Ofatumumab for treating multiple sclerosis in Asian patients

Abstract

The present invention relates to ofatumumab for use in the treatment of multiple sclerosis (MS), where patients of Asian ethnicity are treated.The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, where the treatment is not influenced by ethnic factors.The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, where patients with certain genetic or physiological risk factors are treated.

Description

[Technical field]

[0001] The present invention relates to ofatumumab for use in the treatment of multiple sclerosis (MS), wherein patients of Asian ethnicity are treated. The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, wherein the treatment is not influenced by ethnic factors.

[0002] The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, wherein patients having certain genetic or physiological risk factors are treated. [Background technology]

[0003] Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system characterized by inflammation, demyelination, and axonal / neuronal destruction, ultimately leading to severe physical disability. Although there is no cure for the disease, various disease-modifying therapies (DMTs) are available, which usually slow the progression of the disease. Although the exact etiology of MS remains unknown, epidemiological data indicate that both genetic and environmental factors are important. Genetically susceptible individuals will inevitably develop MS. Genetic epidemiological studies have shown that genetic factors are important in susceptibility to MS.

[0004] Although most disease-modifying therapies for MS are traditionally conceptualized as functioning through T-cell-based mechanisms, growing data indicate that these DMTs also have demonstrable effects on B cells. Common themes include promoting naive B cells rather than memory cells or plasmablasts (alemtuzumab), shifting B cell cytokines to an anti-inflammatory tone (beta-interferon, glatiramer acetate, fingolimod), increasing B-regs (beta-interferon, glatiramer acetate, fingolimod, and dimethyl fumarate), reducing class II MHC expression and costimulatory molecules on B cells required for antigen presentation (beta-interferon and dimethyl fumarate), sequestering B cells in lymphoid organs (fingolimod), blocking VLA-4-mediated B cell trafficking to the CNS (natalizumab), or inducing B cell cytolysis (alemtuzumab, teriflunomide, mitoxantrone). See Greenfield et al., Ann Neurol. 2018 January;83(1):13-26.

[0005] Greenfield further reports that the monoclonal antibodies (mAbs) rituximab, ocrelizumab, and ofatumumab are each anti-CD20 antibodies, and that these anti-CD20 antibodies are currently in clinical use for MS.

[0006] Rituximab, a chimeric mouse-human monoclonal antibody, was approved for B-cell lymphoma in 1997, and was indeed one of the first mAbs ever developed for clinical use. Rituximab works primarily by depleting B cells via complement-dependent cytotoxicity (CDC), but also has significant antibody-dependent cellular cytotoxicity (ADCC) activity.

[0007] Ocrelizumab (approved for relapsing and primary progressive MS) differs from rituximab in that it has a humanized antibody backbone, exhibits greater ADCC than CDC compared to rituximab, and also depletes B cells through multiple mechanisms including apoptosis and antibody-dependent cellular phagocytosis.

[0008] Ofatumumab, a fully human monoclonal antibody previously approved for refractory chronic lymphocytic leukemia, is the only anti-CD20 mAb that exhibits stronger CDC than ADCC activity and is currently being tested using a subcutaneous, rather than intravenous, dosing regimen. The U.S. Food and Drug Administration (FDA) recently approved Kesimpta® (ofatumumab (formerly OMB157)) as an injectable for subcutaneous use for the treatment of relapsing forms of multiple sclerosis (RMS) to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. Similarly, the European Commission also recently approved Kesimpta® for the treatment of relapsing forms of multiple sclerosis (RMS) in adults with active disease defined by clinical or imaging features. Kesimpta is a precisely dosed and delivered targeted B-cell therapy that has shown superior efficacy with a similar safety profile compared to teriflunomide (first-line treatment for MS).

[0009] Other anti-CD20 mAbs include obinutuzumab (a humanized IgG1 that targets part of the same CD20 epitope as rituximab but is engineered to enhance cell death induction due to its binding / dissociation kinetics) and ublituximab (an anti-CD20 antibody that has been glycoengineered to have increased affinity for all Fcγ RIIIa receptors, resulting in stronger ADCC than rituximab and ofatumumab, especially in low CD20 expressing cells).

[0010] On the other hand, treatment with B cell depleting therapy has been reported to increase the risk of serious infectious events (SIE) in Asian patients compared to patients from outside Asia (Emery P, Rigby W, Tak PP, Do¨rner T, Olech E, et al. (2014) Safety with Ocrelizumab in Rheumatoid Arthritis: Results from the Ocrelizumab Phase III). Harigai et al. suggested that treatment with ocrelizumab may increase the risk of Pneumocystis jirovecii pneumonia (PCP) in Japanese RA patients compared to treatment with other biologics (Harigai et al., The Journal of Rheumatology 2012;39:3;doi:10.3899 / jrheum.110994). In this context, it should be noted that treatment with B cell depleting therapies (such as ocrelizumab) has also been reported to reduce serum levels of immunoglobulins IgG, IgM, and / or IgA. See, for example, the presentation by Dr. B. Wildemann in “8.Heidelberger Patiententag”, January 25, 2020. It was reported that a reduction in IgG levels increases the risk of infection three-fold, and a reduction in IgM levels increases the risk of infection two-fold. In this regard, it should be noted that MS treatment is usually a lifelong treatment.

[0011] For example, under treatment with RTX (rituximab), the levels of IgG and IgM in the serum of patients decreased significantly over time (IgG: p = 2.2 × 10 -5 , IgM: p = 4.0 × 10 -4 Total IgG levels declined 5.1% per year, and IgM levels declined 5.0%. See Klein et al., ECTRIMS Online Library, 09 / 13 / 19; 278658; P1618.

[0012] T. Derfuss et al. ("Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions", ECTRIMS Online Library. Derfuss T. 09 / 11 / 19;279399;65) evaluated serum Ig levels over a 5.5-year period. A decrease in serum Ig levels was observed, which was clearly associated with an increased rate of serious infections. This association was strongest for IgG and, to a lesser extent, for IgM or IgA. The decrease in serum Ig levels progressed at an average rate of about 3-4% per year (see Figure 5). There was a clear association between the decrease in IgG levels and serious infections.

[0013] Additionally, the prescribing information for ocrelizumab explains the association between immunoglobulin decline and serious infections: "Treatment with Ocrevus resulted in a decrease in total immunoglobulin levels over the study period. This decrease was primarily due to a decrease in IgM. Clinical trial data indicate that an association exists between decreases in IgG levels (and, to a lesser extent, decreases in IgM or IgA levels) and serious infections." Ocrevus has not yet been approved in major Asian countries such as China, Japan, and South Korea.

[0014] In summary, Asian patients are at particular risk for adverse events associated with B-cell depleting therapies (such as ocrelizumab treatment), and in the long term, this risk needs to be reduced.

[0015] Therefore, the objective of the present invention is to improve the treatment strategy for Asian MS patients, especially for long-term treatment. In particular, it is an objective of the present invention to provide a B-cell depleting MS therapy without undesirably putting Asian patients at risk.

[0016] This problem has been unexpectedly solved by administering ofatumumab.

[0017] Ofatumumab treatment is advantageous compared to other B cell depleting therapies, as it does not increase the risk of serious infections in patients of Asian or Asian genetic background (e.g., patients with Asian phenotype), which is quite unexpected. As a result, the absence or improvement of adverse effects opens new avenues for patients under chronic treatment. This is an important clinical advantage, which will be explained in detail later in this specification.

[0018] In this regard, it is noted that ofatumumab surprisingly does not cause a reduction in immunoglobulins (e.g., IgG) to the extent known from other B cell depletion therapies known in the art. The unexpected absence of such adverse effects on the immune system makes it possible to treat certain patient groups (e.g., those considered difficult to treat), especially in the context of long-term treatment.

[0019] Thus, a subject of the present invention relates to ofatumumab for use in the treatment of multiple sclerosis, wherein a patient is treated who is of Asian ethnicity.

[0020] In a further subject matter of the invention, patients with a genetic background associated with Asian race, specifically patients with an Asian phenotype, are treated. As used herein, the term Asian phenotype refers to: -Cytochrome P450 (CYP) CYP2C9 *the frequency of possession of the two alleles is less than 10%, preferably less than 5%, more preferably less than 4.5%, even more preferably less than 4.4%, and most preferably less than 4%, and / or - Epidermal growth factor receptor (EGFR) mutations, and / or - has the VKORC1 warfarin low-dose haplotype, and / or -Refers to people with the promyelocytic leukemia protein (PML) gene breakpoint cluster region-1 subtype (bcr1) chromosomal translocation t(15:17).

[0021] Thus, the present invention provides personalized or precision medicine for patients with Asian phenotype, which must be taken into account for therapeutic success of MS treatment and improved clinical practice.

[0022] In general, certain physical attributes distinguish Asians from Westerners. Asians generally tend to be smaller in build based on wrist circumference or elbow width compared to Westerners when adjusted for the same age and sex. In addition to the obvious differences in build, studies have confirmed that the average height and weight of Asian populations are generally lower than their Western counterparts. The health implications of these and other differences are of paramount importance, as many disease thresholds are significantly different when comparing Asians with other populations, adjusting for age and sex, for a given range of anthropometric indices.

[0023] Diseases common in Asia have a high disease burden and their prevalence differs in Asia compared to Western countries. Epidemiological data from healthcare organizations and disease registries provide insight into the etiology and disease biology, genetic bias or uniqueness of such diseases in Asians. Some conditions (such as nasopharyngeal carcinoma, Brugada syndrome, and thyrotoxic periodic paralysis) affect Asians significantly compared to non-Asians. Thus, a further subject of the present invention relates to ofatumumab for use in the treatment of multiple sclerosis, wherein the patient is - Neuromyelitis optica (NMO) and / or - Have an NMO spectrum disorder and / or - A family history of sudden death (Brugada syndrome) and / or -Has cardiac sodium channelopathy caused by a loss-of-function mutation in SCN5A with arrhythmia susceptibility, - Have thyrotoxic periodic paralysis, and / or - obesity (preferably with a waist circumference of more than 80 cm for women and more than 90 cm for men, more preferably with central obesity, characterized by the characteristic "thin on the outside, fat on the inside (TOFI)" obesity phenotype); and / or - Have type 2 diabetes mellitus, and / or - Has diabetic nephropathy, and / or - Have aggressive triple-negative or basal-like breast cancer (ER, PR, Her2 / neu negative), and / or - History of lacunar cerebral infarction, and / or - Has a history of intracerebral hemorrhage, and / or - Have systemic lupus erythematosus (SLE) and / or - suffers from obstructive sleep apnea (OSA) and / or - Nasopharyngeal carcinoma (NPC), preferably with differentiated non-keratinizing type (WHO type 2 histology), and / or -Having insulin resistance.

[0024] A further subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, the treatment being not influenced by ethnic factors.

[0025] The ethnic insensitivity of ofatumumab may include one or more of the following features: -As a fully human IgG1 monoclonal antibody (mAb), the pharmacokinetics (PK) of ofatumumab have been demonstrated to be unaffected by ethnic factors: A pivotal Phase 3 study in RMS patients showed that ofatumumab concentrations were similar in Asian and Caucasian subjects. Race (White, Black, Asian, Unknown, Other) was tested as a covariate in a population PK analysis of PK data in patients with MS and found that race was not a significant covariate affecting the PK of ofatumumab. - PK parameters (Cmax, AUC, T) after intravenous (iv) administration of 2000 mg were evaluated in Asian (9 Japanese and 1 Korean) and Caucasian (96% Caucasian) patients with refractory CLL. 1 / 2 ) were found to be equivalent. · After the first injection, the primary clearance pathway of low-dose ofatumumab is via target-mediated clearance by CD20 binding and B-cell lysis. Similar baseline levels of CD20+ B-cells were observed between Asian and non-Asian RMS patients. Thus, the target-mediated clearance of ofatumumab in Asian RMS patients is comparable to that in non-Asian RMS patients. PK exposure was consistent with that seen in previous studies, with rapid and consistent depletion of CD19+ B cells and CD3+CD20+ T cells, indicating similar pharmacodynamic responses in ofatumumab-treated patients between Japanese and non-Japanese subgroups. The primary clearance pathway of low-dose ofatumumab during maintenance therapy is predicted to be mediated by nonspecific catabolic pathways. Catabolism by ubiquitous proteases is predicted to be unaffected by ethnic factors, as shown by many other mAb products. -Efficacy profile demonstrated to be comparable between Asian and non-Asian patients with RMS: The efficacy profile in Asian subpopulations (by race and region) was consistent with the overall efficacy profile of ofatumumab, as demonstrated in the pivotal Phase 3 study. Results from the Phase II study demonstrated superior efficacy of ofatumumab treatment compared with placebo in lesion inhibition, with ofatumumab consistently resulting in fewer lesions in both Japanese and non-Japanese patient subgroups. -Safety profile demonstrated to be comparable between Asian and non-Asian patients with RMS: No new safety concerns were identified in the Asian subgroup (by race and region) and the overall safety profile of ofatumumab was favorable, as demonstrated in a pivotal Phase III study in patients with RMS. The total number of ofatumumab-exposed Asian RMS patients (by race) included in the study was 71. Results from the Phase II study, which included a subgroup of Japanese and non-Japanese RMS patients, showed that no new safety signals were detected and the safety profile was consistent with that seen in the global pivotal study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] Description of the Preferred Embodiments In general, the present invention relates to the treatment of multiple sclerosis. In a preferred embodiment, the present invention relates to the treatment of relapsing multiple sclerosis (RMS). In particular, the present invention relates to the treatment of relapsing-remitting multiple sclerosis (RRMS). Alternatively, the present invention relates to the treatment of secondary progressive MS (SPMS). Still alternatively, the present invention relates to the treatment of first episode syndrome (CIS). Still alternatively, the present invention relates to the treatment of primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS).

[0027] Generally, in accordance with the present invention, ofatumumab may be administered to all MS patients, regardless of race, ethnicity, and / or phenotype.

[0028] In general, the patient does not have to be naive, i.e., prior to the initiation of ofatumumab treatment, the patient, preferably an Asian patient, may have been treated with a disease-modifying therapy (DMT) for multiple sclerosis other than ofatumumab (such as glatiramer acetate, cladribine, fingolimod, siponimod, natalizumab, teriflunomide, mitoxantrone, or dimethyl fumarate).

[0029] In a first aspect of the invention, patients of Asian descent are treated with ofatumumab. Patients of Chinese, Japanese, or Korean descent may be preferred.

[0030] In an alternative embodiment, -Cytochrome P450 (CYP) CYP2C9 * the frequency of possession of the two alleles is less than 10%, preferably less than 5%, more preferably less than 4.5%, even more preferably less than 4.4%, and most preferably less than 4%, and / or - Epidermal growth factor receptor (EGFR) mutations, and / or - has the VKORC1 warfarin low-dose haplotype, and / or -Patients with the promyelocytic leukemia protein (PML) gene breakpoint cluster region-1 subtype (bcr1) chromosomal translocation t(15:17) are treated.

[0031] Such patients may preferably happen to be of Asian descent.

[0032] Generally, the above alleles, genotypes, and mutations can be detected by standard procedures. Examples include, but are not limited to, conventional karyotyping, fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), and next generation sequencing. Methods for use in the present invention are described in Iran J Pediatr.2013 Aug;23(4):375-388 (PMCID:PMC3883366; PMID:24427490).

[0033] In one embodiment of the present invention, ofatumumab is used when there is an indicator of risk of a comorbid disease (e.g., infection) that affects MS treatment, such as a decrease in serum IgG levels. In other words, when serum IgG levels are undesirably low, treatment of MS is performed or continued with ofatumumab as the DMT. In a preferred embodiment of the present invention, ofatumumab is administered as the only active ingredient for MS treatment, i.e., the only disease-modifying drug administered.

[0034] Other risk indicators of comorbidities that may affect MS treatment include: -Neuromyelitis optica (NMO), -NMO spectrum disorder, - Family history of sudden death (Brugada syndrome), -Cardiac sodium channelopathy caused by loss-of-function mutations in SCN5A with arrhythmia susceptibility, - thyrotoxic periodic quadriplegia, - obesity (preferably with a waist circumference of more than 80 cm for women and more than 90 cm for men, more preferably with central obesity, characterized by the characteristic "thin on the outside, fat on the inside (TOFI)" obesity phenotype); - type 2 diabetes, - diabetic nephropathy, - Advanced triple-negative or basal-like breast cancer (ER, PR, Her2 / neu negative), - History of lacunar cerebral infarction, - History of intracerebral hemorrhage, -Systemic lupus erythematosus (SLE), -obstructive sleep apnea (OSA), Nasopharyngeal carcinoma (NPC), preferably a differentiated non-keratinizing type (WHO type 2 histology), and / or -Insulin resistance Includes:

[0035] Thus, the present invention also relates to ofatumumab for use in the treatment of multiple sclerosis, wherein a patient, preferably an Asian patient, has one of the above conditions or is affected by one of the above conditions.

[0036] In a second aspect of the invention, ofatumumab is used for the treatment of multiple sclerosis, the treatment being unaffected by ethnic factors.

[0037] In a preferred embodiment of the invention, ofatumumab is administered as the sole active ingredient for the treatment of MS, i.e., it is the only disease-modifying drug administered.

[0038] As stated above, a subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, the treatment being a long-term treatment and the treatment not being influenced by ethnic factors.

[0039] In a preferred embodiment, adverse events occurring in patients of Asian descent are consistent with the overall safety profile of ofatumumab, i.e., comparable to the safety profile of all other patients who are not Asian.

[0040] In preferred embodiments, the adverse event is selected from infusion-related reactions, infections, malignant and pre-malignant lesions, liver injury or abnormal liver function, and neutropenia.

[0041] In alternative preferred embodiments, the infection is selected from a respiratory tract infection, a urinary tract infection, a herpes virus infection, a varicella zoster virus infection, an opportunistic infection, pulmonary tuberculosis, a flare-up of HBV infection, and progressive multifocal leukoencephalopathy (PML).

[0042] In a preferred embodiment, the infection is a serious infection, preferably selected from opportunistic infections, exacerbations of HBV infection, Pneumocysti jirovecii pneumonia (PCP), and PML.

[0043] For example, clinical trials have shown that patients treated with ocrelizumab (Ocrevus®) have an increased number of malignancies (including breast cancer) compared to controls. The SmPC for Ocrevus recommends that individual benefit / risk considerations should be considered in patients being actively monitored for recurrence of malignancies. Patients known to have active malignancies should not be treated with Ocrevus.

[0044] As mentioned above, side effects and adverse events associated with B cell depletion therapy (such as ocrelizumab treatment) have been reported to be associated with a decrease in immunoglobulin (e.g., IgG). Surprisingly, the present invention has revealed that ofatumumab treatment is advantageous compared to other B cell depletion therapies because it does not cause a decrease in immunoglobulin (e.g., IgG) in the long term, and therefore opens a new avenue for patients under long-term treatment.

[0045] Thus, in a preferred embodiment of the invention, ofatumumab is used to treat MS, and ofatumumab is administered to patients, preferably Asian patients, known to have risk factors for malignancy. In another preferred embodiment of the invention, ofatumumab is used to treat MS, and ofatumumab is administered to patients, preferably Asian patients, who are being actively monitored for recurrence of malignancy. In an alternative embodiment of the invention, ofatumumab is used to treat MS, and ofatumumab is administered to patients, preferably Asian patients, known to have active malignancy.

[0046] In a preferred embodiment of the invention, the patient is switched from a previous disease modifying therapy (DMT) to ofatumumab, the switch preferably being -C, formerly DMT max and / or - AUC of previous DMT, and / or - suppression or depletion of B cells and / or T cells, and / or - Serum IgG levels, and / or - Adverse Events This is done when there is a change in

[0047] In a preferred embodiment of the invention, serum IgG levels are maintained within the range of 500-1800 mg / dl during treatment. In a preferred embodiment, ofatumumab is used when serum IgG levels fall below concentrations of 900 mg / dl, 850 mg / dl, 800 mg / dl, 750 mg / dl, 700 mg / dl, 650 mg / ml, 600 mg / dl, 550 mg / dl, or 500 mg / dl.

[0048] In a preferred embodiment, ofatumumab is used when serum IgG levels fall below the lower limit of normal (hereinafter referred to as "LLN"). In general, the lower limit of normal (LLN) for IgG, IgA, and IgM may be defined as IgG=700 mg / dl or 565 mg / dl, IgM=40 mg / dl, and IgA=70 mg / dl.

[0049] In a preferred embodiment of the present invention, ofatumumab is used to treat MS, and the treatment is long-term treatment.The term long-term treatment indicates that ofatumumab is used for a long period of time.For example, ofatumumab can be used for more than 2 years, more than 3 years, more than 4 years, more than 5 years, more than 10 years.Ofatumumab can be used for up to 5 years, 10 years, 15 years, 20 years, or lifelong.

[0050] In a preferred embodiment of the invention, ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks, preferably at a dose of 20 mg every 4 weeks.

[0051] Preferably, ofatumumab is administered parenterally, for example by epidermal, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intrathecal, intracranial, intrathoracic, epidural, or substernal injection or infusion. The preferred route of administration is subcutaneous injection (sc).

[0052] In a preferred embodiment of the invention, ofatumumab is administered in a loading dose. The term loading dose is defined below. In a preferred embodiment, three loading doses are administered, and the three loading doses are preferably administered at week 0, week 1, and week 2 from the start of ofatumumab treatment. This means that the first loading dose at week 0 marks the start of treatment. In an alternative preferred embodiment, the three loading doses are administered at days 1, 5-9 (preferably day 7), and 12-16 (preferably day 14) from the start of ofatumumab treatment. This means that the first loading dose at day 1 marks the start of treatment.

[0053] In a preferred embodiment of the invention, the loading dose of ofatumumab is 10-30 mg at weeks 0, 1, and 2, preferably 20 mg.

[0054] In an alternative embodiment of the invention, ofatumumab is administered without a loading dose.

[0055] In a preferred embodiment of the invention, a premedication is administered to the patient before the first dose of ofatumumab is administered. Preferably, the premedication comprises a compound selected from acetaminophen, an antihistamine, and a steroid. Methylprednisolone may be the preferred steroid. 100 mg iv may be the preferred dose. Preferably, the premedication is administered 30-60 minutes prior to the ofatumumab injection.

[0056] In certain preferred embodiments of the invention, no premedication is administered prior to the first dose of ofatumumab.

[0057] In a preferred embodiment of the invention, the relapsing multiple sclerosis is either first episode syndrome (CIS) or relapsing remitting multiple sclerosis (RRMS) or secondary progressive multiple sclerosis (SPMS), as these terms are defined below.

[0058] In a preferred embodiment of the invention, the multiple sclerosis is selected from primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS).

[0059] In a preferred embodiment of the invention, ofatumumab is administered as the only active ingredient for treating MS, in other words, ofatumumab is preferably the only disease-modifying drug administered.

[0060] In a preferred embodiment, ofatumumab can be administered regardless of body weight, sex, age, race, or baseline B cell count.For example, it is preferred to administer the same dose to a 35-year-old woman weighing 60 kg as to a 50-year-old man weighing 90 kg.Specifically, body weight, sex, age, race, or baseline B cell count have no clinically meaningful effect on the pharmacokinetics of ofatumumab.

[0061] The MSIS-29 (see definition below) is a clinically useful, evidence-based measure of the impact of MS from the patient's perspective, suitable for clinical trials and epidemiological studies. The MSIS-29 is considered a reliable, valid, and responsive PRO (patient-reported outcome) measure that complements other disease severity measures used to improve our understanding of the impact of MS.

[0062] In the present invention, it has been unexpectedly discovered that administration of ofatumumab to Asian patients favorably reduces the MS Impact Scale MSIS-29, defined as follows:

[0063] In this regard, a further subject of the present invention is ofatumumab for use in the treatment or prevention of relapsing multiple sclerosis, which ofatumumab reduces the MSIS-29 score, preferably in Asian patients. Preferably, ofatumumab reduces the MSIS-29 score by at least 1.5 within 24 months, more preferably by at least 2.0, even more preferably by at least 2.5. This reduction may be up to 3.0 or 3.5 or 4.0.

[0064] In one embodiment of the present invention, the ofatumumab composition is formulated according to a routine procedure as a pharmaceutical composition suitable for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile aqueous isotonic buffer. Where appropriate, the composition may also include a solubilizing agent and a local anesthetic (such as lignocaine) to ease pain at the injection site. Generally, the ingredients are supplied separately in a sealed container (such as an ampoule or sachet) indicating the quantity of active agent, or mixed together as a unit dosage form (e.g., lyophilized powder or water-free concentrate).

[0065] Where the composition is being administered by injection, particularly subcutaneous injection (sc), the composition can be administered using an infusion bottle containing sterile pharmaceutical grade water or saline.

[0066] Where the composition is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients may be mixed prior to administration.

[0067] In one embodiment, a formulation for ofatumumab may be formulated according to the process disclosed in WO2009 / 009407.

[0068] In one embodiment, ofatumumab is formulated in an antibody formulation, and the amount of ofatumumab present in the antibody formulation 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.

[0069] In one embodiment, ofatumumab is formulated in an antibody formulation, the formulation containing 10-100 mM sodium acetate, 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0.2 mM EDTA, 0.01-0.2% polysorbate 80, and adjusted to a pH of 5.0-7.0. Preferably, the ofatumumab formulation contains 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, 0.02% polysorbate 80, and adjusted to a pH of 5.5.

[0070] The preferred dose of ofatumumab is: Initial doses of 20 mg by subcutaneous injection at weeks 0, 1, and 2 (or days 1, 5-9 (preferably day 7), and 12-16 (preferably day 14)); Subsequent doses of 20 mg given subcutaneously once a month starting in week 4 It is.

[0071] If an injection of ofatumumab is missed, ofatumumab should be administered as soon as possible, preferably without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended interval.

[0072] In one embodiment, the ofatumumab formulation is provided in a pre-filled syringe or autoinjector, preferably a single-dose pre-filled syringe or a single-dose pre-filled autoinjector. Preferably, a pre-filled autoinjector designed for subcutaneous administration is used.

[0073] In a preferred embodiment, ofatumumab injection is a sterile, preservative-free solution for subcutaneous use.Preferably, 0.4mL of the solution is delivered by each 20mg / 0.4mL pre-filled pen or pre-filled syringe.Preferably, each 0.4mL contains 20mg ofatumumab, as well as arginine (4mg), edetate disodium (0.007mg), polysorbate 80 (0.08mg), sodium acetate trihydrate (2.722mg), sodium chloride (1.192mg), and water for injection (USP, pH 5.5).Hydrogen acid may be added for pH adjustment.

[0074] In a preferred embodiment, the ofatumumab formulation is intended for self-administration by the patient, preferably by subcutaneous injection.

[0075] In a preferred embodiment, the formulation is administered subcutaneously on the abdomen, thigh, or outer upper arm. In a preferred embodiment, the formulation is not administered to a mole, scar, or area where there is pain, bruising, redness, hardness, or changes in the skin.

[0076] In one embodiment, the first injection of the ofatumumab formulation may be performed under the guidance of a medical professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Prior to administration, the pen or pre-filled syringe is preferably removed from the refrigerator and allowed to reach room temperature, for example, for about 15-30 minutes. In a preferred embodiment, the ofatumumab formulation of the present invention is a clear to slightly glossy, colorless to slightly brownish yellow solution, which is available as follows: Injection: 20 mg / 0.4 mL in a single-dose prefilled pen (e.g., Sensoready® pen) Injection: 20 mg / 0.4 mL in a single-dose prefilled syringe.

[0077] In a preferred embodiment, a subcutaneous dose of 20 mg ofatumumab every 4 weeks is used to achieve a mean AUC tauis about 400 to 550, more preferably 450 to 500 (e.g., 483) mcgh / mL, and / or the average C max will be 1.0 to 2.5, more preferably 1.2 to 1.7 (e.g., 1.43) mcg / mL. In a preferred embodiment, the steady state volume of distribution following repeated subcutaneous administration of a 20 mg dose of ofatumumab may be 4.5 to 6.5, more preferably 5.0 to 6.0 (e.g., 5.42) L.

[0078] After subcutaneous administration, ofatumumab can be absorbed via the lymphatic system.

[0079] In a preferred embodiment of the invention, in patients with an active infection (e.g., COVID-19), administration of ofatumumab is delayed until the infection has resolved. Thus, treatment is interrupted during COVID-19 infection and resumed after the infection has been overcome.

[0080] Alternatively, ofatumumab may be administered during infection (e.g., COVID-19 infection). Thus, administration of ofatumumab may be continued during infection (e.g., COVID-19 infection). In a particularly preferred embodiment, patients acutely or previously infected with COVID-19 are treated with ofatumumab.

[0081] In another preferred embodiment of the invention, clinically indicated immunoglobulin levels are monitored at the initiation, during, and after discontinuation of treatment with ofatumumab until B cell repletion occurs. If immunoglobulin levels indicate immunocompromise, interruption ofatumumab treatment is considered if the patient develops a severe opportunistic or recurrent infection.

[0082] An additional subject of the present invention is a method for treating multiple sclerosis, said treatment comprising administering ofatumumab to a patient in need thereof, said patient being of Asian ethnicity.

[0083] A further subject of the invention is a method for treating multiple sclerosis, said treatment comprising administering ofatumumab to a patient in need thereof, said treatment being not influenced by ethnic factors.

[0084] A further subject of the invention is a process for the manufacture of a medicament for use in the abovementioned treatments.

[0085] All of the above preferred embodiments apply generally to such subject matter.

[0086] definition A race may be defined as a group of people descended from a common ancestor or having different physical and genetic traits or characteristics inherited through birth.

[0087] Asian people may include persons of any ancestry from the Far East, the Indian subcontinent (including Cambodia, China, India, Japan, Korea, Malaysia, Pakistan, the Philippine Islands, Thailand, Vietnam, Hmong, East Indies, Laos, Bangladesh, Indonesia, Sri Lanka, Nepal, Bhutan, Sikhs, Burma), and other indigenous peoples of South and Southeast Asia.

[0088] Chinese - includes individuals who state their race as Chinese or who identify themselves as Cantonese, Tibetan, or Chinese American. Individuals reported in standard census reports as Taiwanese or Native Taiwanese are included therein as Chinese.

[0089] Filipino - Includes people who describe their race as Filipino, Pilipino, or Philippine.

[0090] Japanese - Includes people who identify their race as Japanese, Nipponese, or Japanese American.

[0091] Korean – Includes people who identify their race as Korean or Korean American.

[0092] Vietnamese – Includes individuals who identify their race as Vietnamese or Vietnamese American.

[0093] Other Southeast Asian - Includes people originating from one of the Southeast Asian countries or Southeast Asian ancestries, including Laos, Hmong, Laohmong, Mong, Cambodia, Thailand, Siam, and Malaysia.

[0094] South Asian - Includes a person originating from one of the South Asian countries including Afghanistan, India, Pakistan, Bangladesh, Nepal, and Sri Lanka.

[0095] Other Asian - Includes those of Burmese, Indonesian, Bengali, Bharatiya, Dravidian, East Indian, Goan (Goanese), or Indian descent or those who consider themselves of these descents.

[0096] Caucasian refers to a person of the "white race" originating from the Caucasus Mountains region of Europe. The U.S. National Library of Medicine has now discontinued this racial term as outdated in favor of the term "European." For the purposes of this application, the term Western is used to encompass Europeans as well as British and North American whites.

[0097] The term ethnically insensitive preferably means that there are no therapeutically relevant differences between different races, ethnicities, or phenotypes. The ethnic insensitiveness of ofatumumab specifically means that ofatumumab: - Pharmacokinetics (PK) that are not influenced by ethnic factors; - Have a comparable efficacy profile between Asian and non-Asian patients with RMS, - A comparable safety profile between Asian and non-Asian patients with RMS; Refers to...

[0098] The term "treatment" or "treating" can be defined as the application or administration (e.g., ofatumumab to a patient) for the purpose of eliminating, reducing, or alleviating the symptoms of a disease (such as multiple sclerosis (MS)). Specifically, the term "treatment" includes achieving a clinically meaningful benefit to the patient (e.g., in the case of treatment of RMS, achieving a clinically meaningful reduction in annual relapse rate).

[0099] As used herein, a patient may be "in need of" a treatment if such patient would benefit medically or in terms of quality of life from such treatment.

[0100] The term "patient" as used herein may refer to a mammal, such as a primate, preferably a higher primate, and particularly preferably a human (e.g., a patient at risk of or at risk of having a disorder described herein). Preferably, the patient is an adult. Generally, patients aged 18-60 years are preferred, although elderly patients are also included. The term "administering" ofatumumab or "administration" ofatumumab as used herein may refer to giving ofatumumab to a patient in need of treatment. Administration "in combination" with one or more additional therapeutic agents includes simultaneous (concurrent) and sequential administration in any order and by any route of administration.

[0101] As used herein, a "therapeutically effective amount" can refer to an amount of ofatumumab that is effective, i.e., an amount of ofatumumab that achieves a clinically meaningful effect.

[0102] The term "adverse event" (AE) may refer to any untoward medical occurrence in a clinical study or patient in which a subject is administered a medicinal product, which does not necessarily have a causal relationship to this treatment. Thus, an adverse event (AE) may be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease associated with the use of a medicinal product over time, whether or not related to the medicinal product.

[0103] The phrase "therapeutic regimen" can refer to a regimen (e.g., a medication used) used to treat a disease or prevent the onset of a condition or disorder. A therapeutic regimen can include an induction regimen, a loading regimen, and a maintenance regimen.

[0104] RRMS Relapsing-remitting multiple sclerosis (RRMS) can be characterized by relapses, defined as new neurological deficits or a neurological episode lasting more than 24 hours (preferably in the absence of fever or infection).

[0105] During remission there may be no apparent progression of the disease. At different times, RRMS may be further characterized as either active (with relapses and / or evidence of new activity on MRI) or inactive, and as worsening (with increased disability over a period of time following a relapse) or non-worsening. See Lublin, Neurology. 2014 Jul 15;83(3):278-286.

[0106] RMS The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS, and first episode syndrome (CIS).

[0107] Primary progressive MS (PPMS) PPMS may be characterized by a deterioration of neurological function (accumulation of disability) from symptom onset without early relapses or remissions. PPMS may be further characterized at different time points as either active (with occasional relapses and / or evidence of new activity on MRI) or inactive, as well as progressive (with evidence of disease worsening over time on objective measures, with or without relapses or new activity on MRI) or non-progressive. See Lublin 2014.

[0108] The experience with PPMS is unique to each individual: PPMS may have brief periods of stable disease with or without relapses or new activity on MRI, and periods of increasing disability with or without new relapses or lesions on MRI.

[0109] Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people diagnosed with RRMS will eventually transition to a secondary progressive course with progressive deterioration of neurological function over time (accumulation of physical disability). SPMS can be further characterized at different times as either active (with relapses and / or evidence of new activity on MRI) or inactive, as well as progressive (with evidence of disease worsening over time on objective measures, with or without relapses) or not. See Lublin 2014.

[0110] The experience of SPMS is unique to each individual. SPMS follows relapsing-remitting MS. There is a gradual increase in disability over time with or without evidence of disease activity (relapses or changes on MRI). In SPMS, relapses can occur occasionally, in addition to periods of stability.

[0111] recurrence Relapse can be defined as a new neurological disorder or neurological episode (preferably lasting more than 24 hours).In other words, relapse can be considered as a separate episode of neurological dysfunction (also referred to in the art as "attack", "flare-up" or "exacerbation") (preferably lasting at least 24 hours).Relapse is usually followed by a period of complete or partial recovery, during which symptoms do not progress or physical disability does not accumulate (remission).

[0112] "B cell inhibitors" as used herein may generally refer to any substance that neutralizes, reduces, or attenuates biological B cell functions. B cell inhibitors may interfere with signaling pathways required for biological B cell functions (e.g., cytokine secretion or response to cis and / or trans stimuli). B cell inhibitors may also interfere with the generation of B cells from stem / progenitor cells or negatively affect their maturation. In addition, B cell inhibitors may act by inhibiting crosstalk with other cell populations (such as T cells). Alternatively, B cell inhibitors may deplete B cells by sequestration (e.g., in lymphoid tissues (such as the spleen)) or lysis (e.g., via CDC, ADCC, phagocytosis, or other processes). Some subsets of B cells may express CD20.

[0113] B cells, as used herein, may refer to a lymphocyte subtype, a type of white blood cell. B cells serve as the humoral immune component of the adaptive immune system by selecting antibodies, such as immunoglobulins (e.g., IgG). In addition, B cells may present antigens and secrete cytokines. B cells, unlike T cells and natural killer cells, express a B cell receptor (BCR) on their cell membrane. The BCR allows B cells to bind to a specific antigen against which the B cell initiates an antibody response.

[0114] In a preferred embodiment of the invention, the use of ofatumumab maintains IgG levels essentially within the same range as in untreated patients, preferably in untreated Asian patients. In the context of the present invention, "untreated patients" refers to patients who have been diagnosed with MS or first episode syndrome (CIS) but who have not been administered a B-cell and / or T-cell inhibitor. In a preferred embodiment, untreated patients have IgG levels in the range of 500-1800 mg / dl, particularly 700-1600 mg / dl, more particularly 900-1400 mg / dl. Specifically, untreated patients may have IgG levels of 500mg / dl, 550mg / dl, 600mg / dl, 650mg / dl, 700mg / dl, 750mg / dl, 800mg / dl, 850mg / dl, 900mg / dl-1400mg / dl, 1500mg / dl, 1600mg / dl, 1700mg / dl, or 1800mg / dl.

[0115] First-episode syndrome (CIS): First-episode syndrome (CIS) may refer to a clinically isolated attack of central nervous system (CNS) inflammatory demyelinating symptoms suggestive of multiple sclerosis (MS). CIS symptoms may be single-lesion or multi-lesion, and typically involve the optic nerves, brainstem, cerebellum, spinal cord, or cerebral hemispheres. See Miller et al, Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169.

[0116] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 version 2 is a 29-item self-administered questionnaire that includes two domains: physical and psychological. Responses are captured on a 4-point ordinal scale ranging from 1 (not at all) to 4 (very much), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete, and the questions are designed to determine the patient's perspective on the impact of MS on daily life during the past 2 weeks. Hobart J and Cano S(2009),“Improving the evaluation of therapeutic interventions in multiple sclerosis:the role of new psychometric methods”,Health Technol Assess;13(12):iii,ix-x,1-177. See NS RO to Hobart J,Lamping D,Fitzpatrick R,et al(2001),“The Multiple Sclerosis Impact Scale(MSIS-29):a new patient-based outcome measure”,Brain;124(Pt 5):962-73.

[0117] Ofatumumab: Ofatumumab is a human monoclonal antibody against the CD20 protein. Ofatumumab can specifically bind to both the small and large extracellular loops of the CD20 molecule. The Fab domain of ofatumumab can bind to the CD20 molecule, and the Fc domain mediates immune effector function to cause B cell lysis in vitro. Specifically, ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed (e.g., on B cells). Ofatumumab is produced in a mouse NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains, with a molecular weight of approximately 146 kDa.

[0118] Ofatumumab is described in EP1558648B1 and EP3284753B1. See also drugbank.ca, description of accession number DB06650 and WHO Drug Information, Vol. 20, No. 1, 2006. In one embodiment, the protein formula is C 6480 H 10022 N 1742 O 2020 S 44 and the average protein weight is approximately 146,100 Da. In the US and EP, ofatumumab is sold under the trade name Kesimpta®.

[0119] The metabolic pathway of ofatumumab may be degradation by ubiquitous proteases into small peptides and amino acids. Ofatumumab may be excreted in two ways: a target-independent pathway similar to other IgG molecules, and a target-mediated pathway associated with binding to B cells.

[0120] The half-life of ofatumumab at steady state can be about 16 days, specifically about 16 days from repeated subcutaneous administration of 20 mg doses.

[0121] Ofatumumab preferably does not share common clearance pathways with chemical drugs that are metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Preferably, ofatumumab is not involved in regulating the expression of drug metabolizing enzymes.

[0122] loading dose A loading dose is an initial dose (preferably an initial high dose) of a drug that may be given at the start of treatment (e.g., DMT) before transitioning to a maintenance dose (preferably a dose lower than the loading dose).

[0123] Immunoglobulins (Ig) and the subtypes IgG, IgA, IgM, IgD, and IgE are generally known and are described, for example, in Berg / Tymoczko / Stryer “Biochemie”, 5 thedition, pp. 1015-1018. This application focuses on serum levels of IgG and IgM, and in particular on serum levels of IgG.

[0124] Serum immunoglobulin (Ig) levels may be routinely determined in clinical practice. In the present application, serum Ig levels may preferably be determined by immunoturbidimetry. Preferably, a Roche cobas® analyzer was used, in particular module c of the cobas® analyzer. In a preferred embodiment, Ig levels may be determined by using a cobas® c311 analyzer. It is further preferred that IgG measurements are performed as described in the cobas® leaflet "IGG-2 Tina-quant IgG Gen.2" (preferably version 11.0 dated 2016-02) and IgM measurements are performed as described in the leaflet "IGM-2 Tina-quant IgM Gen.2" (preferably version 13.0 dated 2018-11).

[0125] Serum samples were preferably kept at 2-8°C until measurement. [Brief description of the drawings]

[0126] [Figure 1] Plots of absolute IgG parameters by visit duration and 48-week, 96-week, and 144-week completers in the OMB long-term group. [Diagram 2] Plots of absolute IgG parameters by visit and quartiles of baseline values ​​for the OMB long-term group. [Diagram 3] Plots of absolute IgM parameters by visit duration and 48-week, 96-week, and 144-week completers in the OMB long-term group. [Figure 4] 13 is a plot of absolute IgM parameters by visit period and quartiles of baseline values ​​for the OMB longitudinal group. [Diagram 5]Figure 5 shows the reduction in IgG levels after administration of a prior art anti-CD20 antibody (ocrelizumab). First published as part of T. Derfuss et al.: “Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions”, ECTRIMS Online Library. Derfuss T. 09 / 11 / 19;279399;65. [Figure 6] After 2 years (96 weeks), ocrelizumab treatment showed a decrease in IgG levels of about 5%, while ofatumumab produced an increase of about 3%.

[0127] The invention may be illustrated by the following examples. EXAMPLES

[0128] Example 1 Two identical phase III randomized, double-blind, double-dummy, active-controlled, parallel-group, multicenter studies (Study I and Study II) of identical design were conducted to investigate ofatumumab in 1882 patients with RMS. Patients were randomized to receive either ofatumumab (OMB) (20 mg subcutaneously every 4 weeks following a loading regimen of 3 injections on days 1, 7, and 14) or teriflunomide (TER) (14 mg orally once daily) as an active comparator. For brevity, no teriflunomide data are presented further in this document.

[0129] The maximum treatment duration for individual patients was 30 study months (approximately 2.5 years). A total of 71 patients of Asian ethnicity were included in the two studies (36 patients in the ofatumumab arm and 35 patients in the teriflunomide arm). This example also includes Asian patient data from oncology studies (Study A and Study B) as ancillary data, where appropriate.

[0130] Table 1 provides a summary of completed RMS studies involving Asian subjects. [Table 1]

[0131] a) Annual relapse rate (ARR) ARR was the primary efficacy endpoint in the pivotal Phase III study. Treatment with ofatumumab and teriflunomide were both associated with a relatively low ARR, with 4 to 5 relapses observed in both treatment arms in the Asian subgroup (ARR of 0.08 to 0.09) (Table 2). In the rest of the world (ROW) subgroup and overall population, treatment with ofatumumab significantly (p<0.001 for all) reduced the adjusted ARR by 53.3% and 52.6%, respectively, compared with teriflunomide (Table 2). [Table 2]

[0132] b) Confirmation of worsening of physical disability (3mCDW, 6mCDW) Time to 3mCDW and 6mCDW were the main secondary efficacy endpoints in the pivotal Phase III study. In the overall population, treatment with ofatumumab significantly reduced the risk of both 3mCDW (risk reduction = 33.0%, p = 0.004) and 6mCDW (risk reduction = 31.0%, p = 0.017) compared with teriflunomide. Treatment with ofatumumab demonstrated a numerically greater reduction in confirmed disability deterioration (for both 3mCDW and 6mCDW) compared with teriflunomide treatment in all subgroups analyzed (Tables 3 and 4). [Table 3] [Table 4]

[0133] c) Gd-enhanced T1 lesions The number of Gd-enhanced T1 lesions per scan was the main secondary efficacy endpoint in the pivotal Phase III study. In the overall population, treatment with ofatumumab significantly (p<0.001) reduced the mean number of Gd-enhanced T1 lesions per scan by 95.8% compared with teriflunomide (Table 5). In the Asian subgroup by race and region, treatment with ofatumumab demonstrated a greater reduction in the number of Gd-enhanced T1 lesions per scan compared with teriflunomide. These results were consistent with those in the ROW subgroup and overall population (Table 5). [Table 5]

[0134] d) New or enlarging T2 lesions The annualized rate of new or enlarging T2 lesions was the main secondary efficacy endpoint in the pivotal Phase III study. In the overall population, treatment with ofatumumab significantly (p<0.001) reduced the rate of new or enlarging T2 lesions by 82.9% compared with teriflunomide (Table 6). In Asian subgroups by race and region, treatment with ofatumumab demonstrated a greater reduction in the annualized rate of new or enlarging T2 lesions compared with teriflunomide. These results were generally consistent with those in other global subgroups and in the overall population (Table 6). [Table 6]

[0135] e) Adverse Events (AEs) For the safety analysis in this report, we considered nonserious treatment-emergent adverse events (TEAEs) up to and including the safety cutoff (i.e., day 100 from the last study drug dose) and serious TEAEs unrelated to the safety cutoff (if reported before the data cutoffs for Study I and Study II). The Common Terminology Criteria for Adverse Events (CTCAE) grading was used to record the severity of each AE. The latest version of the CTCAE available at the time of TEAE reporting was used. The AE profile of ethnic subgroups (including system organ class (SOC) and patients with at least one AE) (Asian: ofatumumab 66.7% vs. teriflunomide 82.9%; ROW: ofatumumab 84.4% vs. teriflunomide 84.2%) was similar to that of the overall patient population (ofatumumab 83.6% vs. teriflunomide 84.2%). The three most frequently reported SOC AEs in the Asian and ROW subgroups were “general disorders and administration site conditions,” “infections and infestations,” and “injuries, poisoning, and procedural complications” (Table 7). Analysis of AEs by subgroups defined by race did not suggest any meaningful treatment group differences in type or incidence of AEs by primary SOC and preferred term (PT). In the Asian subgroup, one patient in the ofatumumab group had SAEs of urinary tract infection, urosepsis, and testicular infarction, and one patient in the teriflunomide group had an SAE of nephrolithiasis (Table 8). Given the small numbers of Asian patients by race and region, results should be interpreted with caution. [Table 7-1] [Table 7-2] [Table 8]

[0136] 1. Treatment-emergent adverse events (TEAEs) Overall, in the Asian subgroup, the number of TEAEs by primary SOC was lower in the ofatumumab group than in the teriflunomide group, with the exception of a few SOCs listed below. In the ROW subgroup, there were no notable treatment group differences in AEs by primary SOC. The three most frequently reported SOC AEs in the Asian and ROW subgroups were "General disorders and administration site conditions," "Infections and infestations," and "Injuries, poisoning, and procedural complications" (Table 7).

[0137] The three most frequently reported PT AEs were pyrexia (ofatumumab: 12 patients, 33.3%; teriflunomide: 5 patients, 14.3%), followed by infusion-related reactions (ofatumumab: 7 patients, 19.4%; teriflunomide: 3 patients, 8.6%), and then upper respiratory tract infection (ofatumumab: 4 patients, 11.1%; teriflunomide: 2 patients, 5.7%). The three most frequently reported PT AEs were infusion-related reactions (ofatumumab: 188 patients, 20.7%; teriflunomide: 140 patients, 15.5%), followed by nasopharyngitis (ofatumumab: 168 patients, 18.5%; teriflunomide: 155 patients, 17.2%), followed by alopecia (ofatumumab: 52 patients, 5.7%; teriflunomide: 138 patients, 15.3%).

[0138] 2. Serious Adverse Events (SAEs) The total number of patients with reported SAEs in the Asian subgroup was low overall, and the total number of patients with reported SAEs was similar between the ofatumumab and teriflunomide groups in both the Asian and ROW subgroups (Asian: ofatumumab: 1 patient, 2.8%; teriflunomide: 1 patient, 2.9% and ROW: ofatumumab: 85 patients, 9.3%; teriflunomide: 73 patients, 8.1%) (Table 8). In the Asian subgroup, three SAEs occurred in one patient in the ofatumumab group: urinary tract infection, urosepsis, and testicular infarction. In the teriflunomide group, an SAE of nephrolithiasis was reported in one patient.

[0139] In the ROW subgroup, the most frequently reported SAE due to SOC in both treatment groups (incidence ≥2% of patients) was “infections and infestations” (ofatumumab: 23 patients, 2.5%; teriflunomide: 17 patients, 1.9%). The rates of SAE due to PTs were generally similar between treatment groups. No SAEs with an incidence ≥1% per PT and treatment group were reported. Appendicitis was reported in 2 patients (0.2%) in the teriflunomide group compared with 8 patients (0.9%) in the ofatumumab group. There were no clinically meaningful differences in SAE due to PTs between the ofatumumab and teriflunomide groups. With the exception of appendicitis, only minimal numerical differences (<0.5%) were observed between the ofatumumab and teriflunomide groups.

[0140] 3. AEs of special interest (AESIs) AEs of special interest were summarized by risk name, PT, and treatment. Additionally, the incidence of any AEs that fulfilled the search terms defined in the eCRS was summarized by risk name, level, and maximum CTCAE grade. In this section, AESIs are described first for the racial subgroups, followed by the regional subgroups. Differences existed between the racial and regional subgroups in very few patients, and therefore, no meaningful differences were observed in the number of AESIs between the racial and regional subgroups. The definitions of AEs of special interest correspond to the identified or potential risks of ofatumumab and its class of drugs, as well as that of the comparator (teriflunomide). Based on the safety profiles of ofatumumab, comparators, and other anti-CD20 mABs, the AESIs are as follows: - Systemic and injection-related reactions, including those at the injection site -reaction - Opportunistic infections, recurrent HBV infections, and infections including PML -Malignant and premalignant disorders - Liver safety -Neutropenia Standard Risk Assessment -Suicidal thoughts and behaviors -Drug Abuse and Dependence -pregnancy - Renal safety

[0141] No meaningful differences were observed in the types or incidence of AEs of special interest mentioned above between the Asian and ROW subgroups in patients with RMS.For both the Asian and ROW subgroups, the AESI category of "infection" was the most frequently reported in both the ofatumumab and teriflunomide groups (Table 9). [Table 9]

[0142] f) Region The patterns of AESI in the different exogenous attribution subgroups were broadly consistent with those seen in the overall population. There were no treatment-related differences in patterns between subgroups, and patterns were generally similar to those seen in the overall population (Table 10). [Table 10]

[0143] Example 2: Long-term treatment and effects on Ig levels Patients were treated chronically: they received 20 mg ofatumumab subcutaneously every 4 weeks (following a loading regimen of 20 mg subcutaneous doses at weeks 0, 1, and 2). The exposure durations were as follows: [Table 11] The age distribution was as follows: [Table 12]

[0144] result: 1 to 4 show the results regarding IgG and IgM levels. Figure 1 shows that IgG levels remained stable over a long-term follow-up of over 4 years. This is especially important for the lower quartile. See Figure 2. Although IgM levels showed a decline with increasing duration, levels remained above the lower limit of normal, see Figures 3 and 4.

[0145] Example 3: Characteristics and outcomes of COVID-19 in patients with relapsing multiple sclerosis receiving ofatumumab Objective: To report the clinical characteristics of COVID-19 infection in people with MS (pwMS) receiving ofatumumab 20 mg subcutaneously every 4 weeks. Methods: We reviewed confirmed or suspected cases of COVID-19 infection in patients receiving ofatumumab in the open-label extension study ALITHIOS (data cutoff: December 21, 2020). COVID-19 cases were classified as confirmed if a positive SARS-CoV2 test result was available or if the patient was reported to have a COVID-19 diagnosis. Suspected COVID-19 cases were classified as suspected in the absence of a positive SARS-CoV2 test or a confirmed diagnosis. The following COVID-19 case characteristics were assessed: Patient age distribution COVID-19 Severity Categories * Duration of ofatumumab treatment and actions taken with ofatumumab (treatment interruption) Interventions and COVID-19 outcomes * Severity criteria were based on regulatory reporting definitions established by ICH for regulatory reporting purposes and consisted of fatal, life-threatening, hospitalization, and medically significant. Patient characteristics: Overall population The following table shows the patient age distribution and duration of drug exposure: Forty-five percent (466 / 1026) of patients in the long-term group had a drug exposure duration of 3–4 years. More than 90% (614 / 677) of patients in the newly switched group had an ofatumumab exposure duration of 1–2 years. [Table 13]

[0146] Results: COVID-19 case summary As of December 21, 2020, 35 of 1703 patients in the ongoing ofatumumab open-label extension ALITHIOS clinical trial had confirmed COVID-19 infection and / or COVID-19 pneumonia (Table). All non-serious cases were reported to have made a full recovery. In 21 cases, no change in ofatumumab treatment was required, and in 5 cases, treatment was temporarily interrupted due to confirmed COVID-19 infection. Five of the six severe cases made a full recovery, and in one patient, the COVID-19 outcome was fatal (details below). Associated Risk Factors * ( * A 48-year-old patient with no relevant comorbidities (such as chronic lung disease, diabetes, hypertension, or malignancy) reported symptoms of COVID-19 (pneumonia, fever, weakness, cough, and dyspnea) after approximately 3 years and 7 months of ofatumumab treatment. The patient was hospitalized and received steroids, antivirals, antibiotics, and COVID-19 convalescent plasma. COVID-19 outcomes were reported to be unrelated to ofatumumab treatment. [Table 14]

[0147] Results: Severe COVID-19 cases The following describes the characteristics of the six severe COVID-19 cases in patients treated with ofatumumab: [Table 15-1] [Table 15-2]

[0148] Conclusion: Of the total 1703 patients in the ongoing ALITHIOS trial, 35 confirmed cases of COVID-19 infection and / or COVID-19 pneumonia have been reported. Thirty-four patients experienced complete recovery and one case had a fatal outcome. None of the cases were suspected to be due to ofatumumab treatment.

[0149] Based on a review of reported cases, the clinical findings and outcomes of COVID-19 cases in pwMS treated with ofatumumab are consistent with other reports in the MS population (Richadson S,et al.JAMA.2020;323:2052-2059; Sormani MP,et al.Lancet Neurol.2020 Jun;19(6):481-482; Montero-Escribano P,et al.Mult Scler Relat Disord.2020;42:102185; Safavi F,et al.Mult Scler Relat Disord.2020;43:102195; Barzegar M,et al.Mult Scler Relat Disord.2020;45:102276) and in the general population (Bchetnia M,et al.J Infect Public Health 2020;45:102276). Health.2020;13(11):1601-1610).

Claims

1. 1. A pharmaceutical composition comprising ofatumumab for use in the treatment of multiple sclerosis, wherein a patient is treated who is of Asian ethnicity, wherein serum IgG levels are maintained within the range of 900-1400 mg / dl during said treatment, and said treatment is a chronic treatment for greater than 2 years.

2. - Cytochrome P450 (CYP) CYP2C9 ＊ the frequency of possession of the two alleles is less than 10%, preferably less than 5%, more preferably less than 4.5%, even more preferably less than 4.4%, and most preferably less than 4%, and / or - has an epidermal growth factor receptor (EGFR) mutation, and / or - have the VKORC1 warfarin low dose haplotype, and / or - carrying the chromosomal translocation t(15:17) promyelocytic leukemia protein (PML) gene breakpoint cluster region-1 subtype (bcr1) The pharmaceutical composition of claim 1 , wherein the patient is treated.

3. The patient, - has neuromyelitis optica (NMO); and / or - has an NMO spectrum disorder, and / or - a family history of sudden death (Brugada syndrome); and / or - have a cardiac sodium channelopathy caused by a loss-of-function mutation in SCN5A with arrhythmia susceptibility, - have thyrotoxic periodic paralysis, and / or obesity (preferably with a waist circumference of more than 80 cm in women and more than 90 cm in men, more preferably with central obesity, characterized by the characteristic "thin on the outside, fat on the inside (TOFI)" obesity phenotype); and / or - have type 2 diabetes, and / or - has diabetic nephropathy, and / or - have advanced triple-negative or basal-like breast cancer (ER, PR, Her2 / neu negative), and / or - History of lacunar stroke; and / or - History of intracerebral hemorrhage; and / or - has systemic lupus erythematosus (SLE), and / or - suffers from obstructive sleep apnea (OSA); and / or - Nasopharyngeal carcinoma (NPC), preferably with differentiated non-keratinizing carcinoma (WHO type 2 histology), and / or - have insulin resistance, The pharmaceutical composition of claim 1.

4. 2. The pharmaceutical composition of claim 1, wherein adverse events occurring in patients of Asian descent are consistent with the overall safety profile of ofatumumab.

5. (i) reducing adverse events in Asian patients compared to treatment with teriflunomide; and / or (ii) reducing adverse events in Asian patients compared to non-Asian patients; The pharmaceutical composition of claim 1.

6. 2. The pharmaceutical composition of claim 1, wherein the adverse events are selected from injection-related reactions, infections, malignant and pre-malignant disorders, liver damage or abnormal liver function, and neutropenia.

7. The infection is (i) selected from a respiratory tract infection, a urinary tract infection, a herpes virus infection, a varicella zoster virus infection, an opportunistic infection, pulmonary tuberculosis, a flare-up of HBV infection, and progressive multifocal leukoencephalopathy (PML); and / or (ii) a severe infection selected from opportunistic infections, exacerbations of HBV infection, Pneumocysti jirovecii pneumonia (PCP), and PML; The pharmaceutical composition according to claim 6.

8. The patient is switched to ofatumumab from a previous disease modifying therapy (DMT), the switch preferably comprising: -C of the previous DMT ｍａｘ and / or - the AUC of the previous DMT, and / or - suppression or depletion of B cells and / or T cells, and / or - serum IgG levels, and / or - Adverse events The pharmaceutical composition of claim 1, wherein the composition is administered when a change occurs in the

9. 2. The pharmaceutical composition of claim 1, wherein ofatumumab is administered at a dose of 10-30 mg every 4 weeks.

10. The pharmaceutical composition of claim 9, wherein ofatumumab is administered at a dose of 20 mg every 4 weeks.

11. 2. The pharmaceutical composition of claim 1, wherein ofatumumab is administered subcutaneously.

12. 2. The pharmaceutical composition of claim 1, wherein ofatumumab is administered in a loading dose.

13. 13. The pharmaceutical composition of claim 12, wherein 20 mg ofatumumab is administered as a loading dose at weeks 0, 1, and 2.

14. Multiple sclerosis is (i) relapsing multiple sclerosis, in particular selected from first episode syndrome (CIS), relapsing remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS); and / or (ii) Primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS) The pharmaceutical composition of claim 1.

15. 2. The pharmaceutical composition of claim 1, wherein premedication is administered to the patient before the first dose of ofatumumab is administered.

16. (i) The premedication comprises acetaminophen, an antihistamine, and / or a steroid; and / or (ii) the premedication is administered 30 to 60 minutes prior to the ofatumumab injection; 16. The pharmaceutical composition of claim 15.

17. 2. The pharmaceutical composition of claim 1, wherein no premedication is administered prior to the first dose of ofatumumab. (i) treating patients acutely or previously infected with COVID-19; and / or (ii) the treatment comprises: (a) continues during COVID-19 infection; or (b) said treatment is interrupted during COVID-19 infection and resumed after overcoming said infection; The pharmaceutical composition of claim 1. (i) a patient of Chinese, Japanese, or Korean descent is treated; and / or (ii) Patients are treated who are people of any indigenous ancestry to the Far East. The pharmaceutical composition of claim 1.

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