Ofatumumab for treating MS while preserving serum IgG

Abstract

The present invention relates to ofatumumab for use in the treatment of multiple sclerosis (MS), wherein the treatment is long-term treatment and serum IgG levels are maintained throughout the treatment. The present invention further relates to a B-cell and / or T-cell inhibitor for use in the treatment of MS, wherein the treatment comprises monitoring serum IgG levels and, if serum IgG levels decrease, selecting ofatumumab as the B-cell and / or T-cell inhibitor, and / or wherein the treatment comprises assessing a patient's predisposition to an increased risk of infection and, if a predisposition is identified, selecting ofatumumab as the B-cell and / or T-cell inhibitor. The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, wherein patients with reduced serum IgG levels are treated and / or patients with risk factors associated with serum Ig levels, particularly serum IgG levels, are treated.

Description

[Technical Field]

[0001] The present invention relates to ofatumumab for use in the treatment of multiple sclerosis (MS), wherein the treatment is long-term treatment and serum IgG levels are maintained within a range similar to that of untreated patients. The present invention further relates to a B-cell and / or T-cell inhibitor for use in the treatment of MS, wherein the treatment comprises monitoring serum IgG levels and, if serum IgG levels decrease, selecting ofatumumab as the B-cell and / or T-cell inhibitor, and / or wherein the treatment comprises assessing a patient's predisposition to an increased risk of infection and, if a predisposition is identified, selecting ofatumumab as the B-cell and / or T-cell inhibitor. The present invention further relates to ofatumumab for use in the treatment of multiple sclerosis, wherein patients with reduced serum IgG levels are treated and / or patients with risk factors associated with serum Ig levels, particularly serum IgG levels, are treated. [Background technology]

[0002] 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 disability. There is no cure for the disease, but a variety of disease-modifying therapies (DMTs) are available that usually slow disease progression.

[0003] While most disease-modifying therapies for MS have traditionally been conceptualized as working through T cell-based mechanisms, increasing data indicate that these DMTs also have demonstrable effects on B cells. Common themes include promoting naive B cells rather than memory 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 direct cytolysis of B cells (alemtuzumab, teriflunomide, mitoxantrone) (see Greenfield et al., Ann Neurol. 2018 January;83(1):13-26).

[0004] Greenfield further reports that the monoclonal antibodies (mAbs) rituximab, ocrelizumab, and ofatumumab, each an anti-CD20 antibody, are currently in clinical use for MS.

[0005] Rituximab, a chimeric mouse-human monoclonal antibody, was approved for B-cell lymphoma in 1997 and was indeed one of the first mAbs to be further developed for clinical use. Rituximab works primarily by depleting B cells through complement-dependent cytotoxicity (CDC), but also has significant antibody-dependent cellular cytotoxicity (ADCC) activity.

[0006] Ocrelizumab, currently approved for relapsing and primary progressive forms of MS, differs from rituximab in that it has a humanized antibody backbone. Ocrelizumab exhibits greater ADCC relative to CDC than rituximab and also depletes B cells through multiple mechanisms, including apoptosis and antibody-dependent cellular phagocytosis.

[0007] Ofatumumab, a fully human monoclonal antibody approved for refractory chronic lymphocytic leukemia, results in greater CDC than ADCC activity and is the only anti-CD20 mAb currently being investigated using a subcutaneous rather than intravenous dosing regimen.

[0008] Other anti-CD20 mAbs include obinutuzumab, a humanized IgG1 that targets part of the same epitope on CD20 as rituximab but is designed to induce more cell death due to its on / off binding kinetics, and ublituximab, an anti-CD20 antibody that has been glycoengineered for higher affinity to all Fcγ RIIIa receptors and results in greater ADCC than rituximab and ofatumumab, particularly in cells with low CD20 expression.

[0009] However, treatment with B cell-depleting therapy has been reported to result in a decrease in serum levels of immunoglobulins IgG, IgM, and / or IgA (see, for example, Dr. B. Wildemann's presentation at "8. Heidelberger Patiententag" on January 25, 2020). A decrease in IgG levels has been reported to increase the risk of infection three-fold, and a decrease in IgM levels has been reported to double the risk of infection. In this regard, it should be kept in mind that MS therapy is usually lifelong.

[0010] For example, under therapy with RTX (rituximab), patients experienced a significant time-dependent decrease in serum IgG and IgM levels (IgG: p=2.2×10-5 , IgM: p = 4.0 × 10 -4 Overall IgG levels decreased by 5.1% per year, and IgM levels by 5.0% per year, see Klein et al., ECTRIMS Online Library, 09 / 13 / 19; 278658; P1618.

[0011] 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) assessed serum Ig levels over a 5.5-year period. They observed a decline in serum Ig levels with a clear association with an increased rate of severe infections. The association was strongest for IgG and less so for IgM or IgA. The decline in serum Ig levels progressed at an approximate average rate of 3-4% per year (see Figure 5). There was a clear association between decreasing IgG levels and severe infections.

[0012] Additionally, the ocrelizumab prescribing information describes the association between decreased immunoglobulins and severe infections as follows: "Treatment with Ocrevus resulted in a decrease in overall immunoglobulins over the controlled period of the study, driven primarily by a decrease in IgM. Clinical trial data demonstrate an association between decreased levels of IgG (to a lesser extent for IgM or IgA) and severe infections."

[0013] In summary, one of the most common adverse events associated with B cell-depleting therapy, such as ocrelizumab therapy, in clinical trials has been reported to be a decrease in serum immunoglobulins (e.g., IgG). In the long term, a decrease in serum immunoglobulin levels is significant and undesirable.

[0014] Therefore, the problem underlying the present invention is to provide improved treatment strategies for MS patients, especially for long-term treatment. In particular, it was an object of the present invention to provide a B-cell depleting MS therapy without unnecessarily affecting serum levels of immunoglobulins.

[0015] The problem was unexpectedly resolved by the administration of ofatumumab.

[0016] It is quite surprising that ofatumumab therapy is advantageous compared to other B cell depleting therapies because it does not cause a decrease in immunoglobulins (e.g., IgG) to the extent known from the prior art. Consequently, the absence or amelioration of negative effects on the immune system opens up new avenues for patients under long-term treatment. This is an important clinical benefit, which will be explained in detail below. Summary of the Invention

[0017] A subject of the present invention therefore relates to a B-cell and / or T-cell inhibitor for use in the treatment of multiple sclerosis, said treatment comprising: (a) optionally administering a B-cell and / or T-cell inhibitor, preferably other than ofatumumab; (b) monitoring serum Ig levels, in particular serum IgG levels; (c) if serum IgG levels are decreased, selecting ofatumumab as the B-cell and / or T-cell inhibitor. and / or The treatment comprises: (a) optionally administering a B-cell and / or T-cell inhibitor, preferably other than ofatumumab; (b) assessing the patient's predisposition to an increased risk of infection; (c) if a predisposition to an increased risk of infection is identified, selecting ofatumumab as the B-cell and / or T-cell inhibitor. Includes.

[0018] A further subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, wherein the treatment is long-term treatment and wherein serum IgG levels are maintained within a range, said range being substantially the same as in untreated patients.

[0019] In the context of the present invention, a "treatment-naive patient" refers to a patient diagnosed with MS or first-episode clinically isolated syndrome (CIS) and who is not receiving a B-cell and / or T-cell inhibitor. In a preferred embodiment, the treatment-naive patient exhibits an IgG level in the range of 500-1800 mg / dl, particularly 700-1600 mg / dl, and more particularly 900-1400 mg / dl. In particular, the treatment-naive patient exhibits an IgG level of 500 mg / dl, 550 mg / dl, 600 mg / dl, 650 mg / dl, 700 mg / dl, 750 mg / dl, 800 mg / dl, 850 mg / dl, or 900 mg / dl up to 1400 mg / dl, 1500 mg / dl, 1600 mg / dl, 1700 mg / dl, or 1800 mg / dl.

[0020] Another subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, in which patients with reduced serum IgG levels are treated.

[0021] Yet another subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, in which patients are treated who have risk factors associated with serum Ig levels, in particular serum IgG levels.

[0022] In one embodiment of the present invention, ofatumumab is not administered to patients with active HBV infection, particularly active HBV infection confirmed by positive results for hepatitis B surface antigen [HBsAg] and anti-HBV tests. Ofatumumab may or may not be administered to patients who are HBsAg negative and hepatitis B core antibody positive [HBcAb+] or who are carriers of HBV [HBsAg+]. DETAILED DESCRIPTION OF THE INVENTION

[0023] DESCRIPTION OF THE PREFERRED EMBODIMENT Generally, 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). Again, still further alternatively, the present invention relates to the treatment of primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS).

[0024] Generally, in step (a) of the therapeutic use, a B-cell and / or T-cell inhibitor other than ofatumumab may be administered.

[0025] Generally, B cell and / or T cell inhibitors other than ofatumumab can be any drug that inhibits B cell and / or T cell activity and is suitable as a disease-modifying treatment (DMT) for multiple sclerosis. Such B cell and / or T cell inhibitors that inhibit B cell and / or T cell activity can cause B cell and / or T cell depletion or otherwise interfere with B cell and / or T cell activity. Examples of approved drugs that cause B cell depletion include ocrelizumab, rituximab, obinutuzumab, and ublituximab.

[0026] Examples of other B-cell and / or T-cell inhibitors are, for example, cladribine, fingolimod, natalizumab, teriflunomide, and the like.

[0027] In a preferred embodiment, the B cell and / or T cell inhibitor in step (a) is ocrelizumab or rituximab.

[0028] In the first aspect of the invention, in step (b) at least one serum immunoglobulin (Ig) level is monitored.

[0029] In a preferred embodiment, IgG and IgM are monitored, particularly IgG.

[0030] Generally, monitoring can be performed by measuring the respective serum Ig levels, preferably periodically. In a preferred embodiment, the serum Ig levels can be measured, for example, monthly, every two months, every three months, every six months, or every year. In a preferred embodiment, the monitoring in step (b) is performed every 1 to 12 months, particularly every 3 to 9 months. The IgG levels can be determined, for example, by the treating neurologist during a routine visit.

[0031] In the first aspect of the present invention, in step (c), if the serum IgG level is decreased, ofatumumab is selected as the B cell and / or T cell inhibitor. In other words, if the serum IgG level is unnecessarily low, the treatment of MS is performed or continued using ofatumumab as the DMT. In a preferred embodiment of the present invention, ofatumumab is administered in step (c) as the only active ingredient for treating MS, i.e., the only disease-modifying drug administered.

[0032] According to the present invention, "decreased serum IgG levels", "unnecessarily low serum IgG levels", "decreased serum IgG levels", and "decreasing serum IgG levels" refer to serum IgG levels 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, and / or serum IgG levels below the lower limit of normal, and / or serum IgG levels below 80%, 70%, 60%, or 50% of baseline levels at the start of DMT therapy.

[0033] In a preferred embodiment, in step (c), ofatumumab is selected if the serum IgG level falls below a concentration 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.

[0034] In a preferred embodiment, in step (c), ofatumumab is selected if the serum IgG level is below the lower limit of normal, referred to below as "LLN."

[0035] Generally, the lower limits of normal (LLN) for IgG, IgA, and IgM can be defined as IgG=700 mg / dl or 565 mg / dl, IgM=40 mg / dl, and IgA=70 mg / dl.

[0036] As a result, a serum IgG level of <700 mg / dl or <565 mg / dl is a serum IgG level below LLN, a serum IgM level of <40 mg / dl is a serum IgM level below LLN, and a serum IgA level of <70 mg / dl is a serum IgA level below LLN. In a preferred embodiment, in step (c), ofatumumab is selected as the B cell and / or T cell inhibitor if the serum IgG level is below 80%, 70%, 60%, or 50% of the baseline level at the start of DMT therapy. In other words, the serum Ig level is measured at the start of DMT and set as the baseline value, and in particular the serum IgG level is measured at the start of DMT and set as the baseline value. If the measured level is below the baseline value, in particular below 80%, 70%, 60%, or 50% of the baseline level, ofatumumab is selected as the DMT.

[0037] In a second aspect of the invention, in step (b) the patient's predisposition to risk of infection, in particular to an increased risk of infection, is assessed. In a preferred embodiment, predisposition to bacterial, fungal or viral infection is assessed.

[0038] Methods for assessing a patient's predisposition to an increased risk of infection, such as bacterial, fungal, and viral infections, are well known in the art. For assessing a patient's predisposition to an increased risk of infection, immunoglobulin levels are preferably indicative.

[0039] In a second aspect of the invention, if a predisposition to an increased risk of infection is identified in step (c), in other words, if the predisposition is increased, ofatumumab is selected as the B-cell and / or T-cell inhibitor. In a preferred embodiment of the invention, ofatumumab is administered in step (c) as the only active ingredient for treating MS, i.e., the only disease-modifying drug administered.

[0040] Another subject of the present invention is ofatumumab for use in the treatment or prevention of multiple sclerosis, preferably in patients who have been treated with a B-cell and / or T-cell inhibitor other than ofatumumab.A further subject of the present invention is a method for treating or preventing multiple sclerosis, the method comprising the administration of ofatumumab to a patient suffering from multiple sclerosis, said patient preferably having received a B-cell and / or T-cell inhibitor other than ofatumumab.

[0041] Generally, B-cell and / or T-cell inhibitors other than ofatumumab can be considered as early disease-modifying therapy (DMT). This means that in a preferred embodiment of the present invention, patients are switched from early DMT to ofatumumab. The therapy preferably includes the administration of a B-cell and / or T-cell inhibitor other than ofatumumab. In other words, the present invention relates to ofatumumab for use in the treatment or prevention of multiple sclerosis, wherein ofatumumab is used in patients transitioning from disease-modifying therapy, and the therapy preferably includes the administration of a B-cell and / or T-cell inhibitor other than ofatumumab.

[0042] In a preferred embodiment, patients are switched because their early DMT does not provide stable Ig, e.g., IgG levels, particularly because their early DMT leads to declining Ig, e.g., IgG levels, especially during long-term treatment.

[0043] As mentioned above, a subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, wherein the treatment is a long-term treatment and the serum IgG levels are maintained within a range, said range being substantially the same as in untreated patients.

[0044] In a preferred embodiment, the serum IgG level ranges from 500 to 1800 mg / dl, in particular from 700 to 1600 mg / dl, more in particular from 900 to 1400 mg / dl. As mentioned above, a subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, in which patients with reduced serum IgG levels are treated.

[0045] In a preferred embodiment, the reduced serum IgG level at the start of treatment is below 900 mg / dl, below 850 mg / dl, below 800 mg / dl, below 750 mg / dl, below 700 mg / dl, below 650 mg / dl, below 600 mg / dl, below 550 mg / dl, or below 500 mg / dl. In another preferred embodiment, the reduced serum IgG at the start of treatment is below the lower limit of normal.

[0046] In alternative preferred embodiments, a change in serum IgM levels from baseline of 100 to 600 mg / dl, preferably less than 500 mg / dl, less than 400 mg / dl, less than 300 mg / dl, less than 200 mg / dl, or less than 100 mg / dl.

[0047] As mentioned above, a subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis, in which patients having risk factors associated with serum Ig levels, in particular serum IgG levels, are treated.

[0048] According to the present invention, risk factors associated with serum Ig levels, in particular serum IgG levels, may be metabolic disorders such as obesity and / or metabolic syndrome; or habits such as alcohol consumption and / or smoking.

[0049] In a preferred embodiment, the risk factors relate to drug abuse, particularly alcohol and / or nicotine abuse.

[0050] In a preferred embodiment of the present invention, ofatumumab for treating MS is used in 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, 3 years, 4 years, 5 years, or 10 years.Ofatumumab can be used for up to 5 years, 10 years, 15 years, 20 years, or lifelong.

[0051] In a preferred embodiment of the invention, ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks, preferably 20 mg every 4 weeks.

[0052] 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, intraspinal, intracranial, intrathoracic, epidural, or intrasternal injection or infusion. The preferred route of administration is subcutaneous injection (sc).

[0053] In a preferred embodiment of the present invention, ofatumumab is administered using a loading dose. The term loading dose is defined below. In a preferred embodiment, after initiating ofatumumab therapy, three loading doses are administered, preferably at week 0, week 1, and week 2. This means that the first loading dose at week 0 constitutes the start of therapy. In an alternative preferred embodiment, after initiating ofatumumab therapy, three loading doses are administered on day 1, days 5 to 9, preferably day 7, and days 12 to 16, preferably day 14. This means that the first loading dose at day 1 constitutes the start of therapy.

[0054] In a preferred embodiment of the invention, the loading dose is 10 to 30 mg, preferably 20 mg, ofatumumab.

[0055] In an alternative embodiment of the invention, ofatumumab is administered without a loading dose.

[0056] In a preferred embodiment of the present 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 a preferred steroid. 100 mg iv may be a preferred dose. Preferably, the premedication is administered 30 to 60 minutes before the ofatumumab injection.

[0057] In a particularly preferred embodiment, no premedication is administered prior to the first dose of ofatumumab.

[0058] In preferred embodiments 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.

[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, a 35-year-old woman weighing 60 kg preferably receives the same dose as a 50-year-old man weighing 90 kg. In particular, body weight, sex, age, race, or baseline B-cell count do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab.

[0061] In a preferred embodiment, ofatumumab is administered to patients who have discontinued or interrupted, preferably discontinued, an earlier DMT, e.g., anti-CD20 therapy, due to side effects, such as malignancy, severe infusion-related reactions, or recurrent infections.

[0062] For example, an increased number of malignancies (including breast cancer) has been observed in clinical trials in patients treated with ocrelizumab (Ocrevus®) compared with control groups. The Ocrevus SmPC recommends that the individual benefit / risk profile should be considered in patients who are actively monitored for recurrence of malignancy. Patients with known active malignancies should not be treated with Ocrevus.

[0063] As mentioned above, side effects and adverse events associated with B cell depleting therapies such as ocrelizumab therapy have been reported to be related to a decrease in immunoglobulins (e.g., IgG). In the present invention, it has surprisingly been found that ofatumumab therapy is advantageous compared to other B cell depleting therapies because it does not cause a decrease in immunoglobulins (e.g., IgG) over a long period of time, and therefore opens up new avenues for patients undergoing long-term treatment.

[0064] Thus, in a preferred embodiment of the present invention, ofatumumab is used in the treatment of MS, and ofatumumab is administered to patients with known risk factors for malignancy. In another preferred embodiment of the present invention, ofatumumab is used in the treatment of MS, and ofatumumab is administered to patients who are being actively monitored for relapse of the malignancy. In an alternative embodiment of the present invention, ofatumumab is used in the treatment of MS, and ofatumumab is administered to patients with a known active malignancy.

[0065] The MSIS-29 (see definition below) is a clinically useful and scientifically valid measure of the impact of MS from the patient's perspective, suitable for clinical and epidemiological studies. It is considered a reliable, valid, and responsive PRO (patient-reported outcome) measure that complements other indicators of disease severity used to improve our understanding of the impact of MS.

[0066] In the present invention, it has unexpectedly been found that administration of ofatumumab leads to a beneficial reduction in the MS Impact Scale MSIS-29, as defined below. Reference is made to the Experimental section below.

[0067] In this regard, a further subject of the present invention is ofatumumab for use in treating or preventing relapsing multiple sclerosis, wherein the ofatumumab reduces the MSIS-29 score. Preferably, the ofatumumab reduces the MSIS-29 score by at least 1.5, more preferably at least 2.0, and even more preferably at least 2.5 within 24 months. The reduction can be up to 3.0, 3.5, or 4.0.

[0068] In one embodiment of the present invention, the ofatumumab composition is formulated according to routine procedures as a pharmaceutical composition suitable for intravenous administration to humans. Typically, compositions for intravenous administration are solutions in sterile isotonic aqueous buffer. Where appropriate, the composition may also contain a solubilizing agent and a local anesthetic, such as lignocaine, to ease pain at the injection site. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water-free concentrate, in a hermetically sealed container, such as an ampoule or sachet, indicating the quantity of active agent.

[0069] Where the composition is to be administered by infusion, particularly subcutaneous injection (sc), it can be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.

[0070] 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.

[0071] In one embodiment, a formulation of ofatumumab may be formulated according to the formulations disclosed in WO 2009 / 009407.

[0072] In one embodiment, ofatumumab is formulated into 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.

[0073] In one embodiment, ofatumumab is formulated into an antibody formulation comprising 10-100 mM sodium acetate, 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0.2 mM EDTA, and 0.01-0.2% polysorbate 80, and adjusted to a pH of 5.0-7.0. Preferably, the ofatumumab formulation comprises 50 mM sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM EDTA, and 0.02% polysorbate 80, and adjusted to a pH of 5.5.

[0074] The preferred dosage of ofatumumab is: Initial dose of 20 mg by subcutaneous injection at weeks 0, 1, and 2, followed by Subsequent doses of 20 mg given subcutaneously once a month starting in week 4 is.

[0075] If an injection of ofatumumab is missed, it should be administered as soon as possible, preferably without waiting until the next scheduled dose. Subsequent doses should be administered at the recommended intervals.

[0076] In one embodiment, the ofatumumab formulation is provided in a prefilled syringe or in an autoinjector, preferably a single-dose prefilled syringe or a single-dose prefilled autoinjector. Preferably, a prefilled autoinjector designed for sc administration is used.

[0077] In a preferred embodiment, ofatumumab injection is a sterile, preservative-free solution for subcutaneous use. Preferably, each 20 mg / 0.4 mL prefilled pen or syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains 20 mg ofatumumab and arginine (4 mg), edetate disodium (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg), and water for injection, USP, having a pH of 5.5. Hydrochloric acid may be added to adjust the pH.

[0078] In a preferred embodiment, the ofatumumab formulation is intended for patient self-administration, preferably by subcutaneous injection.

[0079] In a preferred embodiment, the formulation is administered subcutaneously to the abdomen, thigh, or outer upper arm. In a preferred embodiment, the formulation is not administered to moles, scars, or areas where the skin is tender, broken, red, hard, or not intact.

[0080] In one embodiment, the first injection of the ofatumumab formulation may be administered under the guidance of a healthcare professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Prior to administration, the pen or prefilled syringe is preferably removed from the refrigerator and allowed to reach room temperature, for example, for about 15 to 30 minutes. In a preferred embodiment, the ofatumumab formulation of the present invention is a clear to slightly opalescent and colorless to slightly brownish-yellow solution that can be used 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

[0081] In a preferred embodiment, a subcutaneous ofatumumab dose of 20 mg every 4 weeks provides a mean AUC of about 400 to 550, more preferably 450 to 500, e.g., 483 mcg h / mL, at steady state. tau and / or a mean C of 1.0 to 2.5, more preferably 1.2 to 1.7, e.g., 1.43 mcg / mL max In a preferred embodiment, after repeated subcutaneous administration of 20 mg doses of ofatumumab, the volume of distribution at steady state may be 4.5 to 6.5, more preferably 5.0 to 6.0, for example 5.42 L.

[0082] After subcutaneous administration, ofatumumab can be absorbed via the lymphatic system.

[0083] In preferred embodiments of the invention, ofatumumab is administered for the treatment of relapsing forms of multiple sclerosis (MS), including first-episode syndrome, relapsing-remitting disease, and active secondary progressive disease, preferably in adults.

[0084] In a preferred embodiment of the present invention, administration of ofatumumab is delayed in patients with an active infection, such as COVID-19, until the infection is resolved. Alternatively, ofatumumab can be administered during the infection, such as during COVID-19 infection. Thus, administration of ofatumumab can be continued during the infection, such as during COVID-19 infection.

[0085] In another preferred embodiment of the invention, immunoglobulin levels are monitored at the start of, during, and after discontinuation of treatment with ofatumumab until B-cell repletion and as clinically indicated. If the patient develops severe opportunistic or recurrent infections, or if immunoglobulin levels indicate immune deficiency, consideration is given to discontinuing ofatumumab treatment.

[0086] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising: (a) administering to a patient in need thereof, optionally, preferably a B-cell and / or T-cell inhibitor other than ofatumumab; (b) monitoring serum Ig levels, in particular serum IgG levels; (c) if serum IgG levels decrease, selecting and administering ofatumumab as a B-cell and / or T-cell inhibitor; and / or The treatment comprises: (a) administering to a patient in need thereof, optionally, preferably a B-cell and / or T-cell inhibitor other than ofatumumab; (b) assessing the patient's predisposition to an increased risk of infection; (c) if a predisposition to an increased risk of infection is identified, selecting and administering ofatumumab as a B-cell and / or T-cell inhibitor. Includes.

[0087] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising administering ofatumumab to a patient in need thereof, wherein the treatment is long-term treatment and the serum IgG level is maintained throughout the treatment.

[0088] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising the step of administering ofatumumab to a patient in need thereof, wherein patients with reduced serum IgG levels are treated.

[0089] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising the step of administering ofatumumab to a patient in need thereof, wherein the patient has risk factors associated with serum Ig levels, in particular serum IgG levels, and is treated.

[0090] A further subject of the present invention is a process for the manufacture of a medicament for use in the treatment described above.

[0091] definition The term "treatment" or "treating" may be defined as the application or administration of, for example, ofatumumab, to a patient with the purpose of eliminating, reducing, or alleviating the symptoms of a disease such as multiple sclerosis (MS). In particular, the term "treatment" includes achieving a clinically meaningful benefit for the patient, for example, achieving a clinically meaningful reduction in annual relapse rate when treating RMS.

[0092] 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.

[0093] As used herein, the term "patient" refers to a mammal, such as a primate, preferably a higher primate, and particularly preferably a human (e.g., a patient at risk of having a risk or disorder described herein). Preferably, the patient is an adult. Generally, elderly patients are included, however, patients between the ages of 18 and 60 are preferred. As used herein, the terms "administering" or "administration" ofatumumab can refer to providing 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.

[0094] As used herein, a "therapeutically effective amount" may refer to an amount of ofatumumab that is effective, i.e., achieves a clinically meaningful effect.

[0095] The term "adverse event" (AE) can refer to any untoward medical occurrence in a patient or in a clinical trial in which a subject is administered a pharmaceutical product, which does not necessarily have a causal relationship to this treatment. Thus, an adverse event (AE) can be any untoward and unintended sign (including abnormal laboratory findings), symptom, or disease temporally associated with the use of a medical (investigational) product, whether or not related to the medical (investigational) product.

[0096] The phrase "therapeutic regimen" can refer to a regimen, e.g., a medication used, used to treat a disease or to prevent the onset of a disease state or disease. A therapeutic regimen can include an induction regimen, a loading regimen, and a maintenance regimen.

[0097] RRMS Relapsing-remitting multiple sclerosis (RRMS) can be characterized by relapses, defined as episodes of new neurological deficits or neurological deterioration lasting longer than 24 hours, preferably in the absence of fever or infection.

[0098] During periods of remission, there may be no obvious progression of the disease. At different times, RRMS can be further characterized as either active (with evidence of relapse and / or new MRI activity) or inactive, and as either worsening (confirmed increase in disability over a specified period after relapse) or not worsening. Reference is made to Lublin, Neurology. 2014 Jul 15; 83(3): 278-286.

[0099] RMS The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS, and first-episode syndrome (CIS).

[0100] Primary progressive MS (PPMS) PPMS can be characterized by the onset of symptoms leading to a worsening of neurological function (accumulation of disability) without early relapses or remissions. PPMS can be further characterized at different time points as either active (with occasional relapses and / or evidence of new MRI activity) or inactive, and as either progressing (evidence of disease worsening on objective measures of change over time, with or without relapses or new MRI activity) or not progressing. Reference is made to Lublin 2014.

[0101] The experience of each person with PPMS will be unique. PPMS can have brief periods of stable disease, with or without relapses or new MRI activity, as well as periods of increased disability, with or without new relapses or lesions on MRI.

[0102] 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 disability). SPMS can be further characterized at different time points as either active (with relapses and / or evidence of new MRI activity) or inactive, and as either progressing (evidence of disease worsening on objective measures of change over time, with or without relapses) or not progressing. Reference is made to Lublin 2014.

[0103] The experience of each person with SPMS will be unique. SPMS follows relapsing-remitting MS. Disability gradually increases over time, with or without evidence of disease activity (relapses or changes on MRI). SPMS can have occasional relapses, as well as periods of stability.

[0104] recurrence Relapse can be defined as a new neurological deficit or an episode of neurological deterioration that preferably lasts for 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") that preferably lasts for at least 24 hours.Relapse is usually followed by a period (remission) of complete or partial recovery and no symptom progression or accumulation of disability.

[0105] As used herein, the term "B cell inhibitor" generally refers to any substance that eliminates, reduces, or attenuates biological B cell function. B cell inhibitors may disrupt signal transduction pathways necessary for biological B cell function, such as 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. Furthermore, 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 by lysis, for example, through CDC, ADCC, phagocytosis, or other processes. Some subsets of B cells may express CD20.

[0106] As used herein, B cells may refer to a type of white blood cell of the lymphocyte subtype. B cells function in the humoral immune component of the adaptive immune system by secreting antibodies such as immunoglobulins (e.g., IgG). Additionally, B cells can present antigens and secrete cytokines. Unlike T cells and natural killer cells, B cells express a B cell receptor (BCR) on their cell membrane. The BCR enables B cells to bind to specific antigens, against which they initiate an antibody response.

[0107] As used herein, a T cell inhibitor can refer to any substance that eliminates, reduces, and / or weakens biological T cell function. A T cell inhibitor can disrupt signal transduction pathways necessary for biological T cell function, such as cytokine secretion or response to cis and / or trans stimuli. A T cell inhibitor can also interfere with the generation of T cells from stem / progenitor cells or negatively affect their maturation. Furthermore, a T cell inhibitor can act by inhibiting crosstalk with other cell populations, such as B cells. Alternatively, a T cell inhibitor can deplete T cells by sequestration (e.g., in lymphoid tissues such as the spleen) or by lysis, for example, through CDC, ADCC, phagocytosis, or other processes.

[0108] As used herein, T cells may refer to a type of lymphocyte that develops in the thymus. T cells can be distinguished from other lymphocytes by the presence of T cell receptors on the cell surface.

[0109] First-episode syndrome (CIS): First-episode syndrome (CIS) can refer to a single clinical attack of central nervous system (CNS) inflammatory demyelinating symptoms suggestive of multiple sclerosis (MS). CIS presentations can be unifocal or multifocal and typically involve the optic nerve, brainstem, cerebellum, spinal cord, or cerebral hemispheres. See Miller et al., Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169.

[0110] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 version 2 is a 29-item self-administered questionnaire covering two domains: physical and psychological. Responses are captured on a 4-point ordinal scale ranging from 1 (not at all) to 4 (extremely), with higher scores reflecting greater impact on daily life. The MSIS-29 takes approximately 5 minutes to complete, and the questions are designed to assess patients' views of the impact of MS on their daily lives over the past two weeks. Reference is made to 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; 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.

[0111] Ofatumumab: Ofatumumab is a human monoclonal antibody against the CD20 protein. It 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, resulting in in vitro B cell lysis. In particular, ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed on, for example, B cells. Ofatumumab is produced in a mouse NS0 cell line, has a molecular weight of approximately 146 kDa, and consists of two IgG1 heavy chains and two kappa light chains.

[0112] Ofatumumab is described in EP 1 558 648 and EP 3 284 753. Further reference is made to the description at drugbank.ca, accession number DB06650, and to 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 United States, ofatumumab is sold under the trade name Kesimpta®.

[0113] The metabolic pathway of ofatumumab may be degradation by universal proteases into small peptides and amino acids. Ofatumumab may be eliminated in two ways: a target-independent pathway, similar to other IgG molecules, and a target-mediated pathway involving binding to B cells.

[0114] The half-life of ofatumumab at steady state, particularly after repeated subcutaneous administration of 20 mg doses, can be approximately 16 days.

[0115] Ofatumumab preferably does not share a common clearance pathway with chemical drugs metabolized by the cytochrome P450 system or other drug-metabolizing enzymes. Preferably, ofatumumab is not involved in regulating the expression of drug-metabolizing enzymes.

[0116] patient The term "patient" preferably refers to a human patient, preferably an adult.

[0117] loading dose A loading dose is an initial dose, preferably an initial higher dose, of a drug that may be given at the beginning of treatment (e.g., DMT) before transitioning to a maintenance dose that is preferably lower than the loading dose.

[0118] Immunoglobulins (Ig) and subtypes IgG, IgA, IgM, IgD, and IgE are generally known, for example, as described in Berg / Tymoczko / Stryer "Biochemie", 5 th edition, pp. 1015-1018. This application focuses on the serum levels of IgG and IgM, particularly IgG.

[0119] Serum immunoglobulin (Ig) levels can be routinely determined in clinical practice. In this application, serum Ig levels can preferably be determined by immunoturbidimetry. Preferably, a Roche cobas® analyzer, particularly module c of the cobas® analyzer, was used. In a preferred embodiment, Ig levels can be determined by using a cobas® c 311 analyzer. IgG measurements are performed as described in the cobas® leaflet "IGG-2 Tina-quant IgG Gen.2", preferably version 11.0 dated February 2016, and IgM measurements are more preferably performed as described in the leaflet "IGM-2 Tina-quant IgM Gen.2", preferably version 13.0 dated November 2018.

[0120] Serum samples were preferably kept at 2-8°C before measurement.

Brief Description of the Drawings

[0121] [Figure 1] It is a diagram depicting the setup of a clinical trial according to Example 1 and the measurements of IgG and IgM. [Figure 2] It is a diagram illustrating the change in serum IgG level from baseline. [Figure 3] It is a diagram illustrating the change in serum IgM level from baseline. [Figure 4] It is a diagram showing the proportion of patients having an IgG level < LLN and < 50% of LLN (at least once during the period after baseline hospital visit). [Figure 5] This is a figure showing the decrease in IgG levels after administration of the prior art anti-CD20 antibody (ocrelizumab). Figure 5 was 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] This is a figure showing that after 2 years (96 weeks), ocrevus treatment (pooled OPERA, see Figure 1) led to an approximately 5% decrease in IgG levels, while ofatumumab led to an approximately 3% increase. [Figure 7] This is a figure illustrating the changes in serum IgM and IgG levels from baseline. The mean IgM and IgG levels remained well within the reference range over time. A decrease in IgM levels from baseline was observed in both treatment groups in both studies (ASCLEPIOS I and II). A decrease in IgG levels from baseline was observed up to week 36 in both treatment groups in both studies (ASCLEPIOS I and II), and then recovered. In ofatumumab-treated patients, IgG levels recovered to the highest baseline level by W72. [Figure 8] This is a figure showing the proportion of patients with IgM and IgG levels at <LLN, <10%LLN, and <20%LLN. At any time point after baseline and at week 96, a higher proportion of patients in ofatumumab had IgM levels below LLN and 10% below LLN compared to teriflunomide. At any time point after baseline, a lower proportion of patients in ofatumumab had IgG levels below LLN compared to teriflunomide. At week 96, there were no ofatumumab patients with IgG levels 20% below LLN. [Figure 9] Figure 1 shows the proportion of patients with IgM and IgG levels of ≥ LLN, ≥ 10% LLN, and ≥ 20% LLN. At any time point after baseline, approximately 82-89% of patients on ofatumumab had IgM levels at or above the LLN compared with teriflunomide (>90%), and >85% of patients on ofatumumab had IgG levels at or above the LLN compared with teriflunomide (>77%). [Figure 10] FIG. 1 illustrates the occurrence of severe infection in relation to immunoglobulin levels. [Figure 11] FIG. 1 illustrates the occurrence of severe infection in relation to immunoglobulin levels. [Figure 12] FIG. 1 illustrates the change in serum IgG levels from baseline. [Figure 13] FIG. 1 illustrates the change in serum IgM levels from baseline. [Figure 14] Plots of absolute values ​​of IgG parameters by visit window and 48, 96, and 144 week completers in the OMB longitudinal group. [Figure 15] Plot of absolute values ​​of IgG parameters by visit window and quartiles of baseline values ​​in the OMB longitudinal group. [Figure 16] Plots of absolute values ​​of IgM parameters by visit window and 48, 96, and 144 week completers in the OMB longitudinal group. [Figure 17] 10 is a plot of absolute values ​​of IgM parameters by visit window and quartiles of baseline values ​​in the OMB longitudinal group. [Example]

[0122] [Example 1] background Ofatumumab, the first fully human anti-CD20 monoclonal antibody, demonstrated superior efficacy compared to teriflunomide in the Phase 3 ASCLEPIOS I / II trial, ECTRIMS Online Library. Hauser S. et al. 09 / 13 / 19; 279581; 336. MS patients on ofatumumab had a 50.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) reduction in annualized relapse rate (ARR) compared to Aubagio® (teriflunomide) in the ASCLEPIOS I and II studies, respectively (p<0.001 for both studies). Ofatumumab showed highly significant suppression of gadolinium (Gd)T1 lesions and demonstrated a greater suppression of new inflammatory activity when compared to Aubagio®. Ofatumumab demonstrated a relative risk reduction of 34.4% (p=0.002) for 3-month confirmed disability progression (CDP) and 32.5% (p=0.012) for 6-month CDP compared with Aubagio® in a pre-specified pooled analysis.

[0123] the purpose Patients with multiple sclerosis were treated with ofatumumab to determine serum immunoglobulin (Ig) levels and to examine the association between IgG or IgM levels and new treatment options.

[0124] method ASCLEPIOS I and II are double-blind, double-dummy, active comparator-controlled, parallel-group, innovative, adaptive-design, multicenter trials. Patients were randomized (1:1) to receive either ofatumumab 20 mg sc injections every 4 weeks (following a loading regimen of 20 mg sc doses on days 1, 7, and 14) or teriflunomide 14 mg orally once daily for up to 30 months. The studies have a flexible duration and termination occurs during the blinded core treatment phase according to pre-specified criteria. Patients aged 18 to 55 years with an Expanded Disability Status Scale (EDSS) score of 0 to 5.5 at screening (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444-52) who had experienced ≥1 relapse within the past year or ≥2 relapses within the past 2 years, or a positive gadolinium-enhanced (Gd+) MRI scan within the year prior to randomization were included.

[0125] Serum IgG / IgM levels were monitored at baseline, week 4 (W), W12, and every 12 weeks (see Figure 1). The lower limit of normal (LLN) was defined as IgG, 7 g / L and IgM, 0.4 g / L. Outcomes included the proportion of patients with significantly low IgG / IgM levels and the association between significantly low IgG / IgM levels and the incidence of infection.

[0126] result a) B cell depletion The majority of patients (77.0%) in the ofatumumab group had CD19+ B cells below the LLN reported as early as week 1, and the proportion of patients with CD19+ B cells below the LLN further increased (95.0%) at week 2. Depletion was achieved in nearly all patients with the ofatumumab initial loading regimen (3 weeks of 20 mg doses on days 1, 7, and 14).

[0127] By week 12, almost all patients (99.3%) had CD19+ B cells below the LLN, and CD19+ B cell depletion was maintained in >96% of patients throughout the treatment period. The median CD19+ B cell count was zero after week 2. In contrast, up to 4.5% of patients in the teriflunomide group had B cells below the LLN throughout the study treatment period. The median CD19+ B cell count was above the LLN at all time points up to week 120.

[0128]

Table 1

[0129] b) Ig levels

[0130]

Table 2

[0131] Changes in serum IgG levels from baseline are shown in Figure 2. Changes in serum IgM levels from baseline are shown in Figure 3.

[0132] The proportion of patients with Ig levels below the LLN is illustrated in Figure 4 for IgG.

[0133] <Infections observed after the first decline in IgG below the LLN: Ofatumumab N = 134: 61 (45.5%) Teriflunomide N = 214: 78 (36.4%)

[0134] conclusion In ofatumumab-treated patients, there is no decline in IgG levels at week 72 and beyond. Furthermore, there is a turning point at week 36 where the trend of declining IgG levels reverses, ultimately resulting in a net increase in IgG starting around week 72. Therefore, long-term MS therapy is provided without unnecessarily affecting serum levels of immunoglobulins. The absence or amelioration of negative effects on Ig, particularly IgG, levels, and therefore on the immune system, provides benefits to patients, especially in long-term treatment.

[0135] [Example 2] method In a cross-sectional analysis, the results of Example 1 and those obtained by Derfuss et al. were compared.

[0136] result After 2 years (96 weeks), Ocrevus treatment (pooled OPERA, see Figure 5) leads to an approximately 5% decrease in IgG levels, while ofatumumab leads to an approximately 3% increase. See Figure 6.

[0137] conclusion Ofatumumab sustains and even increases IgG levels in the long term, while ocrelizumab leads to a decrease in IgG levels.

[0138] [Example 3] Maintenance of ofatumumab efficacy in relapsing MS patients transitioning from intravenous anti-CD20 therapy background B-cell depletion in patients with relapsing forms of multiple sclerosis (RMS) using anti-CD20 monoclonal antibodies (mAbs) reduces annual relapse rates and inflammatory lesion activity on magnetic resonance imaging, and delays the time to documented disability worsening. The anti-CD20 mAbs ocrelizumab and rituximab are administered by intravenous infusion in the clinic; ofatumumab is administered subcutaneously using a prefilled syringe or autoinjector (AI) pen to facilitate self-administration.

[0139] the purpose: A 12-month, prospective, single-arm, multicenter clinical trial to confirm the maintenance of efficacy of ofatumumab in patients with RMS transitioning from intravenous anti-CD20 mAb therapy.

[0140] method Approximately 100 adults with RMS will be enrolled at 10 to 20 sites in the United States. Eligible patients will have previously been treated with two to five consecutive courses of intravenous ocrelizumab or rituximab (other anti-CD20 mAbs are excluded), with the last dose administered 4 to 9 months prior to baseline. Other inclusion criteria are a Composite Disability Scale score of 5.5 or lower at screening and CD19 B cell depletion to less than 1% of baseline anti-CD20 therapy. Patients with a suboptimal response to anti-CD20 therapy in the past 6 months (relapse, ≥2 active gadolinium-enhancing [Gd+] lesions, any new / enlarging T2 lesions, clinical deterioration), or who discontinued anti-CD20 therapy due to severe infusion-related reactions or recurrent infections, or who have progressive disease, will be excluded. All participants will receive ofatumumab 20 mg subcutaneously administered by AI pen on days 1, 7, and 14, then monthly from months 1 to 12. The primary endpoint is stability or decline in Gd+ lesion counts at 12 months. Secondary endpoints include participant retention and changes in immune biomarkers, treatment satisfaction, safety, and tolerability at months 6 and 12. There will be a 6-month interim analysis.

[0141] result The study complements the ofatumumab Phase 3 program in RMS by generating efficacy maintenance, retention, and satisfaction data based on monthly subcutaneous drug delivery with an AI pen in patients previously treated with ocrelizumab or rituximab.

[0142] conclusion : The study provides important data on the maintenance of efficacy of ofatumumab in patients with RMS transitioning from intravenous anti-CD20 therapy.

[0143] [Example 4] Primary immunodeficiency The majority of patients with primary antibody deficiency present with recurrent bacterial infections of the sinopulmonary tract, including recurrent otitis media, sinusitis, and pneumonic sepsis (Gupta S 2017). Additionally, up to 25% of these patients have autoimmune manifestations, with autoimmune hemolytic anemia and autoimmune thrombocytopenia being the most commonly observed deficiencies (Goldstein MF et al. 2006. Selective IgM immunodeficiency: retrospective analysis of 36 adult patients with review of the literature. Ann Allergy Asthma Immunol. 2006 Dec; 97(6):717-30; Yel L et al. 2009. Clinical and immunological features of IgM deficiency. Int Arch Allergy Immunol. 2009; 150(3):291-8). Primary immunodeficiency should be suspected when recurrent infections are severe, intercurrent, involve multiple locations, are resistant to treatment, are caused by atypical organisms, or are present in families. In general clinical practice, physicians treating MS patients are aware of the immunosuppressive effects of MS DMTs and the risk of infection-related MS and should therefore assess the patient's immune status using relevant medical history or examination findings.

[0144] Secondary immunoglobulin deficiency and risk of infection Decline in serum immunoglobulins and risk of infection have been reported in patients with MS treated with anti-CD20 therapy. Rates may vary according to the measurement device used, population setting (e.g., outpatient or inpatient, sociodemographic characteristics), and study design (e.g., immunoglobulin assay, normal values, frequency of monitoring, etc.), or the methods used to demonstrate or refute the association.

[0145] Among 3595 patients treated with rituximab over 11 years with 14,816 PY (Patient-Years) with over 1246 patients having > 5 years of follow-up, 863 (24%) developed < LLN IgM for at least 4 months, while 143 / 3595 (4%) developed < LLN IgG for at least 4 months. For both of these Ig classes, the severe infection rate per 100 PY was similar before (IgM 2.80, 95% CI 2.09–3.75; IgG 6.75, 95% CI 4.48–10.15) and during / after (IgM 3.84, 95% CI 3.20–4.62; IgG 8.16, 95% CI 5.86–11.36) the onset of low Ig. The severe infection rate in patients who developed low IgG levels was higher than the corresponding rate in patients who never developed low IgG, both before and after the onset of low IgG levels, and higher than in all exposed populations, suggesting that these patients may have a higher intrinsic risk of developing severe infection events (van Vollenhoven RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 Years. J Rheumatol. 2015;42(10):1761-1766. doi:10.3899 / jrheum.15005).

[0146] Another single-center study of 700 patients treated with rituximab to assess the impact of severe infection and hypogammaglobulinemia during therapy in rheumatic and musculoskeletal diseases showed similar results regarding the association between IgM and infection risk. Regarding IgM, the rate of severe infection was similar in patients with low IgM at baseline (10.6 / 100PY), patients who acquired low IgM during treatment (9.8 / 100PY), and those with normal IgM (9.2 / 100PY) (Md Yusof MY, et al. Predicting Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rituximab in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2019;71(11):1812-1823). However, the rate of severe infection was higher in patients with low IgG at baseline (16.4 / 100PY) and in those who acquired low IgG during or after rituximab (RTX) treatment (21.3 / 100PY) compared with those with normal IgG (9.7 / 100PY). This is supported by a single-center retrospective review of 177 patients with multisystem autoimmune diseases who received rituximab between 2002 and 2010. There was no difference in the proportion of patients affected by infection according to IgM levels (normal IgM 37% vs. low IgM 43%) (Marco H, Smith RM, Jones RB, et al. The effect of rituximab therapy on immunoglobulin levels in patients with multisystem autoimmune disease. BMC Musculoskelet Disord. 2014;15:178. Published 2014 May 25. doi:10.1186 / 1471-2474-15-178).

[0147] However, factors known to be associated with decreased gamma-globulin levels with rituximab in rheumatoid arthritis patients include underlying chronic corticosteroid use and older age (van Vollenhoven RF, Emery P, Bingham CO 3rd, et al. Long-term safety of patients receiving rituximab in rheumatoid arthritis clinical trials [published correction appears in J Rheumatol. 2010 Oct;37(10):2198]. J Rheumatol. 2010;37(3):558-567). This is significantly different compared to the baseline characteristics of multiple sclerosis patients treated with other anti-CD20 therapies.

[0148] In ocrelizumab-treated patients with multiple sclerosis, over 5.5 years of treatment in clinical studies revealed that the association with infection was noted to be strongest for IgG (6.50 / 100PY vs. 2.11 / 100PY) and less so for IgM (3.66 / 100PY vs. 1.88 / 100PY) (https: / / onlinelibrary.ectrims-congress.eu / ectrims / 2019 / stockholm / 279399 / tobias.derfuss.serum.immunoglobulin.levels.and.risk.of.serious.infecti).

[0149] It can therefore be speculated that in patients treated with anti-CD20 therapy, the decline in IgG may be more clinically meaningful compared to the decline in IgM.

[0150] Pharmacological differences between Kesimpta, Ocrevus, and Rituxan Pharmacologically, ofatumumab has a distinct mechanism of action when compared with other anti-CD20 therapies, such as rituximab or ocrelizumab. Although all of these antibodies bind to the CD20 receptor on B cells, preclinical data indicate some unique properties of ofatumumab. No relevant differences in ADCC activity were observed for ofatumumab compared with ocrelizumab, while rituximab was less active [Clinical Pharmacology Summary (SCP) - Figure 12]. In addition, B cell binding studies demonstrated a slower off-rate (i.e., the rate of dissociation of the antibody from the CD20 receptor) for ofatumumab compared with rituximab, which is functionally significant [Nonclinical Review].

[0151] Both ocrelizumab and rituximab are administered intravenously at high doses of 600 mg and 2000 mg, respectively, and as a result, they must pass through the blood circulation and organs, including the liver and spleen, before ultimately reaching the lymphatic system. In contrast, ofatumumab, administered subcutaneously at a dose of 20 mg, enters the systemic circulation via an indirect route through the lymphatics (Richter et al., 2012), which contributes to a lower dose in achieving equivalent clinical efficacy, better tolerability, and lower clinical risks (i.e., no low IgG, no neutropenia, more rapid repletion of CD20) when compared with high-dose intravenous administration. Clinically, ofatumumab differs from other anti-CD20 mAbs in the clinical characteristics measured below: As expected for CD20 therapy, treatment with ofatumumab was associated with some level of IgM decline, but the majority of patients remained above LLN. Decline in mean serum IgM was predominantly noted only during the first 48 weeks. In contrast to ocrelizumab, a 2.2% increase in mean serum IgG levels (+0.249 g / L) from baseline to week 96 was observed in ofatumumab (OMB)-treated patients in the ASCLEPIOS study, while a 4.1% decrease in mean IgG levels (-0.421 g / L) from baseline was observed at week 96 in the teriflunomide group. No risk of neutropenia was noted with ofatumumab treatment in patients with MS. Mean and median neutrophil counts remained within the normal range, and baseline neutrophil counts did not predict any decline over the course of the studies, based on summary statistics by visit window in both the G2301 and G2302 studies. In Pool C2, after study treatment was discontinued, 28 of 40 patients (70.0%) in the ofatumumab group who reached 48 weeks after the last dose date demonstrated B-cell repletion (had LLN or B cells at or above baseline) compared with 22 of 35 patients (62.9%) in the teriflunomide group. In the OMS115102 study, B-cell repletion was observed for all but one subject at approximately 48 weeks into the study [OMS115102 - Section 8.2.3]. Per Ocrevus USPI, in 51 patients from an MS clinical study, the median time to recovery of B-cell counts to either baseline or LLN was 72 weeks (range 27-175 weeks) after the last Ocrevus infusion and within 2.5 years of the last infusion, with B-cell counts rising to either baseline or LLN in 90% of patients. As per the Rituxan label, the majority of rheumatoid arthritis patients demonstrated peripheral B-cell depletion for at least 6 months. A small proportion of patients (approximately 4%) had prolonged peripheral B-cell depletion lasting longer than 3 years after a single course of treatment.

[0152] Serum immunoglobulins and ofatumumab in MS research In Pool C2, the serum immunoglobulin results demonstrated that the mean serum IgM level remained well within the reference range (>19 years of age patient reference range: 0.40 - 2.30 g / L) over time (Figures 12 and 13). A 30.9% decrease (-0.420 g / L) in the mean IgM value from baseline to week 48 was noted, but the slope of the mean IgM decline among completers at week 96 was lower compared to completers at the first 48 weeks (38.8%, -0.537 g / L). In both completers at week 48 and week 96, the mean serum IgM level remained well within the reference range.

[0153] Immunoglobulin leading to discontinuation <LLN of serum IgG and / or serum IgM are exclusion criteria for studies G2301 and G2302, but protocol recommendations regarding significantly low levels of IgG / M for treatment discontinuation were defined as levels 20% below LLN for IgG and 10% below LLN for IgM. From a clinical practice perspective, these protocols specify thresholds that can be considered quite conservative.

[0154] Overall, 167 (17.7%) patients out of 944 treated with ofatumumab reported IgM below LLN at any time after baseline. Of the 167 patients, only 32 (3.2%) patients discontinued treatment with ofatumumab, while the majority of the remaining patients continued treatment with ofatumumab in ongoing clinical studies. Among the 32 (3.2%) patients who discontinued treatment with ofatumumab, · Six out of 32 patients in the ofatumumab group and two out of seven patients in the teriflunomide group reported infections after study drug discontinuation. Most of these infections were upper respiratory or urinary tract infections; · No cases of severe opportunistic infections were reported in the MS clinical studies; · None of the patients received immunoglobulin replacement therapy for the decrease in IgG / M.

[0155] In chronic diseases such as MS and due to the nature of double - blind clinical studies, treating physicians were unable to continue protocol - based study treatment interruptions in order to avoid any risk of disease activity and potential relapse. Therefore, discontinuation rates may have been induced by the thresholds specified in the protocol and to initiate alternative treatment for MS disease activity.

[0156] Immunoglobulins and Infection Risk Table 2.1 below provides an overview of the proportion of patients with IgM / IgG levels below the lower limit of normal (<LLN [g / L]: IgM, 0.4; IgG, 7.0) and analyzes the association (<LLN vs. ≥LLN) between IgM / IgG levels and the incidence of infections occurring up to 1 month before and 1 month after any decrease in IgM / IgG levels.

[0157] Overall, 167 out of 944 (17.7%) patients treated with ofatumumab reported IgM below LLN at any time after baseline. Of the 167 patients, · 124 (74.3%) patients with at least one episode of <LLN IgM had ofatumumab treatment temporarily interrupted by protocol; · The majority of patients continued treatment with ofatumumab in ongoing clinical studies and did not discontinue study treatment; · The overall incidence of infections was lower in patients with a decrease in <LLN IgM (52 patients, 31.1%) compared to patients who maintained >LLN IgM (400 patients, 51.5%); · The pattern of severe infections also mirrored the overall infections, with a higher incidence of severe infections noted in patients who maintained >LLN IgM (18 patients, 2.3%) compared to patients who had infections from 1 month before to 1 month after a decrease in <LLN IgM (2 patients, 1.2%). Both severe infections (upper respiratory tract infection, urinary tract infection) in the <LLN IgM group were not opportunistic in nature and were typically expected in MS patients; · The most frequently reported infectious adverse events (AEs, ≥2%) were upper respiratory tract infection, urinary tract infection, and oral herpes, which were consistent across all patients with IgM ≥LLN and the overall MS patient population; · Consistent with patients with IgM ≥LLN, the majority of infections in patients in the IgM <LLN group were mild to moderate, patients recovered with standard care, and the infections were not treatment limiting.

[0158] For serum IgG, there was no decrease in the mean value over time compared to baseline. The proportion of patients with IgG below LLN at any time after baseline visit was lower in the ofatumumab group (14.2%; 134 / 944) compared to the teriflunomide group (22.9%; 214 / 934). Among completers at week 96, no patients were reported to have the protocol-specified attenuation of immunoglobulin G levels 20% below LLN [SCS Annex 1 Table C2 3.53][SCS Annex 1 - Table C2 3.5 - 3a].

[0159] Overall, there were no cases of PML or hepatitis B reactivation identified in any MS clinical trials using ofatumumab, nor any severe potential OIs such as disseminated zoster. Review of the data did not show an increase in the incidence of malignancies associated with ofatumumab treatment. The risk of malignancies remains potential for any immunomodulator, while the data show no increase in the risk of any malignancies.

[0160]

Table 3 - 1

[0161]

Table 3 - 2

[0162] overview Kesimpta (ofatumumab) may be considered under the umbrella class of B-cell depleting antibodies. However, a comprehensive analysis of data from preclinical safety and clinical trial data, including immunoglobulin and infectious AEs, Low dose subcutaneous administration; No decrease in mean serum IgG over 96 weeks of treatment compared with baseline; · Mean serum IgM levels remained well within the reference range over time; The infections noted in association with IgM decline were similar to those in patients without any decline in immunoglobulins, i.e., mostly non-severe, grade 1 or 2, and not treatment-limiting; No cytopenias were noted during ofatumumab therapy Based on these findings, we have demonstrated that ofatumumab exhibits distinct mechanisms and clinical effects compared with other anti-CD20 therapies.

[0163] As noted in the section on immune globulin, Kesimpta is given as a low subcutaneous dose on a monthly schedule, unlike other CD20 antibodies, which are given as a higher dose intravenous regimen every six months.

[0164] These major differences make it a positive outlier in terms of its impact on immunoglobulin levels.

[0165] [Example 5] long term study Patients were placed on long-term treatment and received ofatumumab 20 mg sc injections every 4 weeks (after an initial loading regimen of 20 mg sc doses at weeks 0, 1, and 2).

[0166] The duration of exposure was as follows:

[0167] [Table 4-1]

[0168] [Table 4-2]

[0169] [Table 4-3]

[0170] The population composition was as follows:

[0171] [Table 5]

[0172] result: The results for IgG and IgM levels are shown in Figures 14-17.

[0173] Figure 14 shows that IgG levels remained stable over a long-term follow-up of >4 years. This was particularly important for the lower quartile, see Figure 15.

[0174] For longer durations, a decrease in IgM levels was seen; however, levels remained above the lower limit of normal, see Figures 16 and 17.

[0175] [Example 6] 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.

[0176] method: 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).

[0177] COVID-19 cases were classified as confirmed if a positive SARS-CoV2 test result was available or if the patient reported being diagnosed with COVID-19.

[0178] Suspected COVID-19 cases were classified as suspected in the absence of a positive SARS-CoV2 test or a confirmed diagnosis.

[0179] The following COVID-19 case characteristics were assessed: Patient Demographics COVID-19 Severity Category* Duration of ofatumumab treatment and actions taken regarding ofatumumab (treatment discontinuation) Interventions and COVID-19 outcomes *Severity criteria consist of fatal, life-threatening, hospitalization, and medically significant, based on regulatory reporting rules established by the ICH for purposes of regulatory reporting obligations.

[0180] Patient characteristics: Overall population Patient demographics and drug exposure are shown in the table below: Forty-five percent (466 / 1026) of patients in the long-term group had drug exposure for 3 to 4 years. More than 90% (614 / 677) of patients in the newly switched group had 1 to 2 years of ofatumumab exposure.

[0181] [Table 6]

[0182] Results: COVID-19 Case Overview As of December 21, 2020, 35 of 1703 patients had confirmed COVID-19 infection and / or COVID-19 pneumonia in the ongoing open-label, extension ALITHIOS clinical trial of ofatumumab (Table). All non-severe cases were reported to have fully recovered. In 21 cases, no change in ofatumumab treatment was required, and in 5 cases, treatment was temporarily interrupted due to confirmed COVID-19 infection. Of the six severe cases, five had a complete recovery and in one patient, the COVID-19 outcome was fatal (details below).

[0183] A 48-year-old patient with no associated risk factors* (*relevant comorbidities such as chronic lung disease, diabetes, hypertension, or malignancy) reported symptoms of COVID-19 (pneumonia, fever, weakness, cough, and dyspnea) approximately 3 years and 7 months after 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.

[0184] [Table 7]

[0185] Results: Severe COVID-19 cases Characteristics of six severe cases of COVID-19 in patients who received ofatumumab are listed below.

[0186] [Table 8]

[0187] Conclusion: Of a total of 1,703 patients in the ongoing ALITHIOS study, 35 confirmed cases of COVID-19 infection and / or COVID-19 pneumonia have been reported. 34 cases had a complete recovery; one case had a fatal outcome. No cases were suspected to be due to ofatumumab treatment.

[0188] Based on a review of reported cases, the clinical presentation and outcomes of COVID-19 cases in pwMS on ofatumumab therapy are comparable to those 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;13(11):1601-1610) This was similar to other reports.

[0189] New patients may start therapy with ofatumumab according to local guidelines for SARS-CoV2 testing. The present invention includes the following aspects. <1> 1. A B cell and / or T cell inhibitor for use in the treatment of multiple sclerosis, said treatment comprising: (a) optionally administering a B-cell and / or T-cell inhibitor other than ofatumumab; (b) monitoring serum IgG levels; (c) if serum IgG levels are decreased, selecting ofatumumab as the B-cell and / or T-cell inhibitor. 10. A B cell and / or T cell inhibitor for use comprising: <2> In step (c), if the serum IgG level is below the lower limit of normal, ofatumumab is selected as the B-cell and / or T-cell inhibitor; <1> 2. A B cell and / or T cell inhibitor for use as described in claim 1. <3> In step (c), if the serum IgG level falls below a concentration of 900 mg / dl, ofatumumab is selected as the B-cell and / or T-cell inhibitor; <1> 2. A B cell and / or T cell inhibitor for use as described in claim 1. <4> In step (c), if the serum IgG level falls below 80% of the baseline level at the start of therapy, ofatumumab is selected as the B-cell and / or T-cell inhibitor. <1> 2. A B cell and / or T cell inhibitor for use as described in claim 1. <5> 1. A B cell and / or T cell inhibitor for use in the treatment of multiple sclerosis, said treatment comprising: (a) optionally administering a B-cell and / or T-cell inhibitor other than ofatumumab; (b) assessing the patient's predisposition to an increased risk of infection; (c) selecting ofatumumab as the B-cell and / or T-cell inhibitor if a predisposition to an increased risk of infection is identified. 10. A B cell and / or T cell inhibitor for use comprising: <6> The predisposition to bacterial, fungal, or viral infection is assessed; <5> 2. A B cell and / or T cell inhibitor for use as described in claim 1. <7> wherein the B cell and / or T cell inhibitor in step (a) is ocrelizumab or rituximab; <1> from <6> 1. A B cell and / or T cell inhibitor for use according to any one of the preceding claims. <8> Monitoring in step (b) will be conducted every 1 to 12 months; <1> from <7> 1. A B cell and / or T cell inhibitor for use according to any one of the preceding claims. <9> 1. Ofatumumab for use in the treatment of multiple sclerosis, wherein said treatment is long-term treatment and serum IgG levels are maintained within a range, said range being substantially the same as in an untreated patient. <10> The serum IgG level is in the range of 500 to 1800 mg / dl. <9> 2. Ofatumumab for use in the treatment described in claim 1. <11> Ofatumumab for use in the treatment of multiple sclerosis, wherein patients with reduced serum IgG levels are treated. <12> The reduced serum IgG level at the start of treatment is below 900 mg / dl. <11> 2. Ofatumumab for use in the treatment described in claim 1. <13> The reduced serum IgG level at the start of treatment is below the lower limit of normal. <11> or <12> 2. Ofatumumab for use in the treatment described in claim 1. <14> A change in serum IgM levels from baseline of less than 100 mg / dl <11> from <13> ofatumumab for use in any of the treatments described in any of the preceding claims. <15> Ofatumumab for use in the treatment of multiple sclerosis, wherein patients having risk factors associated with serum Ig levels, particularly serum IgG levels, are treated. <16> The risk factors are metabolic disorders, in particular obesity and metabolic syndrome; <15> 2. Ofatumumab for use in the treatment described in claim 1. <17> The risk factors are habits, in particular alcohol consumption and / or smoking; <15> 2. Ofatumumab for use in the treatment described in claim 1. <18> the risk factor is malignant tumor; <15> 2. Ofatumumab for use in the treatment described in claim 1. <19> being actively monitored for recurrence of malignancy; have known risk factors for malignancy, and / or Known active malignancy The patient is treated <18> 2. Ofatumumab for use in the treatment described in claim 1. <20> The treatment is a long-term treatment. <11> from <19> 2. Ofatumumab for use in the treatment described in claim 1. <21> Ofatumumab is administered at a dose of 10 to 30 mg every four weeks, preferably 20 mg every four weeks. <1> from <20> or ofatumumab for the use according to any of the preceding claims. <22> Ofatumumab is administered subcutaneously. <1> from <21> or ofatumumab for the use according to any of the preceding claims. <23> Ofatumumab is administered using a loading dose. <1> from <22> or ofatumumab for the use according to any of the preceding claims. <24> A loading dose of 20 mg ofatumumab will be administered at weeks 0, 1, and 2. <23> 2. A B-cell and / or T-cell inhibitor or ofatumumab for use as described in claim 1. <25> The multiple sclerosis is selected from relapsing forms of multiple sclerosis, in particular first-episode syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS). <1> from <24> B cells for use according to any one of the preceding claims and and / or T-cell inhibitors or ofatumumab. <26> The multiple sclerosis is selected from primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS), <1> from <25> or ofatumumab for the use according to any of the preceding claims. <27> A premedication is administered to the patient before the first dose of ofatumumab is administered. <1> from <26> or ofatumumab for the use according to any of the preceding claims. <28> The premedication includes acetaminophen, an antihistamine, and / or a steroid. <27> 2. A B-cell and / or T-cell inhibitor or ofatumumab for use as described in claim 1. <29> The premedication is administered 30 to 60 minutes before the ofatumumab injection. <27> or <28> 2. A B-cell and / or T-cell inhibitor or ofatumumab for use as described in claim 1. <30> No premedication will be administered before the first dose of ofatumumab. <1> from <26> or ofatumumab for the use according to any of the preceding claims. <31> Patients with acute or previous COVID-19 infection will be treated, <1> from <30> or ofatumumab for the use according to any of the preceding claims. <32> The treatment is continued for the duration of COVID-19 infection. <1> from <31> or ofatumumab for the use according to any of the preceding claims. <33> The treatment is interrupted during COVID-19 infection and continued after the infection is resolved. <1> from <31> or ofatumumab for the use according to any of the preceding claims.

Claims

1. 1. A pharmaceutical composition for use in the treatment of multiple sclerosis while maintaining serum IgG levels above 900 mg / dl, comprising: the pharmaceutical composition comprises ofatumumab; The pharmaceutical composition, wherein the treatment is a long-term treatment for more than two years.

2. 1. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising: The pharmaceutical composition comprises ofatumumab as a B-cell and / or T-cell inhibitor; The treatment comprises: (a) administering a B-cell and / or T-cell inhibitor other than ofatumumab, wherein said B-cell and / or T-cell inhibitor other than ofatumumab is selected from the group consisting of ocrelizumab, rituximab, obinutuzumab, ublituximab, cladribine, fingolimod, natalizumab, and teriflunomide; (b) monitoring serum IgG levels; (c) if serum IgG levels are decreased, administering ofatumumab as said B-cell and / or T-cell inhibitor. A pharmaceutical composition comprising:

3. 3. The pharmaceutical composition of claim 2, wherein in step (c), ofatumumab is administered if the serum IgG level falls below the lower limit of normal.

4. 3. The pharmaceutical composition of claim 2, wherein in step (c), ofatumumab is administered if the serum IgG level falls below a concentration of 900 mg / dl.

5. 3. The pharmaceutical composition of claim 2, wherein in step (c), ofatumumab is administered if serum IgG levels fall below 80% of baseline levels at the start of therapy.

6. 1. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising: The pharmaceutical composition comprises ofatumumab as a B-cell and / or T-cell inhibitor; The treatment comprises: (a) administering a B-cell and / or T-cell inhibitor other than ofatumumab, wherein said B-cell and / or T-cell inhibitor other than ofatumumab is selected from the group consisting of ocrelizumab, rituximab, obinutuzumab, ublituximab, cladribine, fingolimod, natalizumab, and teriflunomide; (b) assessing the patient's predisposition to an increased risk of infection; (c) if a predisposition to an increased risk of infection is identified, administering ofatumumab as said B-cell and / or T-cell inhibitor. A pharmaceutical composition comprising:

7. The pharmaceutical composition of claim 6, wherein the predisposition to bacterial, fungal, or viral infection is assessed.

8. 8. The pharmaceutical composition of claim 2, wherein the B-cell and / or T-cell inhibitor in step (a) is ocrelizumab or rituximab.

9. The pharmaceutical composition of any one of claims 2 to 5 or claim 8, wherein the monitoring in step (b) is performed every 1 to 12 months.

10. The pharmaceutical composition according to any one of claims 6 to 8, wherein the assessment in step (b) is carried out every 1 to 12 months.

11. 1. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising: the pharmaceutical composition comprises ofatumumab; The pharmaceutical composition, wherein the treatment is a long-term treatment, and serum IgG levels are maintained within a range, the range being substantially the same as that in untreated patients.

12. The pharmaceutical composition of claim 11, wherein the serum IgG level is in the range of 500 to 1800 mg / dl.

13. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising: the pharmaceutical composition comprises ofatumumab; The pharmaceutical composition is used to treat patients with depressed serum IgG levels.

14. 14. The pharmaceutical composition of claim 13, wherein the reduced serum IgG level at the start of treatment is below 900 mg / dl.

15. 15. The pharmaceutical composition of claim 13 or 14, wherein the reduced serum IgG level at the start of treatment is below the lower limit of normal.

16. 16. The pharmaceutical composition of any one of claims 13 to 15, wherein the change in serum IgM levels from baseline is less than 100 mg / dl.

17. A pharmaceutical composition for use in the treatment of multiple sclerosis, comprising: the pharmaceutical composition comprises ofatumumab; The pharmaceutical composition, wherein a patient having risk factors associated with serum Ig levels is treated.

18. The pharmaceutical composition described in claim 17, wherein a patient having risk factors associated with serum IgG levels is treated.

19. The pharmaceutical composition according to claim 17 or 18, wherein the risk factor is a metabolic disorder.

20. The pharmaceutical composition described in claim 19, wherein the metabolic disorder is obesity and metabolic syndrome.

21. The pharmaceutical composition of claim 17 or 18, wherein the risk factor is a habit.

22. The pharmaceutical composition described in claim 21, wherein the habit is alcohol consumption and / or smoking.

23. The pharmaceutical composition of claim 17 or 18, wherein the risk factor is malignant tumor.

24. A method for treating a patient with known risk factors for malignant tumors. Patients are treated who are actively monitored for recurrence of malignant tumors; and / or Patients with known active malignancies are treated, 24. The pharmaceutical composition of claim 23.

25. A pharmaceutical composition for use in the treatment of multiple sclerosis in a patient in need thereof, comprising: the pharmaceutical composition comprises ofatumumab; the patient has been treated with an earlier disease-modifying therapy other than ofatumumab; the patient's serum IgG level is below a concentration of 900 mg / dl; the treatment is continued with ofatumumab as the disease-modifying therapy; Pharmaceutical compositions.

26. a) the early disease-modifying therapy is a B-cell depletion therapy; b) the early disease-modifying therapy is anti-CD20 therapy; or c) the early disease-modifying therapy is ocrelizumab or rituximab; 26. The pharmaceutical composition of claim 25.

27. 27. A pharmaceutical composition comprising ofatumumab for use in treatment according to any one of claims 13 to 26, wherein the treatment is a long-term treatment, optionally for more than 2 years.

28. 28. The pharmaceutical composition of any one of claims 1 to 27, wherein ofatumumab is administered at a dose of 10 to 30 mg every 4 weeks.

29. The pharmaceutical composition of claim 28, wherein ofatumumab is administered at a dose of 20 mg every four weeks.

30. 30. The pharmaceutical composition of any one of claims 1 to 29, wherein ofatumumab is administered subcutaneously.

31. 31. The pharmaceutical composition of any one of claims 1 to 30, wherein ofatumumab is administered using a loading dose.

32. 32. The pharmaceutical composition of claim 31, wherein 20 mg ofatumumab is administered as a loading dose at weeks 0, 1, and 2.

33. 33. The pharmaceutical composition of any one of claims 1 to 32, wherein the multiple sclerosis is selected from relapsing forms of multiple sclerosis.

34. The pharmaceutical composition described in claim 33, wherein the multiple sclerosis is selected from first-episode syndrome (CIS), relapsing-remitting multiple sclerosis (RRMS), and secondary progressive multiple sclerosis (SPMS).

35. 33. The pharmaceutical composition of any one of claims 1 to 32, wherein the multiple sclerosis is selected from primary progressive multiple sclerosis (PPMS) or progressive relapsing multiple sclerosis (PRMS).

36. 36. The pharmaceutical composition of any one of claims 1 to 35, wherein premedication is administered to the patient before the first dose of ofatumumab is administered.

37. 37. The pharmaceutical composition of claim 36, wherein the premedication comprises acetaminophen, an antihistamine, and / or a steroid.

38. 38. The pharmaceutical composition of claim 36 or 37, wherein the premedication is administered 30 to 60 minutes prior to injection of ofatumumab.

39. 36. The pharmaceutical composition of any one of claims 1 to 35, wherein no premedication is administered before the first dose of ofatumumab is administered.

40. 40. The pharmaceutical composition of any one of claims 1 to 39, for treating patients acutely or previously infected with COVID-19.

41. 41. The pharmaceutical composition of any one of claims 1 to 40, wherein the treatment is continued for the duration of COVID-19 infection.

42. 41. The pharmaceutical composition of any one of claims 1 to 40, wherein the treatment is interrupted during COVID-19 infection and continued after overcoming the infection.

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