provided a means to achieve B cell depletion without additional CS premedication. This study determined that the duration of peripheral B cell depletion increased with the dose of the anti-CD20 antibody ofatumumab.

[0026] Ofatumumab has also been studied in patients with MS. Ofatumumab (OMS115102 and OMS112831 / MIRROR study) has been evaluated in two Phase 2 studies in patients with RRMS. The OMS115102 study was a 48-week (24-week crossover), double-blind, placebo-controlled study that evaluated the effect of intravenous ofatumumab in 38 patients with RRMS (Soerensen et al., 2014). The study consisted of three dose cohorts (100 mg, 300 mg, 700 mg), with 12 patients randomized 2:1 to ofatumumab or placebo in each cohort. After 24 weeks, ofatumumab patients were switched to placebo and placebo patients were switched to the ofatumumab dose of their cohort and followed for an additional 24 weeks (weeks 24-48). The study showed that intravenous ofatumumab resulted in a profound reduction in circulating B cell counts and inhibition of MRI lesion activity at each dose level evaluated during both treatment periods (up to 96% reduction in lesion activity compared to placebo) (Teeling et al. (2004), Blood 104(6):1793-800).

[0027] OMS112831 / MIRROR was a Phase 2b, 48-week study (24-week double-blind treatment period followed by a 24-week follow-up period) that examined the efficacy and safety of subcutaneous ofatumumab at widely repeated doses in relapsing-remitting multiple sclerosis (RRMS) (Bar-Or, 2016). In this study, called MIRROR (MRI study in RRMS: evaluation Ofatumumab protocol), 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 tolerance to higher ofatumumab doses (30 mg and 60 mg) could be improved by giving an initial, lower, conditioning dose of ofatumumab (theoretically leading to gradual lysis of B cells and potentially reduced cytokine release responses), patients in the 30 mg q12w, 60 mg q12w, and 60 mg q4w dose groups were randomized (1:1) to receive placebo or a conditioning dose of ofatumumab 3 mg at week 0.

[0028] The primary endpoint was the cumulative number of new gadolinium-enhancing lesions on brain magnetic resonance imaging (MRI) during weeks 0-12. Other endpoints included

[0029] (i) the cumulative number of new Gd-enhancing lesions at other time points;

[0030] (ii)(ii) a) Total volume of new Gd-enhancing lesions, b) new / newly enlarged T2 lesions, and c) T1 hypointense lesions at week 12 and week 24;

[0031] (iii) Proportion of patients without relapse;

[0032] (iv) Expanded Disability Status Scale (EDSS) score;

[0033] (v) Multiple Sclerosis Functional Composite (MSFC) and its component scores;

[0034] (vi) Modified Fatigue Impact Scale (MFIS); and

[0035] (vii) Evaluate the use of the initial regulatory dose of ofatumumab.

[0036] In a post hoc analysis with a cumulative ofatumumab dose ≥ 30 mg (p < 0.001), during the 0 - 12 week period, compared with placebo, ofatumumab reduced the mean cumulative number of new gadolinium-enhancing lesions by 65% (p < 0.001), and during the 4 - 12 week period, compared with placebo, ofatumumab reduced the mean cumulative number of new gadolinium-enhancing lesions by ≥ 90%. During the 0 - 12 week period, compared with placebo, ofatumumab reduced cumulative new / newly enlarged T2 lesions (60% - 72%; p ≤ 0.002), and depleted CD19 B cells in a dose-dependent manner. During the 0 - 12 week period, compared with 9 / 67 patients (13%) receiving placebo, 17 / 164 patients (10%) receiving ofatumumab experienced relapse. Notably, there was no benefit in giving a 3 mg regulatory dose. Overall, these results showed that ofatumumab SC can inhibit new brain MRI lesions at doses far lower than those previously studied in MS patients. The results also demonstrated a rapid dose- and dose-frequency-dependent reduction in B cell counts, with less obvious effects for the 3 mg q12 regimen. Monthly dosing showed no signs of B cell recovery during the dosing interval. Both 30 mg and 60 mg q12 weeks showed approximately 95% B cell inhibition in the blood compartment before redosing. Once dosing was stopped, compared with high-dose intravenous anti-CD20 antibodies, all treatments showed relatively rapid B cell re-proliferation during 60 weeks of follow-up. Inhibition of CD19+ B cells in the treatment groups was as Figure 1 shown. Monthly dosing showed no signs of B cell recovery during the interval between doses, while both 30 and 60 mg q12 weeks showed approximately 75% B cell inhibition before redosing. On a semi-log scale, once dosing had been stopped, all treatments showed similar B cell re-proliferation rates, as demonstrated by parallel growth curves ( Figure 1)。At the dose that results in the greatest depletion of peripheral B cells, the continuous suppression of new Gd-enhancing lesions and T2 lesions with ofatumumab is consistent with the effects demonstrated by other anti-CD20 mAbs (von Budingen et al. 2012; Bleeker et al. 2008).

[0037] Overall, ofatumumab is safe and well tolerated in patients with RRMS. The safety profile of ofatumumab is consistent with previous data; no new signals were reported.

[0038] In the OMS112831 / MIRROR study of subcutaneous ofatumumab, the most frequently reported AEs in the ofatumumab dose groups were injection-related reactions (52% for ofatumumab vs. 15% for placebo). Injection-related reactions occurred mainly after the first dose, decreased with subsequent dosing, and were of mild / moderate severity (97% of events). There was no significant difference between treatment groups in the overall incidence of infection-related AEs, including urinary and respiratory tract infections. The reported serious adverse events (SAEs) were rare. These were mainly systemic injection-related reactions (3 patients), all occurring in the 60 mg ofatumumab dose group on day 1. No cases of opportunistic infections were reported during the study.

[0039] The term “comprising” encompasses “including” as well as “consisting of”, e.g., a composition “comprising” X can consist only of X or can include something additional, e.g., X + Y.

[0040] The term “about” with respect to a numerical value x means + / - 10%, unless the context dictates otherwise.

[0041] As used herein, the term "immunoglobulin" refers to a class of structurally related glycoproteins composed of two pairs of polypeptide chains, one pair of light (L) low molecular weight chains and one pair of heavy (H) chains, all four chains being linked to each other by disulfide bonds. The structure of immunoglobulins has been well characterized. See, e.g., Fundamental Immunology Ch.7 (Paul, W. ed., 2nd ed. Raven Press, N.Y. (1989)). Briefly, each heavy chain generally consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region CH generally consists of three domains, namely CH1, CH2, and CH3. Each light chain generally consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region generally consists of one domain CL. The VH and VL regions can be further subdivided into hypervariable regions (or hypervariable loops, which can be hypervariable in the sequence and / or form of structurally defined loops), also known as complementarity determining regions (CDRs), which are interspersed with more conserved regions, called framework regions (FRs). Each VH and VL generally consists of three CDRs and four FRs arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mol. Biol. [Journal of Molecular Biology] 196, 901-917 (1987)). Generally, the numbering of amino acid residues in this region is carried out by the method described in: Kabat et al., Sequences of Proteins of Immunological Interest [Sequences of Proteins of Immunological Interest], 5th ed. Public Health Service [Public Health Service], National Institutes of Health [National Institutes of Health], Bethesda [Bethesda], Maryland (1991) (phrases such as Kabat numbering of variable domain residues in Kabat or herein refer to the numbering system for the heavy chain variable domain or the light chain variable domain). Using this numbering system, the actual linear amino acid sequence of a peptide may contain fewer or additional amino acids that correspond to deletions or insertions in the FR or CDR of the variable domain. For example, the heavy chain variable domain may include a single amino acid insert after residue 52 of VH CDR2 (e.g., residue 52a according to Kabat) and insert residues after residue 82 of the heavy chain FR (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of the residues of a given antibody can be determined by aligning the antibody sequence with the homologous regions of the "standard" Kabat numbering sequence.

[0042] As used herein, the term "antibody" refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or a derivative of either, which has the ability to specifically bind to an antigen for a substantial period of time under typical physiological conditions, such as at least about 30 minutes, 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 longer, about 48 hours or longer, about 3 days, 4 days, 5 days, 6 days, 7 days or more, or any other relevant functionally defined period (e.g., a time sufficient to induce, promote, enhance, and / or modulate a physiological response associated with antibody binding to an antigen and / or a time sufficient to enable the antibody to recruit Fc-mediated effector activity). As used herein, the "antigen-binding portion" of an antibody refers to a fragment of the antibody that retains the ability to specifically bind to an antigen (e.g., CD20). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include Fab fragments, a monovalent fragment consisting of the V L 、V H 、CL and CH1 domains; F(ab)2 fragments, a divalent fragment comprising two Fab fragments linked by a disulfide bridge in the hinge region; Fd fragments consisting of the V H and CH1 domains; Fv fragments consisting of the V L and V H domains of a single arm of the antibody; dAb fragments consisting of the V H domain (Ward et al., 1989, Nature 341:544-546); and isolated CDRs.

[0043] The variable regions of the heavy and light chains of an immunoglobulin molecule contain binding domains that interact with an antigen. The constant region of an antibody can mediate the binding of the immunoglobulin 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 of the classical complement activation pathway.

[0044] As described above, unless otherwise specified or clearly inconsistent with the context, the term "antibody" as used herein includes antibody fragments provided by any known technique (such as enzymatic cleavage, peptide synthesis, and recombinant techniques that retain the ability to specifically bind an antigen). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length (intact) antibody. Examples of antigen-binding fragments encompassed by the term "antibody" include, but are not limited to, (i) Fab fragments, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) F(ab)2 and F(ab')2 fragments, bivalent fragments comprising two Fab fragments linked by a disulfide bridge in the hinge region; (iii) Fd fragments consisting essentially of the VH and CH1 domains; (iv) Fv fragments consisting essentially of the VL and VH domains of a single arm of an antibody, (v) dAb fragments (Ward et al., Nature 341, 544-546 (1989)), which consist essentially of the VH domain and are also referred to as domain antibodies (Holt et al. (November 2003) Trends Biotechnol. 21(11):484-90); (vi) camelid antibodies or nanobodies (Revets et al. (January 2005) Expert Opin Biol Ther. 5(1):111-24)), (vii) isolated complementarity-determining regions (CDRs), such as VH CDR3, (viii) UniBody TM , such as the monovalent antibody disclosed in WO 2007 / 059782, (ix) single-chain antibodies 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) diabodies (scFv dimers), triabodies, or tetra-bodies, which diabodies can be monospecific or bispecific (see, for example, the diabodies described in PNAS USA 90(14), 6444-6448 (1993), EP 404097, or WO 93 / 11161). Although these fragments are generally included within the definition of an antibody, they are, both jointly and independently, unique features of the present invention, exhibiting different biological properties and utilities. These and other useful antibody fragments in the context of the present invention are further discussed herein.

[0045] It should be understood that the term antibody generally includes monoclonal antibodies as well as polyclonal antibodies. Antibodies can be human antibodies, humanized antibodies, chimeric antibodies, murine antibodies, etc. The antibodies produced can have any isotype.

[0046] As used herein, the term "human antibody" is intended to include antibodies having variable and constant regions derived from human germline immunoglobulin sequences. The human antibodies of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random mutagenesis in vitro or site-specific mutagenesis or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to include antibodies in which CDR sequences derived from the germline of another mammalian species (e.g., mouse) have been grafted onto human framework sequences.

[0047] As used herein, a human antibody "derives from" a particular germline sequence if the antibody is obtained from a system using human immunoglobulin sequences, such as by immunizing transgenic mice carrying human immunoglobulin genes or by screening a human immunoglobulin gene library, and wherein the amino acid sequence of the selected human antibody is at least 90%, such as at least 95%, such as at least 96%, such as at least 97%, e.g., at least 98%, or such as at least 99% identical to the amino acid sequence encoded by the germline immunoglobulin gene. Typically, a human antibody that derives from a particular human germline sequence will show no more than 10 amino acid differences, such as no more than 5 (e.g., no more than 4, 3, 2, or 1) amino acid differences from the amino acid sequence encoded by the germline immunoglobulin gene. For VH antibody sequences, the VH CDR3 domain is not included in such comparison.

[0048] 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, bivalent, or multivalent antibodies. A monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain linked to a chimeric L chain via a disulfide bridge. A bivalent chimeric antibody is a tetramer (H2L2) formed by two HL dimers linked by at least one disulfide bridge. For example, multivalent chimeric antibodies can also be produced by using CH regions (such as from an IgM H chain or μ chain) assembled into a molecule with 2+ binding sites. Generally, a chimeric antibody is an antibody in which a portion of the heavy chain and / or light chain is identical or homologous to the corresponding sequence in an antibody derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the one or more chains is identical or homologous to the corresponding sequence in an antibody derived from another species or belonging to another antibody class or subclass and fragments of such antibodies, provided that they exhibit the desired biological activity (see, e.g., U.S. Patent No. 4,816,567; see also Morrison et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 81, 6851-6855 (1984)). Chimeric antibodies are produced by recombinant methods well known in the art (see, e.g., Cabilly et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 81, 3273-3277 (1984), Morrison et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 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. [Journal of Immunology] 137, 1066-1074 (1986), WO 87 / 02671, Liu et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 84, 3439-3443 (1987), Sun et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 84, 214-218 (1987), Better et al., Science 240, 1041-1043 (1988), and Harlow et al., Antibodies: A Laboratory Manual [Antibodies: A Laboratory Manual], Cold Spring Harbor Laboratory Press [Cold Spring Harbor Laboratory Press], Cold Spring Harbor [Cold Spring Harbor], New York, (1988)).

[0049] The term "humanized antibody" refers to a human antibody that contains the minimal sequence derived from a non-human antibody. Generally, a humanized antibody is a human immunoglobulin (recipient antibody) in which the residues from the recipient hypervariable regions are replaced with residues from the hypervariable regions (donor antibody) of a non-human species (such as mouse, rat, rabbit, or non-human primate) having the desired specificity, affinity, and capacity.

[0050] In addition, a humanized antibody may contain residues not found in the recipient antibody or the donor antibody. These modifications are made to further improve antibody performance. Generally, a humanized antibody will contain substantially all of the following: at least one (usually two) variable domains in which all or substantially all of the hypervariable loops correspond to those of a non-human immunoglobulin, and all or substantially all of the FR regions are those of a human immunoglobulin sequence. A humanized antibody optionally will also contain at least a portion of a human immunoglobulin constant region. Further details can be found in 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).

[0051] The term "CD19" refers to B lymphocyte antigen CD19 (CD19 = cluster of differentiation 19), a protein encoded by the CD19 gene in humans and found on the surface of B cells (a type of white blood cell). The term "B cell" refers to a type of white blood cell. B cells are also known as B lymphocytes and they function in the humoral immune component of the adaptive immune system by secreting antibodies. In addition, B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines. As used herein, "CD19 cells" and "B cells" refer to the same type of cell.

[0052] The term "patient" refers to a human patient.

[0053] As used herein, the term "monoclonal antibody" or "monoclonal antibody composition" refers to a preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition exhibits a single binding specificity and affinity for a particular epitope. Thus, the term "human monoclonal antibody" refers to an antibody that exhibits a single binding specificity and has variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by hybridomas that include B cells obtained from transgenic or transchromosomic non-human animals (such as transgenic mice) that are fused with immortalized cells and have a genome that contains a human heavy chain transgene and a human light chain transgene.

[0054] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, produced, or isolated by recombinant methods, such as (a) antibodies isolated from transgenic or transchromosomic animals (e.g., mice) that are engineered to express human immunoglobulin genes or from hybridomas made therefrom (further described elsewhere herein), (b) antibodies isolated from host cells transformed to express the antibody (such as from transfectomas), (c) antibodies isolated from recombinant, combinatorial human antibody libraries, and (d) antibodies prepared, expressed, produced, or isolated by any other means that involve splicing human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences. However, in certain embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when using transgenic animals engineered to express human Ig sequences, in vivo somatic mutagenesis), such that the amino acid sequences of the VH and VL regions of the recombinant antibody, although derived from and related to human germline VH and VL sequences, may not be sequences that are naturally present within the human antibody germline repertoire in vivo.

[0055] The CD20 molecule (also known as human B lymphocyte-restricted differentiation antigen or Bp35) is a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD that is located on pre-B lymphocytes 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 has been found on the surface of more than 90% of B cells from peripheral blood or lymphoid organs, and is expressed during early pre-B cell development and persists until plasma cell differentiation. CD20 is present on both normal B cells and malignant B cells. In particular, CD20 is expressed on greater than 90% of B cell non-Hodgkin lymphomas (NHL) (Anderson et al. (1984) Blood 63(6):1424-1433), but is not found on hematopoietic stem cells, progenitor B cells, normal plasma cells, or other normal tissues (Tedder et al. (1985) J. Immunol. 135(2):973-979).

[0056] The carboxy-terminal region of 85 amino acids of the CD20 protein is located within the cytoplasm. The length of this region is in contrast to the lengths of other B-cell specific surface structures (e.g., the lengths of the IgM, IgD, and IgG heavy chains or the class II histocompatibility antigen alpha or beta chains, which have relatively short cytoplasmic 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 residues while only 2 are basic residues, indicating that this region has a strong net negative charge. GenBank accession number is NP_690605.

[0057] The anti-CD20 antibody ofatumumab of the present invention can be administered by any suitable route, such as orally, nasally, inhalably, intratracheally, intraalveolarly, topically (including oral, transdermal, and sublingual), rectally, vaginally, and / or parenterally. In one embodiment, the pharmaceutical composition of the present invention is typically administered subcutaneously (s.c.) by injection. In one embodiment, the subcutaneous (SC) administration of the pharmaceutical composition containing ofatumumab is achieved using an autoinjector. Non-limiting examples of autoinjectors suitable for use according to the present invention are pens.

[0058] As used herein, the phrases "parenteral administration" and "administered parenterally" mean a mode of administration other than enteral and topical administration, typically by injection, and include epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, intratracheal, subcutaneous, subepidermal, intraarticular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural, and intrasternal injection and infusion.

[0059] In one embodiment of the present invention, the ofatumumab composition is formulated into a pharmaceutical composition suitable for intravenous administration to humans according to conventional procedures. Generally, the composition for intravenous administration is a sterile isotonic aqueous buffered solution. Where appropriate, the composition may also include solubilizing agents and local anesthetics (such as lidocaine) to relieve the pain at the injection site. Generally, the components are supplied separately or mixed together in unit dosage forms indicating the amount of the active agent, for example, as dry lyophilized powders or anhydrous concentrates in airtight sealed containers (such as ampoules or vials).

[0060] If the composition is administered by infusion, it can be dispensed using an infusion bottle containing sterile pharmaceutical grade water or saline.

[0061] If the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided to mix the components before administration.

[0062] In one embodiment, a formulation for ofatumumab can be prepared according to the formulations disclosed in WO / 2009 / 009407.

[0063] In one embodiment, ofatumumab is formulated in an antibody formulation, wherein the amount of ofatumumab present is 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 50 mg / ml.

[0064] In one embodiment, ofatumumab is formulated in an antibody formulation, wherein the formulation contains 10 to 100 mM sodium acetate, 25 to 100 mM sodium chloride, 0.5% to 5% arginine free base, 0.02 to 0.2 mM EDTA, 0.01% to 0.2% polysorbate 80, and the pH is adjusted to 5.0 to 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 the pH is adjusted to 5.5.

[0065] In one embodiment, the ofatumumab formulation is provided in a prefilled syringe.

[0066] In one embodiment, a method of treating multiple sclerosis (MS) is provided, which comprises a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance regimen.

[0067] In one embodiment, a method for alleviating or delaying the progression of multiple sclerosis symptoms is provided, which comprises a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance regimen.

[0068] In one embodiment, a method for slowing the progression of multiple sclerosis is provided, which comprises a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance regimen.

[0069] In one embodiment, the loading dose is of ofatumumab between about 15 mg and about 25 mg, preferably ofatumumab between about 18 mg and about 22 mg, and most preferably ofatumumab of about 20 mg. In one embodiment, the maintenance dose is ofatumumab between about 15 mg and about 25 mg, preferably ofatumumab between about 18 mg and about 22 mg, and preferably ofatumumab of about 20 mg. In one embodiment, both the loading dose and the maintenance dose are ofatumumab between about 15 mg and about 25 mg, preferably ofatumumab between about 18 mg and about 22 mg, and most preferably ofatumumab of about 20 mg.

[0070] In one embodiment, a method of treating multiple sclerosis (MS) is provided, which comprises the following regimen: a) administering ofatumumab to a patient in need during a loading dose regimen,

[0071] The loading dose regimen comprises subcutaneous injection of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) administering ofatumumab to a patient in need during a maintenance dose regimen, the maintenance dose regimen comprising subcutaneous injection of 20 mg ofatumumab starting at the fourth week of the dosing regimen, and subsequently continuing subcutaneous injection of 20 mg ofatumumab every four weeks for the duration of the treatment regimen.

[0072] In one embodiment, a method of alleviating or delaying the progression of symptoms of multiple sclerosis (MS) is provided, which comprises the following regimen: a) administering ofatumumab to a patient in need during a loading dose regimen, the loading dose regimen comprising subcutaneous injection of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) administering ofatumumab to a patient in need during a maintenance dose regimen, the maintenance dose regimen comprising subcutaneous injection of 20 mg ofatumumab starting at the fourth week of the dosing regimen, and subsequently continuing subcutaneous injection of 20 mg ofatumumab every four weeks for the duration of the treatment regimen.

[0073] In one embodiment, a method of slowing the progression of multiple sclerosis (MS) is provided, which comprises the following regimen: a) administering ofatumumab to a patient in need during a loading dose regimen, the loading dose regimen comprising subcutaneous injection of 20 mg ofatumumab on day 0, day 7, and day 14 of the dosing regimen; and b) administering ofatumumab to a patient in need during a maintenance dose regimen, the maintenance dose regimen comprising subcutaneous injection of 20 mg ofatumumab starting at the fourth week of the dosing regimen, and subsequently continuing subcutaneous injection of 20 mg ofatumumab every four weeks for the duration of the treatment regimen.

[0074] In one embodiment, ofatumumab is provided for use in a method of treating multiple sclerosis (MS), the method comprising a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance regimen.

[0075] In one embodiment, ofatumumab is provided for use in a method of treating multiple sclerosis (MS), the method comprising a) administering ofatumumab to a patient in need thereof during a loading dose regimen comprising subcutaneous injection of 20 mg ofatumumab on days 0, 7, and 14 of the dosing regimen; and b) administering ofatumumab to a patient in need thereof during a maintenance dose regimen comprising subcutaneous injection of 20 mg ofatumumab starting at week four of the dosing regimen and continuing subcutaneous injection of 20 mg ofatumumab every four weeks for the duration of the treatment regimen.

[0076] In one embodiment, ofatumumab is provided for use in the manufacture of a medicament for use in a method of treating multiple sclerosis (MS), wherein the method comprises a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance regimen.

[0077] This disclosure provides the following non-limiting examples.

[0078] Example 1. A method of treating multiple sclerosis (MS) comprising:

[0079] a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and

[0080] b) subsequently administering ofatumumab to the patient during a maintenance dose regimen.

[0081] Example 2. The method according to Example 1, wherein ofatumumab is administered by subcutaneous (s.c.) injection during the loading dose regimen and during the maintenance dose regimen.

[0082] Example 3. The method according to Example 1, wherein the dose of ofatumumab administered during the loading dose regimen is between about 15 mg and about 25 mg of ofatumumab.

[0083] Example 4. The method according to Example 1, wherein the dose of ofatumumab subsequently administered during the maintenance regimen is between about 15 mg and about 25 mg of ofatumumab.

[0084] Example 5. The method according to Example 1, wherein the dose of ofatumumab administered during the loading dose regimen is ofatumumab between about 18 mg and about 22 mg.

[0085] Example 6. The method according to Example 1, wherein the dose of ofatumumab administered subsequently during the maintenance regimen is ofatumumab between about 18 mg and about 22 mg.

[0086] Example 7. The method according to Example 1, wherein the dose of ofatumumab administered during the loading dose regimen is ofatumumab at about 20 mg.

[0087] Example 8. The method according to Example 1, wherein the dose of ofatumumab administered subsequently during the maintenance regimen is ofatumumab at about 20 mg.

[0088] Example 9. The method according to Example 1, wherein

[0089] a) the dose of ofatumumab administered during the loading dose regimen is ofatumumab between about 15 mg and about 25 mg; and

[0090] b) the dose of ofatumumab administered subsequently during the maintenance regimen is ofatumumab between about 15 mg and about 25 mg.

[0091] Example 10. The method according to Example 1, wherein

[0092] a) the dose of ofatumumab administered during the loading dose regimen is ofatumumab between about 18 mg and about 22 mg; and

[0093] b) the dose of ofatumumab administered subsequently during the maintenance regimen is ofatumumab between about 18 mg and about 22 mg.

[0094] Example 11. The method according to Example 1, wherein

[0095] a) the dose of ofatumumab administered during the loading dose regimen is ofatumumab at about 20 mg; and

[0096] b) the dose of ofatumumab administered subsequently during the maintenance regimen is ofatumumab at about 20 mg.

[0097] Example 12. The method according to Example 1, wherein

[0098] a) ofatumumab is administered to a patient in need during a loading dose regimen, the loading dose regimen comprising administering 20 mg ofatumumab on days 0, 7, and 14 of the dosing regimen; and

[0099] b) During the maintenance dosing regimen, ofatumumab is administered to patients in need thereof, the maintenance dosing regimen comprising administering 20 mg ofatumumab starting at the fourth week of the dosing regimen, and continuing to administer 20 mg ofatumumab every four weeks for the duration of the treatment regimen thereafter.

[0100] Example 13. The method according to Example 1, wherein

[0101] a) During the loading dosing regimen, ofatumumab is administered to patients in need thereof, the loading dosing regimen comprising subcutaneous injection of 20 mg ofatumumab on days 0, 7, and 14 of the dosing regimen; and

[0102] b) During the maintenance dosing regimen, ofatumumab is administered to patients in need thereof, the maintenance dosing regimen comprising subcutaneous injection of 20 mg ofatumumab starting at the fourth week of the dosing regimen, and continuing to administer 20 mg ofatumumab subcutaneously every four weeks for the duration of the treatment regimen thereafter.

[0103] Example 14. The method according to Example 13, wherein 20 mg ofatumumab is administered during the dosing regimen and the maintenance regimen by using an autoinjector loaded with a formulation containing ofatumumab at a concentration of 50 mg / ml.

[0104] Example 15. The method according to Example 13, wherein 20 mg ofatumumab is administered during the dosing regimen and the maintenance regimen by using a prefilled syringe filled with a formulation containing ofatumumab at a concentration of 50 mg / ml.

[0105] Example 16. The method according to Example 1, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS).

[0106] Example 17. The method according to Example 1, wherein the multiple sclerosis is primary progressive multiple sclerosis (PPMS).

[0107] Example 18. The method according to Example 1, wherein the multiple sclerosis is secondary progressive multiple sclerosis (SPMS).

[0108] Details of one or more embodiments of the present disclosure are set forth in the specification appended above. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. Other features, objects, and advantages of the present disclosure will be apparent from the specification and from the claims. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains, unless otherwise defined. All patents and published documents cited in this specification are incorporated by reference. The following examples are presented to more fully illustrate the preferred embodiments of the present disclosure. The examples should in no way be construed as limiting the scope of the disclosed patient issues as defined by the appended claims.

[0109] A randomized, double-blind, double-dummy, parallel-group study comparing the efficacy and safety of ofatumumab and teriflunomide in patients with relapsing multiple sclerosis Study design

[0110] This study was designed in combination with a second study of the same design conducted in parallel to provide efficacy, safety, and tolerability data of subcutaneous ofatumumab compared to oral teriflunomide in patients with relapsing multiple sclerosis (MS). compared to oral teriflunomide.

[0111] The primary objective of this study was to demonstrate that subcutaneous (s.c.) ofatumumab 20 mg every 4 (q4) weeks was superior to oral teriflunomide 14 mg once daily in reducing the frequency of confirmed relapses, which was evaluated by the annual relapse rate (ARR) in patients with relapsing MS.

[0112] Secondary objectives included (i) time to disability worsening measured by 3-month confirmed disability worsening (3mCDW) on the Expanded Disability Status Scale (EDSS); (ii) time to disability worsening measured by 6-month confirmed disability worsening (6mCDW) on the EDSS; (iii) time to disability improvement measured by 6-month confirmed disability improvement (6mCDI) on the EDSS; (iv) number of T1Gd-enhancing lesions per MRI scan; (v) number of new or enlarging T2 lesions on MRI per year (annual T2 lesion rate); (vi) brain volume loss (BVL) rate based on the assessment of the percentage change in brain volume relative to baseline.

[0113] The safety and tolerability of subcutaneous ofatumumab 20 mg q4 weeks compared to oral teriflunomide 14 mg once daily were also evaluated.

[0114] Loading dose regimen and maintenance dose regimen

[0115] This is a randomized, double-blind, double-dummy, active comparator-controlled, parallel-group, multi-center study in patients with relapsing MS with variable treatment duration. Eligible patients will be randomly assigned to receive subcutaneous ofatumumab 20 mg every 4 weeks (after an initial loading regimen of three 20 mg doses weekly for the first 14 days) or oral teriflunomide 14 mg once daily. To blind the different formulations, a double-dummy design will be used: patients in the active ofatumumab treatment group will additionally receive a placebo capsule once daily; patients in the active teriflunomide treatment group will additionally receive a placebo-containing subcutaneous injection every 4 weeks (after the initial regimen of three injections weekly for the first 14 days).

[0116] Patients with relapsing multiple sclerosis (MS) with an EDSS score of 0 to 5.5 (RRMS or SPMS with disease activity, as defined by Lublin et al. 2014) will be enrolled. Specific disease activity criteria define the population with active inflammatory disease based on recent relapse within the previous one or two years prior to enrollment or one or more gadolinium-enhancing lesions on MRI in the year prior to randomization. The defined trial population is typical relapsing MS.

[0117] Figure 1

[0118] 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 dose regimen of 20 mg every 4 weeks starting from Week 4. The dose selection relies on the clinical hypothesis that depletion of B cells in lymphoid tissues is key to efficacy (measured by MRI and relapse), and that depletion of B cells in the brain parenchyma and meninges may be another factor in the mode of action; blood B cell count is an imperfect and spurious measure of tissue status. This hypothesis suggests that in order to achieve the desired efficacy, two conditions should be met:

[0119] ● A loading dose regimen with a sufficiently high initial PK for lymphoid depletion, and

[0120] ● A continuous maintenance dose that can keep the level of B cell depletion below the required threshold.

[0121] The Phase 2 study of subcutaneous ofatumumab in patients with relapsing MS (OMS112831 / MIRROR study) provided important information on the relationship between peripheral B cell depletion and efficacy as measured by MRI Gd-enhanced brain lesions. In this study, a clear dose-response relationship was detected using a quasi-Poisson regression model that related the volume of new Gd-enhanced lesions, the number of baseline lesions, and the treatment group. The dose response was fully explained by the degree of decline in CD19+ cell counts. The model indicated that lower CD19+ cell levels led to better control of lesion volume and that subsequently a high level of CD19+ cell depletion (e.g., ≤8 cells / μL) should be maintained throughout the treatment course to ensure the desired efficacy.

[0122] Modeling study

[0123] It was desired to achieve maximum MRI efficacy and B cell depletion of < 8 cells / μL without any delay ( Figure 2 ). Exploratory modeling based on the Phase 2 data of the OMS112831 / MIRROR study indicated that a single subcutaneous dose of 20 mg ofatumumab was insufficient to reduce B cell levels to ≤8 cells / μL (see Figure 3 ). It was also seen from Figure 4 and Figure 5 that the modeling study predicted that administering ofatumumab 20 mg in multiple loading doses would provide a high level of target depletion and that subsequent maintenance doses (also 20 mg) would maintain or increase the initial depletion. More specifically, we determined that a loading dose regimen of 3 separate 20 mg doses (weeks 0, 1, and 2) was required to achieve target depletion (≤8 cells / μL) based on modeling in >95% of patients and was inferred to be more effective than a single 60 mg loading dose. Therefore, this loading dose regimen was selected.

[0124] In the OMS112831 / MIRROR study, ofatumumab was administered at 3 mg every 12 weeks, 30 mg every 12 weeks, 60 mg every 12 weeks, and 60 mg every 4 weeks. Although 3 mg had a significant MRI effect and 30 mg every 12 weeks seemed very close to maximum MRI efficacy, 60 mg every 12 weeks was also studied to ensure that maximum MRI efficacy would truly translate into maximum clinical effects on relapse and disability. Compared with 60 mg every 12 weeks, the highest dose level (60 mg every 4 weeks) did not increase any efficacy ( Figure 4)。However, when observing B cell recovery, we noticed a trend towards B cell recovery before the next 12-week dose was given. Since patients receiving 60 mg every 4 weeks (q4 weeks) did not show signs of B cell recovery during the dosing interval, we decided to maintain the dosing interval at 4 weeks (once every 4 (q4) weeks). Modeling studies estimated the B cell recovery rate relative to dose and dosing frequency. The B cell recovery rate in MS patients was estimated from MIRROR study data. Modeling studies indicated that for the average case in MS, a 3 mg maintenance dose was considered sufficient to maintain B cell depletion for 4 weeks (see Figure 4 , the figure above). However, the same modeling estimates that for patients with a very high recovery rate (corresponding to 95% as evaluated from the MIRROR study), i.e., in the "worst case", neither 3 mg nor 10 mg maintenance was sufficient to maintain B cell depletion at 4-week intervals, while a 20 mg or higher dose would maintain sufficient depletion (see ​ , the figure below). Thus, based on exploratory modeling, even in patients with a high recovery rate, ofatumumab at 20 mg appears sufficient to maintain or further deplete B cells in >95% of patients who have previously been depleted. Therefore, to ensure continued maintenance efficacy, the inventors decided to split the tested MIRROR dosing regimen (60 mg every 12 weeks) to 20 mg every 4 weeks.

[0125] In the OMS112831 / MIRROR study, with respect to safety and tolerability, the 60 mg dosing regimens at q12 weeks and q4 weeks were associated with more adverse events (AEs) compared to the lower dose regimens of 3 mg or 30 mg at q12 weeks. In particular, post-injection systemic reactions reported as SAEs on day 1 were only observed in the 60 mg dosing regimens. Systemic reactions are expected AEs in the presence of B cells at the first dose and when B cells have started to recover, and their severity may be dose- and B cell count-related.

[0126] Since relapsing MS is a chronic disease with an expected long-term treatment, dose selection should aim to balance efficacy and safety aspects. A loading dose regimen of subcutaneous ofatumumab 20 mg on days 1, 7, and 14, followed by a monthly maintenance dose regimen of 20 mg every 4 weeks (starting from week 4) was selected because for almost all patients, it will deplete and subsequently maintain B cell levels below 8 cells / μL and is predicted to have the greatest clinical benefit and better tolerability compared to higher doses. In summary, in combination with maintaining B cells below the threshold, the strong relationship between MRI lesions and relapses (Sormani et al. 2009; Sormani et al. 2013) and lesion suppression observed at the cumulative doses tested supports the choice of the recommended dosing regimen.

[0127] References Cited in This Article

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[0129] 2. Polman et al., A Randomized, Placebo-Controlled Trial of Natalizumab for Relapsing Multiple Sclerosis, N Engl J Med 2006; 354:899-910.

[0130] 3. Rudick et al., Natalizumab plus Interferon Beta-1a for Relapsing Multiple Sclerosis, N Engl J Med 2006; 354:911-923.

[0131] 4. Kappos et al., A Placebo-Controlled Trial of Oral Fingolimod in Relapsing Multiple Sclerosis, N Engl J Med 2010; 362:387-401.

[0132] 5. Cohen et al., Oral Fingolimod or Intramuscular Interferon for Relapsing Multiple Sclerosis, N Engl J Med 2010; 362:402-415.

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[0134] 7. Frohman et al., Multiple sclerosis – the plaque and its Pathogenesis, New Engl J Med 2006; 354:942-955.

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[0136] 9. Bouaziz et al., Therapeutic B-cell depletion impairs adaptive and autoreactive CD4+ T-cell activation in mice, Pro. Natl. Acad. Sci. USA 2007; 104:20882 - 20887.

[0137] 10. Lund, Cytokine-producing B lymphocytes – key regulators of immunity, Curr Opin Immunol. 2008; 20(3):332–38.

[0138] 11. Klaus Lehmann-Horn et al., Targeting B-cells in the Treatment of Multiple Sclerosis, Ther Adv Neurol Disorders 2013; 6(3):161 - 173.

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Claims

1. A method for treating multiple sclerosis (MS), which comprises: a) administering ofatumumab to a patient in need thereof during a loading dose regimen; and b) subsequently administering ofatumumab to the patient during a maintenance dose regimen.

2. The method according to claim 1, wherein ofatumumab is administered by subcutaneous (s.c.) injection during the loading dose regimen and during the maintenance dose regimen.

3. The method according to claim 1, wherein the dose of ofatumumab administered during the loading dose regimen is between about 15 mg and about 25 mg of ofatumumab.

4. The method according to claim 1, wherein the dose of ofatumumab subsequently administered during the maintenance regimen is between about 15 mg and about 25 mg of ofatumumab.

5. The method according to claim 1, wherein the dose of ofatumumab administered during the loading dose regimen is between about 18 mg and about 22 mg of ofatumumab.

6. The method according to claim 1, wherein the dose of ofatumumab subsequently administered during the maintenance regimen is between about 18 mg and about 22 mg of ofatumumab.

7. The method according to claim 1, wherein the dose of ofatumumab administered during the loading dose regimen is about 20 mg of ofatumumab.

8. The method according to claim 1, wherein the dose of ofatumumab subsequently administered during the maintenance regimen is about 20 mg of ofatumumab.

9. The method according to claim 1, wherein a) the dose of ofatumumab administered during the loading dose regimen is between about 15 mg and about 25 mg of ofatumumab; and b) the dose of ofatumumab subsequently administered during the maintenance regimen is between about 15 mg and about 25 mg of ofatumumab.

10. The method according to claim 1, wherein a) the dose of ofatumumab administered during the loading dose regimen is between about 18 mg and about 22 mg of ofatumumab; and b) the dose of ofatumumab subsequently administered during the maintenance regimen is between about 18 mg and about 22 mg of ofatumumab.

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