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 the Chinese invention patent application with application number 201780049932.7, application date August 11, 2017, and invention name “Schemes and methods for treating multiple sclerosis using ofatumumab”. The original application is a national phase application with international application number PCT / IB2017 / 054909, which claims priority to the U.S. provisional patent application with application number 62 / 374,986, filed on August 15, 2016. Technical Field

[0002] The present disclosure relates to a dosing regimen of the anti-CD20 monoclonal antibody ofatumumab to treat multiple sclerosis (MS). The dosing regimen uses a lower dose than the doses of other anti-CD20 monoclonal antibodies previously used, and the dosing regimen allows subcutaneous administration of ofatumumab. The 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 destruction, ultimately leading to severe disability.

[0004] The first-line standard of care therapy includes injectable compounds (interferon-β and glatiramer acetate) with moderate efficacy, good safety profiles, and well-known tolerability issues. More effective drugs for the treatment of MS are natalizumab and fingolimod. Natalizumab is a monoclonal antibody (mAb) against α-4 integrins 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., US) therapy or a second-line (e.g., EU) therapy. Compared with both placebo and one of the current first-line therapies, interferon β-1a IM, fingolimod shows efficacy (Kappos et al. (2010); Cohen et al. (2010)). Fingolimod is associated with the well-known S1P-related safety risks (e.g., bradyarrhythmias at the start of treatment requiring first-dose monitoring), macular edema, hypertension, and elevated liver transaminases.

[0005] Given that highly effective drugs for the treatment of MS have associated risks and first-line therapies have only modest efficacy, there is a need to identify drugs and concomitant dosing regimens that provide high efficacy and a safety profile comparable to or better than first-line therapies. Summary of the invention

[0006] The present invention provides a method for treating, inhibiting or preventing multiple sclerosis (MS) in a patient suffering from multiple sclerosis (MS) using 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 are methods for treating MS comprising: 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 to the patient at least one loading dose of ofatumumab prior to administering a first maintenance dose; and b) thereafter administering to the patient ofatumumab or an antigen-binding fragment thereof during a maintenance regimen, wherein the maintenance regimen comprises administering to the patient about 3 mg to about 60 mg ofatumumab or an antigen-binding fragment thereof at week 4 and every four weeks thereafter.

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

[0009] Disclosed herein are methods for treating MS comprising: 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 at least three loading doses of ofatumumab to the patient prior to administering a 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 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.

[0010] Disclosed herein are methods of treating MS comprising:

[0011] 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 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 to the patient on day 0, day 7, and day 14 prior to administering the first maintenance dose. Preferably, the loading dose is 20 mg of ofatumumab; and

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

[0013] Disclosed herein are methods for treating MS comprising 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 ofatumumab to the patient on days 0, 7, and 14 prior to administering a 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 approximately 20 mg ofatumumab or an antigen-binding fragment thereof to the patient at week 4 and every four weeks thereafter. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Figure 1 Shown are 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 Mean CD19 B cell counts expressed as percentage of baseline (semi-log scale) are shown (ITT population).

[0016] Figure 3 Results of modeling studies predicting CD19 cell depletion versus loading dose regimens are shown.

[0017] Figure 4 Results of modeling studies predicting CD19 cell depletion and maintenance doses are shown.

[0018] Figure 5 The time course of the number of new GdE lesions in the treatment groups is shown. DETAILED DESCRIPTION

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

[0020] There is increasing evidence that immune-mediated damage in MS involves more than just T cells. Specifically, the early role of B cells in contributing to immune-mediated histopathology in MS (Archelos et al. 2000; Frohman et al. 2006; McFarland 2008) has become more clear. B cells have important functions in regulating immune responses and can contribute to disease pathogenesis through self-antigen presentation, as cellular adjuvants for CD4+ T cell activation (Bouaziz et al., 2007), and by regulating T cell function and inflammation via cytokine production (Lund 2008), in addition to the production of autoantibodies. B cells are present in chronic plaques, areas of demyelination, 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) showed that B cell depletion by these agents resulted in a significant reduction in MRI-measured inflammatory activity in patients with relapsing MS. More recently, the efficacy of ocrelizumab was demonstrated in phase 2, phase 3 trials in patients with RMS (Hauser et al., 2015; Hauser et al., 2017). These studies showed that ocrelizumab significantly reduced relapse rates, reduced MRI disease activity, and delayed the time to disability worsening (compared to 2 years with interferon β1a, which resulted in disability worsening).

[0022] The use of anti-CD20 monoclonal antibodies such as rituximab and ocrelizumab to treat MS can be problematic. 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 in turn can lead to a higher incidence of infections and a concurrent loss of effective management of B cell effects compared to regimens using doses of anti-CD20 monoclonal antibodies that can produce more precise and reversible B cell depletion. In addition, high doses of rituximab and ocrelizumab are given as intravenous infusions, which must be given by a healthcare professional 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 equal or better efficacy.

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

[0024] Ofatumumab is a human anti-CD20 monoclonal antibody (mAb) approved for the treatment of chronic lymphocytic leukemia patients. Ofatumumab has effects on B cells similar to those of rituximab and ocrelizumab. Ofatumumab recognizes a unique epitope located near the cell membrane on the 2 extracellular domains of the CD20+ molecule, which is N-proximal to the epitope of the anti-CD20 monoclonal antibody (mAb) rituximab. CD20 binding by ofatumumab induces B cell lysis primarily through complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), rather than through apoptosis (unlike rituximab). As a fully human antibody (Ab), ofatumumab is predicted to have a low immunogenic potential, as demonstrated by the very low incidence of anti-drug antibodies (ADA) to ofatumumab observed in clinical studies (<1% of patients in oncology studies; US Prescribing Information, 2016).

[0025] Ofatumumab targets a neoepitope on the CD20 molecule (unlike 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 is a Phase I / II study to investigate whether the use of a low-dose subcutaneous (SC) ofatumumab formulation (given without CS) in rheumatoid arthritis (RA) may provide more controlled B cell depletion than observed in the RTX study. The primary objective is to investigate the safety and tolerability of a single SC dose of ofatumumab on background methotrexate (MTX) in patients with rheumatoid arthritis (RA). Secondary objectives include investigating the minimum dose to achieve target peripheral B cell depletion, pharmacodynamic dose-response curves, and B cell recovery curves. In this study of RA patients on a stable MTX dose, SC ofatumumab doses of 30 mg, 60 mg, or 100 mg resulted in profound and sustained peripheral B-cell depletion. Single doses up to 60 mg were tolerated and may provide a means of achieving B-cell depletion without additional CS premedication. This study established 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 has been evaluated in Phase 2 studies in patients with RRMS (OMS115102 and OMS112831 / MIRROR studies). The OMS115102 study was a 48-week (24-week crossover), double-blind, placebo-controlled study that evaluated the effects of intravenous administration of ofatumumab in 38 patients with RRMS (Soerensen et al., 2014). The study consisted of 3 dose groups (100 mg, 300 mg, 700 mg), with 12 patients randomly assigned to ofatumumab or placebo in each group at a ratio of 2: 1. After 24 weeks, ofatumumab patients were switched to placebo, and placebo patients were switched to their group's ofatumumab dose, and then for 24 weeks (weeks 24-48). The study showed that intravenous administration of ofatumumab resulted in profound reductions in circulating B cell counts and inhibition of MRI lesion activity (up to 96% reduction in lesion activity compared with placebo) at every dose level evaluated over two treatment periods (Teeling et al. (2004), Blood 104(6):1793-800).

[0027] OMS112831 / MIRROR is a phase 2b, 48-week study (24-week double-blind treatment period followed by 24-week follow-up period) that examined the efficacy and safety of extensive repeated doses of subcutaneous ofatumumab in relapsing-remitting multiple sclerosis (RRMS) (Bar-Or, 2016). Ofatumumab In the 1:1 regimen, patients received ofatumumab 3 mg, 30 mg, or 60 mg every 12 weeks (q12w) or 60 mg every 4 weeks (q4w). To evaluate whether tolerability to higher ofatumumab doses (30 mg and 60 mg) could be improved by giving an initial, lower, conditioning dose of ofatumumab (theoretically resulting in 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) the total volume of a) new Gd-enhancing lesions, b) new / newly enlarging T2 lesions, and c) T1 hypointense lesions at weeks 12 and 24;

[0031] (iii) the 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 initial conditioning ofatumumab doses.

[0036] In a post hoc analysis of cumulative ofatumumab doses ≥30 mg (p<0.001), ofatumumab reduced the mean cumulative number of new gadolinium-enhancing lesions by 65% ​​(p<0.001) compared with placebo during weeks 0-12, and reduced the mean cumulative number of new gadolinium-enhancing lesions by ≥90% compared with placebo during weeks 4-12. Ofatumumab reduced cumulative new / newly enlarging T2 lesions (60%-72%; p≤0.002) and dose-dependently depleted CD19 B cells compared with placebo during weeks 0-12. During weeks 0-12, 17 / 164 patients (10%) receiving ofatumumab experienced a relapse compared with 9 / 67 patients (13%) receiving placebo. Notably, there was no benefit from administering a 3 mg adjustment dose. Overall, these results show that ofatumumab SC can suppress new brain MRI lesions at doses much lower than previously studied in MS patients. The results also demonstrated rapid dose- and dose-frequency-dependent reductions in B cell counts, with a less pronounced effect with the 3mg q12 regimen. Monthly dosing showed no signs of B cell recovery during the dosing interval. Both 30mg and 60mg q12weeks showed approximately 95% suppression of B cells in the blood compartment prior to re-dosing. Once dosing was stopped, all treatments showed relatively rapid B cell repopulation at 60 weeks of follow-up compared to high-dose intravenous anti-CD20 antibodies. Suppression of CD19+ B cells by treatment group was as shown Figure 1 Monthly dosing showed no signs of B cell recovery during the interval between dosing, while both 30 and 60 mg q12w showed approximately 75% B cell suppression before re-dosing. On a semi-logarithmic scale, all treatments showed similar rates of B cell repopulation once dosing had ceased, as evidenced by the parallel growth curves ( Figure 1At doses that resulted in maximal peripheral B cell depletion, sustained suppression of new Gd-enhancing lesions and T2 lesions with ofatumumab was consistent with effects demonstrated with other anti-CD20 mAbs (von Budingen et al. 2012; Bleeker et al. 2008).

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

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

[0039] The term "comprising" encompasses "including" as well as "consisting", for example a composition "comprising" X may consist of X only, or may include something else, for example X+Y.

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

[0041] The term "immunoglobulin" as used herein refers to a class of structurally related glycoproteins consisting of two pairs of polypeptide chains, a pair of light (L) low molecular weight chains and a pair of heavy (H) chains, all four of which are interconnected by disulfide bonds. The structure of immunoglobulins has been well characterized. See, for example, Fundamental Immunology Ch.7 (Paul, W. ed., 2nd ed. Raven Press, NY (1989)). In short, each heavy chain is usually composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region CH is usually composed of three domains, namely CH1, CH2 and CH3. Each light chain is usually composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is usually composed of a domain CL. The VH and VL regions can be further subdivided into regions of hypervariability (or hypervariable regions, which can be hypervariable in sequence and / or form of structurally defined loops), also called complementarity determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). Each VH and VL is typically composed of three CDRs and four FRs arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4 (see also Chothia and Lesk J. Mol. Biol. [Journal of Molecular Biology] 196, 901-917 (1987)). Typically, the numbering of amino acid residues in this region is by the method described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th ed. Public Health Service, National Institutes of Health, Bethesda, Maryland (1991) (the phrase, "variable domain residue numbering as in Kabat or herein according to Kabat" refers 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 corresponding to a shortening or insertion of a FR or CDR of the variable domain. For example, a heavy chain variable domain may include a single amino acid insertion after residue 52 of VH CDR2 (e.g., residue 52a according to Kabat) and inserted residues after heavy chain FR residue 82 (e.g., residues 82a, 82b, and 82c, etc. according to Kabat). The Kabat numbering of residues for a given antibody can be determined by aligning the antibody sequence with regions of homology to a "standard" Kabat numbering sequence.

[0042] The term "antibody" as used herein refers to an immunoglobulin molecule, a fragment of an immunoglobulin molecule, or any derivative thereof, which has the ability to specifically bind to an antigen under typical physiological conditions for a considerable period of time, 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 days, or any other relevant functionally defined period (e.g., a period sufficient to induce, promote, enhance and / or regulate a physiological response associated with antibody binding to an antigen and / or a period sufficient to allow the antibody to recruit Fc-mediated effector activity). The term "antigen-binding portion" of an antibody as used herein refers to a fragment of an 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 a fragment of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include Fab fragments, a Fab fragment consisting of a V L 、V H A monovalent fragment consisting of the V, CL and CH1 domains; a F(ab)2 fragment, a bivalent fragment consisting of two Fab fragments linked by a disulfide bridge at the hinge region; H The Fd fragment consists of the V and CH1 domains of a single arm of the antibody. L and V H Fv fragment composed of V H dAb fragments composed of domains (Ward et al., 1989, Nature 341:544-546); and isolated CDRs.

[0043] The variable regions of the heavy and light chains of the immunoglobulin molecules contain binding domains that interact with antigens. The constant regions of antibodies mediate the binding of immunoglobulins 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 mentioned above, unless otherwise indicated or clearly contradictory to the context, the term "antibody" as used herein includes antibody fragments provided by any known technology (such as enzymatic cleavage, peptide synthesis, and recombinant technology that retains the ability to specifically bind to an antigen). It has been shown that the antigen-binding function of an antibody can be performed by a fragment of a full-length (intact) antibody. Examples of antigen-binding fragments encompassed within the term "antibody" include, but are not limited to, (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) F(ab)2 and F(ab')2 fragments, which are bivalent fragments comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting essentially of the VH and CH1 domains; (iv) a Fv fragment consisting essentially of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., Nature 341, 544-546 (1989)), which consists essentially of the VH domain, also known as a domain antibody (Holt et al. (November 2003) Trends Biotechnol. [Biotech Trends] 21(11):484-90); (vi) camelid antibodies or nanobodies (Revets et al. (January 2005) Expert Opin Biol. Ther. [Expert Opinion in Biotherapy] 5(1):111-24), (vii) isolated complementarity determining regions (CDRs), such as VH CDR3, (viii) UniBody TM , such as monovalent antibodies disclosed in WO 2007 / 059782, (ix) single-chain antibodies or single-chain Fv (scFv), see, for example, Bird et al., Science [Science] 242, 423-426 (1988) and Huston et al., PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 85, 5879-5883 (1988)), (x) diabodies (scFv dimers), triabodies or tetrabodies, which diabodies can be monospecific or bispecific (see, for example, PNAS USA [Proceedings of the National Academy of Sciences of the United States of America] 90 (14), 6444-6448 (1993), EP 404097 or WO 93 / 11161. Although these fragments are generally included in the definition of antibodies, they are collectively and independently unique features of the present invention, exhibiting different biological properties and utility. 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. The antibody can be a human antibody, a humanized antibody, a chimeric antibody, a mouse antibody, etc. The antibody 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 present invention may include amino acid residues that are not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro 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 transplanted into human framework sequences.

[0047] As used herein, a human antibody is "derived 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%, for example 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 derived 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 this comparison.

[0048] The term "chimeric antibody" refers to an antibody containing 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 multivalent antibodies. A monovalent chimeric antibody is a dimer (HL) formed by a chimeric H chain connected to a chimeric L chain by a disulfide bridge. A divalent chimeric antibody is a tetramer (H2L2) formed by two HL dimers connected by at least one disulfide bridge. For example, multivalent chimeric antibodies can also be produced by using CH regions (e.g., from IgM H chains or μ chains) assembled into molecules with 2+ binding sites. Generally, a chimeric antibody refers to 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, as well as fragments of such antibodies, as long as they exhibit the desired biological activity (see, e.g., U.S. Pat. No. 4,816,567; see also Morrison et al., PNAS USA 81, 6851-6855 (1984)). Chimeric antibodies are produced by recombinant methods 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), EP 125023, Neuberger et al., Nature 314, 268-270 (1985), EP 171496, EP 173494, WO 86 / 01533, EP 184187, 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, New York, (1988)).

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

[0050] In addition, humanized antibodies may be included in residues not found in the receptor antibody or the donor antibody. These modifications are carried out to further improve antibody performance. Generally, humanized antibodies will include substantially all of the following items: at least one (usually two) variable domains, wherein all or substantially all hypervariable loops correspond to those hypervariable loops of non-human immunoglobulins, and all or substantially all FR regions are those FR regions of human immunoglobulin sequences. Humanized antibodies will optionally also include at least a portion of a human immunoglobulin constant region. Further details are provided by Jones et al., Nature [Nature] 321, 522-525 (1986), Riechmann et al., Nature [Nature] 332, 323-329 (1988) and Presta, Curr. Op. Struct. Biol. [Current Structural Biology Viewpoints] 2, 593-596 (1992).

[0051] The term "CD19" refers to the 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 called B lymphocytes, and they play a role in the humoral immunity 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 cells.

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

[0053] The term "monoclonal antibody" or "monoclonal antibody composition" as used herein 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 exhibiting a single binding specificity having variable and constant regions derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by a hybridoma comprising a B cell obtained from a transgenic or transchromosomal non-human animal (e.g., a transgenic mouse) fused to an immortalized cell, the B cell having a genome comprising a human heavy chain transgene and a light chain transgene.

[0054] As used herein, the term "recombinant human antibody" includes all human antibodies prepared, expressed, generated or isolated by recombinant methods, such as (a) antibodies isolated from animals (e.g., mice) transgenic or transchromosomal for human immunoglobulin genes or hybridomas prepared therefrom (further described elsewhere herein), (b) antibodies isolated from host cells transformed to express antibodies (e.g., from transfectomas), (c) antibodies isolated from recombinant, combinatorial human antibody libraries, and (d) antibodies prepared, expressed, generated or isolated by any other means involving splicing of 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 animals transgenic for human Ig sequences, in vivo somatic mutagenesis), so that although derived from and related to human germline VH and VL sequences, the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that may not naturally occur 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 of approximately 35 kD located on pre-B lymphocytes and mature B lymphocytes (Valentine et al. (1989) J. Biol. Chem. [Journal of Biological Chemistry] 264 (19): 11282-11287; and Einfield et al. (1988) EMBO J. [EMBO Magazine] 7 (3): 711-717). CD20 is 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 continues 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 85 amino acid whose carboxyl terminal region of CD20 protein is located in cytoplasm. The length of this region is contrasted with the length of other B cell specific surface structures (such as the length of IgM, IgD and IgG heavy chain or histocompatibility antigen II class α chain or β chain, which have 3,3,28,15 and 16 amino acid whose relatively short cytoplasmic region respectively) (Komaromy et al. (1983) NAR 11:6775-6785). In the last 61 carboxyl terminal amino acids, 21 are acidic residues, and only 2 are basic residues, indicating that this region has 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 oral, nasal, inhalable, intrabronchial, intraalveolar, topical (including oral, transdermal and sublingual), rectal, vaginal and / or parenteral. In one embodiment, the pharmaceutical composition of the present invention is administered subcutaneously (sc), typically by injection. In one embodiment, subcutaneous (SC) administration of a pharmaceutical composition comprising ofatumumab is achieved using an automatic injector. Non-limiting examples of automatic injectors suitable for use according to the present invention are Pen.

[0058] As used herein, the phrases "parenteral administration" and "administered parenterally" mean modes of administration other than enteral and topical administration, usually by injection, and 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.

[0059] In one embodiment of the invention, the Ofatumumab composition is formulated into a pharmaceutical composition suitable for intravenous administration in humans according to conventional procedures. Typically, the composition for intravenous administration is a sterile isotonic aqueous buffer solution. Where appropriate, the composition may also include a solubilizer and a local anesthetic (such as lidocaine) to relieve pain at the injection site. Typically, the components are supplied separately or mixed together in a unit dosage form indicating the amount of the active agent, such as a dry lyophilized powder or anhydrous concentrate in an airtight sealed container (such as an ampoule or a sachet).

[0060] If the composition is to be administered by infusion, it can be dispensed with 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 so that the ingredients can be mixed prior to administration.

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

[0063] In one embodiment, ofatumumab is formulated in 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 50 mg / ml.

[0064] In one embodiment, ofatumumab is formulated in an antibody formulation, wherein the formulation comprises 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 comprises 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 pre-filled syringe.

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

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

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

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

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

[0071] The loading dose regimen consisted of 20 mg ofatumumab administered subcutaneously on days 0, 7, and 14 of the dose regimen; and b) ofatumumab was administered to patients in need during a maintenance dose regimen consisting of 20 mg ofatumumab administered subcutaneously beginning on day 4 of the dose regimen and continuing every four weeks thereafter for the duration of the treatment regimen.

[0072] In one embodiment, a method for alleviating or delaying the progression of multiple sclerosis (MS) symptoms is provided, comprising the following regimens: a) administering ofatumumab to a patient in need thereof during a loading dose regimen, the loading dose regimen comprising subcutaneous injections 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, the maintenance dose regimen comprising subcutaneous injections of 20 mg ofatumumab starting on the fourth day of the dosing regimen, and continuing subcutaneous injections of 20 mg ofatumumab every four weeks thereafter for the duration of the treatment regimen.

[0073] In one embodiment, a method of slowing the progression of multiple sclerosis (MS) is provided, comprising the following regimens: a) administering ofatumumab to a patient in need thereof during a loading dose regimen, the loading dose regimen comprising subcutaneous injections 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, the maintenance dose regimen comprising subcutaneous injections of 20 mg ofatumumab starting on the fourth day of the dosing regimen, and continuing subcutaneous injections of 20 mg ofatumumab every four weeks thereafter 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) thereafter 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 injections 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 injections of 20 mg ofatumumab starting on the fourth week of the dosing regimen and continuing subcutaneous injections of 20 mg ofatumumab every four weeks thereafter for the duration of the treatment regimen.

[0076] In one embodiment, ofatumumab is provided 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) thereafter administering ofatumumab to the patient during a maintenance regimen.

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

[0078] Embodiment 1. A method for treating multiple sclerosis (MS), comprising:

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

[0080] b) thereafter administering ofatumumab to the patient during a maintenance dosing regimen.

[0081] Embodiment 2. The method of Embodiment 1, wherein ofatumumab is administered by subcutaneous (sc) injection during the loading dose regimen and during the maintenance dose regimen.

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

[0083] Embodiment 4. The method of embodiment 1, wherein the dose of ofatumumab administered thereafter during the maintenance regimen is between about 15 mg and about 25 mg ofatumumab.

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

[0085] Embodiment 6. The method of embodiment 1, wherein the dose of ofatumumab administered thereafter during the maintenance regimen is between about 18 mg and about 22 mg ofatumumab.

[0086] Embodiment 7. The method of embodiment 1, wherein the dose of ofatumumab administered during the loading dose regimen is about 20 mg ofatumumab.

[0087] Embodiment 8. The method of embodiment 1, wherein the dose of ofatumumab administered thereafter during the maintenance regimen is about 20 mg ofatumumab.

[0088] Embodiment 9. The method according to embodiment 1, wherein:

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

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

[0091] Embodiment 10. The method according to embodiment 1, wherein:

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

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

[0094] Embodiment 11. The method according to embodiment 1, wherein:

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

[0096] b) The dose of ofatumumab administered thereafter during the maintenance regimen was approximately 20 mg ofatumumab.

[0097] Embodiment 12. The method according to embodiment 1, wherein:

[0098] a) administering ofatumumab to patients in need during a loading dose regimen consisting of 20 mg ofatumumab on Days 0, 7, and 14 of the dosing regimen; and

[0099] b) administering ofatumumab to patients in need during a maintenance dosing regimen consisting of 20 mg ofatumumab beginning in the fourth week of the dosing regimen and continuing to administer 20 mg ofatumumab every four weeks thereafter for the duration of the treatment regimen.

[0100] Embodiment 13. The method according to embodiment 1, wherein:

[0101] a) administering ofatumumab to patients in need during a loading dose regimen consisting of 20 mg ofatumumab subcutaneously on Days 0, 7, and 14 of the dosing regimen; and

[0102] b) administer ofatumumab to patients in need during a maintenance dosing regimen consisting of 20 mg ofatumumab subcutaneously beginning on the fourth week of the dosing regimen and continuing with 20 mg ofatumumab subcutaneously every four weeks thereafter for the duration of the treatment regimen.

[0103] Embodiment 14. The method according to embodiment 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] Embodiment 15. The method according to embodiment 13, wherein 20 mg ofatumumab is administered during the dosing regimen and the maintenance regimen by using a pre-filled syringe filled with a formulation containing ofatumumab at a concentration of 50 mg / ml.

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

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

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

[0108] The details of one or more embodiments of the present disclosure are set forth in the specification attached above. Although any method and material similar or equivalent to those methods and materials described herein can be used for the practice or testing of the present disclosure, preferred methods and materials are now described. According to the specification and according to the claims, other features, objects and advantages of the present disclosure will be clear. Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those of ordinary skill in the art to which the present disclosure belongs. All patents and public documents cited in this specification are incorporated by reference. The following examples are proposed to more fully illustrate the preferred embodiments of the present disclosure. This example should never be interpreted as limiting the scope of the disclosed patient problem as defined by the appended claims.

[0109] Example Comparison of the Efficacy and Safety of Ofatumumab and Teriflunomide in Patients with Relapsing Multiple Sclerosis A randomized, double-blind, double-dummy, parallel-group study

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

[0111] The primary objective of this study was to demonstrate the superiority of ofatumumab 20 mg subcutaneously (sc) every 4 weeks (q4) over teriflunomide 14 mg orally once daily in reducing the frequency of confirmed relapses as assessed by the annualized relapse rate (ARR) in patients with relapsing MS.

[0112] Secondary objectives included (i) time to disability worsening as measured by 3-month confirmed worsening (3mCDW) on the Expanded Disability Status Scale (EDSS); (ii) time to disability worsening as measured by 6-month confirmed worsening (6mCDW) on the EDSS; (iii) time to disability improvement as measured by 6-month confirmed 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); and (vi) rate of brain volume loss (BVL) based on an assessment of the percentage change in brain volume from baseline.

[0113] The safety and tolerability of ofatumumab 20 mg subcutaneously every 4 weeks was also evaluated compared with teriflunomide 14 mg orally once daily.

[0114] Study Design

[0115] This is a randomized, double-blind, double-dummy, active comparator-controlled, parallel-group, multicenter study with variable treatment duration in patients with relapsing MS. Eligible patients will be randomized to receive either ofatumumab 20 mg subcutaneously q4 weeks (after an initial loading regimen of 20 mg three times weekly for the first 14 days) or teriflunomide 14 mg orally once daily. To blind the different agents, a double-dummy design will be used: patients in the active ofatumumab treatment group will additionally receive a placebo capsule orally once daily; patients in the active teriflunomide treatment group will additionally use a placebo-containing subcutaneous injection q4 weeks (after an initial regimen of three injections per week 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 a population with active inflammatory disease based on a recent relapse within one or two years prior to enrollment or one or more Gd-enhancing lesions on MRI in the year prior to randomization. The defined trial population is typical relapsing MS.

[0117] Loading and maintenance dose regimens

[0118] The dosing regimen of ofatumumab in this study was a loading dose of 20 mg on days 1, 7, and 14, followed by a monthly maintenance dose of 20 mg every 4 weeks starting in week 4. The dose selection relied on the clinical hypothesis that depletion of B cells in lymphoid tissues is key to efficacy (as measured by MRI and relapse) and that depletion of brain parenchymal and meningeal B cells may be another factor in the mode of action; blood B cell counts are an imperfect, artifactual measure of tissue status. This hypothesis suggests that in order to achieve the desired efficacy, 2 conditions should be met:

[0119] A loading dose regimen with sufficiently high initial PK for lymphodepletion, and

[0120] • Continued maintenance doses that keep B cell depletion levels below the desired threshold.

[0121] A Phase 2 study of subcutaneous ofatumumab in relapsing MS patients (OMS112831 / MIRROR study) provides important information about the relationship between peripheral B cell depletion and efficacy 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 extent of the decline in CD19+ cell counts. The model suggests that lower CD19+ cell levels lead to better control of lesion volume, and that high levels of CD19+ cell depletion (e.g., ≤8 cells / μL) should be maintained throughout the course of treatment in order to ensure the desired efficacy.

[0122] Modeling studies

[0123] It is expected that maximum MRI efficacy and B cell depletion below 8 cells / μL can be achieved without any delay ( Figure 1 Exploratory modeling based on phase 2 data from the OMS112831 / MIRROR study suggested that a single subcutaneous dose of ofatumumab 20 mg was insufficient to reduce B cell levels to ≤8 cells / μL (see Figure 2 ).from Figure 3 and Figure 4 As can also be seen in the Figure 1, modeling studies predicted that providing ofatumumab 20 mg in multiple loading doses would achieve a high degree 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) in >95% of patients based on modeling and was inferred to be more effective than a single 60 mg loading. Therefore, this loading dose regimen was selected.

[0124] In the OMS112831 / MIRROR study, ofatumumab administration was investigated 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 clear MRI effect, and 30 mg every 12 weeks appeared to be very close to maximal MRI efficacy, 60 mg every 12 weeks was also investigated to ensure that maximal MRI efficacy would truly translate into maximal clinical effect on relapse and disability. The highest dose level (60 mg every 4 weeks) did not increase any efficacy compared to 60 mg every 12 weeks ( Figure 5). However, when looking at B cell recovery, we noticed a trend toward B cell recovery before the next 12-week dose was given. Because patients given 60 mg q4 weeks showed no 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 rate of B cell recovery relative to dose and dosing frequency. The rate of B cell recovery in MS patients was estimated from the MIRROR study data. Modeling studies indicate that for the average case of MS, a 3 mg maintenance dose is considered sufficient to maintain B cell depletion for 4 weeks (see Figure 4 , above). However, the same modeling estimates that for patients with very high recovery rates (corresponding to 95 percent estimated from the MIRROR study), i.e. in a “worst case scenario”, neither 3 mg nor 10 mg maintenance would be sufficient to maintain B cell depletion over 4-week intervals, whereas 20 mg or higher doses would maintain adequate depletion (see Figure 4 , lower figure). Therefore, based on exploratory modeling, 20 mg ofatumumab appeared sufficient to maintain or further deplete B cells in >95% of patients who had previously been depleted, even in patients with high recovery rates. Therefore, to ensure continued maintenance efficacy, the inventors decided to split the tested MIRROR dose regimen (60 mg every 12 weeks) so that 20 mg was taken every 4 weeks.

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

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

[0127] References Cited in This Article

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

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

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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 ofatumumab between about 15 mg and about 25 mg.

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

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

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

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

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

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

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

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