Ofatumumab for treating MS while preserving serum IgG

Abstract

The present invention provides an improved treatment strategy for multiple sclerosis (MS) patients, particularly for long-term treatment, and in particular provides a B-cell depleting MS therapy without unduly affecting serum levels of immunoglobulins. [Solution] A B cell and / or T cell inhibitor for use in the treatment of multiple sclerosis, the treatment comprising the steps of: (a) optionally administering a B cell and / or T cell inhibitor other than ofatumumab; (b) monitoring serum IgG levels; and (c) selecting ofatumumab as the B cell and / or T cell inhibitor if the serum IgG levels decrease.

Description

[Technical Field]

[0001] The present invention relates to ofatumumab for use in the treatment of multiple sclerosis (MS), Treatment is long-term, and serum IgG levels are maintained within a range similar to that of untreated patients. The invention further relates to B-cell and / or T-cell inhibitors for use in the treatment of MS. wherein said treatment includes steps of monitoring serum IgG levels, and If bell is decreased, ofatumumab is the B-cell and / or T-cell inhibitor of choice. and / or said treatment comprises a step of treating a patient predisposed to an increased risk of infection. and if a predisposition is identified, administering ofatumumab to B-cell and / or or a T cell inhibitor. The present invention is useful for treating multiple sclerosis. Further, with respect to ofatumumab for use in patients with reduced serum IgG levels, Patients were treated and / or risk factors associated with serum Ig levels, especially serum IgG levels A patient with a child is treated. [Background technology]

[0002] Multiple sclerosis (MS) is characterized by inflammation, demyelination, and axonal / neuronal destruction. It is a chronic immune-mediated disease of the central nervous system that can lead 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. ) is available.

[0003] Most disease-modifying therapies for MS have traditionally been directed via T cell-based mechanisms. Although these DMTs have been conceptualized as acting on B cells, they also have clear effects on B cells. A common theme is that the majority of patients are resistant to HIV-1, rather than memory or plasmablasts. Promoting naive B cells (alemtuzumab); anti-inflammatory tone of B cell cytokines Transition of steroids (beta interferon, glatiramer acetate, fingolimod); Increasing B-reg (beta interferon, glatiramer acetate, fingolimod) Modified methyl fumarate and dimethyl fumarate); Class II MHC on B cells required for antigen presentation Reducing the expression and costimulatory molecules (beta interferon and dimethicone fumarate) sequestering B cells in lymphoid organs (fingolimod); VLA-4 mediators to the CNS blocking mediated B cell trafficking (natalizumab); or direct B cell lysis (alemtuzumab, teriflunomide, mitoxantrone), Greenfield et al ., Ann Neurol. 2018 January; 83(1): 13-26.

[0004] Greenfield and Greenfield have developed monoclonal antibodies (mAbs) that are anti-CD20 antibodies. ) rituximab, ocrelizumab, and ofatumumab are currently in clinical use for MS. It further reports that it is in use.

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

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

[0007] A fully human monoclonal antibody approved for refractory chronic lymphocytic leukemia Ofatumumab produces greater CDC than ADCC activity and is administered intravenously rather than intravenously. It is the only anti-CD20 mAb currently being investigated using a sub-dosing regimen.

[0008] Other anti-CD20 mAbs target part of the same CD20 epitope as rituximab. designed to target the ATP-dependent ATPase but induce more cell death due to its on / off binding kinetics. Obinutuzumab, a humanized IgG1, and all Fcγ RIIIa receptors glycoengineered for higher affinity to receptors, especially low C In cells with D20 expression, AD was greater than with rituximab and ofatumumab and ublituximab, an anti-CD20 antibody that results in CC.

[0009] However, treatment with B cell depletion therapy has not been shown to reduce the production of immunoglobulins IgG, IgM, and It has been reported that this may result in a decrease in serum levels of IgA and / or IgA. January 25th, 2018, "8.Heidelberger Patiententag" Dr. See the presentation by B. Wildemann. The decrease in IgG levels is It has been reported that IgM levels increase the risk of infection by threefold. It has been reported that MS therapy is usually lifelong. You need to keep that in mind.

[0010] For example, under therapy with RTX (rituximab), patients experience increased serum IgG and and experienced a significant time-dependent decrease in IgM levels (IgG: p = 2.2 × 10 -5 , I gM:p=4.0×10 -4 The overall IgG level was 5.1% per year, and the IgM level was The bell decreased by 5.0%, Klein et al., ECTRIMS Online Library, 09 / 13 / 19; 278658; P See 1618.

[0011] T. Derfuss et al. ("Serum immunoglobulin levels and risk of serious infecti ons in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and the ir open-label extensions", ECTRIMS Online Library. Derfuss T. 09 / 11 / 19; 279399; 65) assessed serum Ig levels over a 5.5-year period. They found an increased rate of severe infections. We observed a decrease in serum Ig levels, with a clear association with IgG. The effect of IgA on serum Ig levels was most pronounced, and less so for IgM or IgA. The decline progressed at an approximate average rate of 3-4% per year (see Figure 5). There was a clear association between decreased levels of G and severe infection.

[0012] Additionally, the ocrelizumab prescribing information notes the association between immunoglobulin decline and severe infections. It states: "Treatment with Ocrevus is primarily due to a decrease in IgM. This resulted in a decrease in overall immunoglobulins over the controlled period of the study, driven by the steroid hormone. Clinical trial data show a reduction in IgG levels (less so for IgM or IgA). "This study shows an association between flu-like symptoms (not related to the flu) and severe infection."

[0013] In summary, the most common side effects associated with B cell depletion therapies such as ocrelizumab in clinical trials are One common adverse event is a decrease in serum immunoglobulins (e.g., IgG). In the long term, the decline in serum immunoglobulin levels is significant and undesirable. Not likely.

[0014] Therefore, the problem underlying the present invention is to provide a solution to the problem of MS patients, especially for long-term treatment. The goal is to provide improved therapeutic strategies, particularly for serum levels of immunoglobulins. It is an object of the present invention to provide a B cell depletion MS therapy without unnecessarily affecting It was.

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

[0016] Ofatumumab therapy is intended to be effective insofar as it is known from the prior art in combination with immunoglobulins (e.g. It has advantages over other B cell depletion therapies because it does not cause a decrease in B cell levels (e.g., IgG). This is quite surprising, as it results in the absence or amelioration of negative effects on the immune system. opens up new avenues for patients on long-term treatment, which are explained in more detail below. This is an important clinical benefit. Summary of the Invention

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

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

[0019] In the context of the present invention, a "treatment-naive patient" is a patient with MS or a first episode of MS. diagnosed with clinically isolated syndrome (CIS) and B-cell and In a preferred embodiment, untreated refers to a patient who is not receiving a T-cell inhibitor. Patients should have a blood glucose level of 500-1800 mg / dl, especially 700-1600 mg / dl, and more especially 90 IgG levels in the range of 0 to 1400 mg / dl are presented. 00mg / dl, 550mg / dl, 600mg / dl, 650mg / dl, 700mg / dl, 750mg / dl, 800mg / dl, 850mg / dl, 900mg / dl? The maximum levels were 1400mg / dl, 1500mg / dl, 1600mg / dl, and 1700mg / dl, presenting with an IgG level of 1800 mg / dl.

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

[0021] Yet another subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis. and patients with risk factors associated with serum Ig levels, especially serum IgG levels, are cured. Be treated.

[0022] In one embodiment of the present invention, ofatumumab is administered to patients with active HBV infection, particularly B confirmed by positive results for hepatitis surface antigen [HBsAg] and anti-HBV tests It is not given to patients with active HBV infection. Negative for HBsAb and positive for hepatitis B core antibody [HBcAb+], or HB It may or may not be administered to [HBsAg+] patients who are carriers of V. 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 The present invention relates to the treatment of relapsing forms of multiple sclerosis (RMS). In particular, the present invention relates to the treatment of relapsing-remitting multiple sclerosis (RMS). Alternatively, the present invention relates to the treatment of secondary progressive MS (SPMS). Alternatively, the present invention relates to the treatment of first episode syndrome (CIS). ). Again further alternatively, the present invention relates to the treatment of primary progressive multiple sclerosis (PPMS). ) or for the treatment of progressive relapsing multiple sclerosis (PRMS).

[0024] Generally, in step (a) of using the treatment, B-cell and and / or a T cell inhibitor may be administered.

[0025] In general, B-cell and / or T-cell inhibitors other than ofatumumab or inhibit T cell activity and are suitable as disease-modifying treatments (DMTs) for multiple sclerosis. It can be any drug that inhibits B cell and / or T cell activity. and / or T cell inhibitors can result in depletion of B cells and / or T cells, or or otherwise interfere with B cell and / or T cell activity. Examples of approved drugs include ocrelizumab, rituximab, obinutuzumab, and uvexamin. It is brituximab.

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

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

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

[0029] In a preferred embodiment, IgG and IgM are monitored. In particular, IgG will be monitored.

[0030] Generally, monitoring involves measuring the respective serum Ig levels, preferably periodically. In a preferred embodiment, serum Ig levels can be measured, for example, monthly. Measurements may be taken every two months, every three months, every six months, or annually. In such cases, monitoring in step (b) should be conducted every 1-12 months, especially every 3-9 months. IgG levels should be monitored by the treating neurologist, for example, during a routine visit. Thus, it can be determined.

[0031] In the first aspect of the present invention, in step (c), if the serum IgG level is decreased , ofatumumab is selected as a B-cell and / or T-cell inhibitor. If serum IgG levels are unnecessarily low, the treatment of MS should consist of ofatumumab as a DMT. In a preferred embodiment of the present invention, the method is carried out or continued using ofatumumab. has only one active ingredient for treating MS, the only disease-modifying drug administered. is administered in step (c).

[0032] According to the present invention, "decreased serum IgG level" and "unnecessarily low serum IgG level" "Decreased serum IgG levels" and "decreasing serum IgG levels" refer to 0mg / dl, 850mg / dl, 800mg / dl, 750mg / dl, 700mg / dl, 650mg / ml, 600mg / dl, 550mg / dl, or 500mg / Serum IgG levels below the concentration of dl and / or serum Ig below the lower limit of normal G levels, and / or 80% of baseline levels at the start of DMT therapy, % or 60% or less than 50%.

[0033] In a preferred embodiment, in step (c), the serum IgG level is 900 mg / mL or more. dl, 850mg / dl, 800mg / dl, 750mg / dl, 700mg / dl, 6 Concentrations of 50mg / ml, 600mg / dl, 550mg / dl, or 500mg / dl If the serum creatinine level is lower than 0.05, ofatumumab is used.

[0034] In a preferred embodiment, in step (c), the serum IgG level is determined to be If the blood glucose level falls below the lower limit of normal, called the normal limit, ofatumumab is used.

[0035] Generally, the lower limit of normal (LLN) for IgG, IgA, and IgM is IgG=7 00mg / dl or 565mg / dl, IgM=40mg / dl, and IgA=70 It may be specified as mg / dl.

[0036] Consequently, serum IgG levels of <700 mg / dl or <565 mg / dl , serum IgG levels below LLN, and serum IgM levels <40 mg / dl are L A serum IgM level below LN and a serum IgA level of <70 mg / dl indicates LLN. In a preferred embodiment, in step (c), the serum IgA level is Serum IgG levels were 80% or 70% higher than baseline levels at the start of DMT therapy. If the response rate is above 60% or below 50%, ofatumumab is not associated with B-cell and / or In other words, serum Ig levels are measured at the start of DMT. The serum IgG level, in particular, should be measured at the start of DMT and set as a baseline value. The measured level is set as the baseline value, particularly less than 80%, 70%, 60%, or 50% below the baseline level When it comes to treatment, ofatumumab is the DMT of choice.

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

[0038] Patient background information on increased risk of infections, including bacterial, fungal, and viral infections Methods for assessing factors are well known in the art. For assessing a patient's predisposition to the disease, preferably immunoglobulin levels are indicative.

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

[0040] Another subject of the present invention is the use of Ofatum for the treatment or prevention of multiple sclerosis. ofatumumab is preferably a B-cell and / or It is used in patients who have been treated with a T cell inhibitor. and a method for treating or preventing multiple sclerosis, the method comprising administering to a subject suffering from multiple sclerosis The method comprises administering ofatumumab to a patient suffering from the disease, said patient preferably receiving ofatumumab. have received B-cell and / or T-cell inhibitors other than ibuprofen;

[0041] In general, B-cell and / or T-cell inhibitors other than ofatumumab have not shown early disease modification. This may be considered a DMT, which in a preferred embodiment of the present invention involves a patient receiving: This means that patients can switch from early DMT to ofatumumab. or administration of B-cell and / or T-cell inhibitors other than ofatumumab. Thus, the present invention relates to ofatumumab for use in treating or preventing multiple sclerosis. Regarding the use of ofatumumab in patients transitioning from disease-modifying therapy, , preferably including the administration of a B-cell and / or T-cell inhibitor other than ofatumumab.

[0042] In a preferred embodiment, early DMT provides stable Ig, e.g., IgG levels. In particular, early DMTs can cause side effects, especially during long-term treatment. This leads to decreased Ig levels, e.g., IgG levels, so patients are switched.

[0043] As mentioned above, the subject of the present invention is an ofatum for use in the treatment of multiple sclerosis. The treatment is long-term, and serum IgG levels are maintained within a certain range. The range is essentially the same as in untreated patients.

[0044] In a preferred embodiment, the serum IgG level range is 500 to 1800 mg / d l, particularly 700 to 1600 mg / dl, more particularly 900 to 1400 mg / dl. As stated, the subject of the present invention is ofatumumab for use in the treatment of multiple sclerosis. and patients with depressed serum IgG levels are treated.

[0045] In a preferred embodiment, the reduced serum IgG level at the start of treatment is 90 Better than 0mg / dl, better than 850mg / dl, better than 800mg / dl, better than 750mg / dl 700mg / dl, 650mg / dl, 600mg / dl, 550mg In another preferred embodiment, the treatment is The decreased serum IgG at the start of treatment is below the lower limit of normal.

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

[0047] As mentioned above, the subject of the present invention is an ofatum for use in the treatment of multiple sclerosis. Mab and patients with risk factors associated with serum Ig levels, especially serum IgG levels is treated.

[0048] According to the present invention, risk factors associated with serum Ig levels, particularly serum IgG levels, include obesity, metabolic disorders such as obesity and / or metabolic syndrome; or alcohol use and and / or habits such as smoking.

[0049] In a preferred embodiment, the risk factors are drugs, particularly alcohol and / or nicotine Related to penis abuse.

[0050] In a preferred embodiment of the present invention, an offer for use in treating MS is Ofatumumab is used in long-term treatment. The term long-term treatment refers to the long-term use of ofatumumab. For example, ofatumumab is used for 2 years, 3 years, It can be used for longer than 4, 5, or 10 years. Ofatumumab can be used for up to 5, 10, or It can be used for a year, 15 years, 20 years, or a lifetime.

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

[0052] Preferably, ofatumumab is administered parenterally, e.g., epidermally, intravenously, intramuscularly, intraarterially, Intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intraarticular, For 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 invention, ofatumumab is administered using a loading dose. The term loading dose is defined below. In a preferred embodiment, ofatumumab therapy Three loading doses are administered, preferably at weeks 0, 1, and 2, after initiating the regimen. This means that the first loading dose at week 0 constitutes the start of therapy. In an alternative preferred embodiment, on day 1 after initiating ofatumumab therapy, On days 12-9, preferably 7, and 12-16, preferably 14, Two loading doses are administered. This means that the first loading dose on day 1 marks the start of therapy. This means that...

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

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

[0056] In a preferred embodiment of the invention, before the first dose of ofatumumab is administered: A premedication is administered to the patient. Preferably, the premedication is acetaminophen, an antihistamine, or The compounds include compounds selected from drugs, and steroids. Methylprednisolone is a preferred steroid. steroids. 100 mg iv may be a preferred dose. Premedication is preferred. 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. I can't.

[0058] In a preferred embodiment of the present invention, relapsing multiple sclerosis is a disease that has progressed from the first episode Clinically Significant Inflammatory Syndrome (CIS) or Relapsing-Remitting Multiple Sclerosis (RRMS) or Secondary Progressive Multiple Sclerosis (SSMS) These terms are defined below.

[0059] In a preferred embodiment of the invention, ofatumumab is the only In other words, ofatumumab is preferably administered as a single active ingredient. It is the only disease-modifying drug approved for this purpose.

[0060] In a preferred embodiment, ofatumumab is administered without regard to weight, sex, age, race, or background. For example, a 35-year-old woman weighing 60 kg may receive IV steroids regardless of the patient's B cell count. Preferably, each gender receives the same dose as a 50-year-old man weighing 90 kg. Weight, sex, age, race, or baseline B-cell count may have an effect on the pharmacokinetics of ofatumumab. It has no clinically meaningful effect.

[0061] In a preferred embodiment, ofatumumab is administered to patients with a reduced risk of side effects, such as malignancies, severe infusion Early DMT, e.g., anti-CD20 therapy, due to side effects such as related reactions or recurrent infections It is administered to patients who have discontinued or interrupted, preferably discontinued,

[0062] For example, compared to a control group, patients treated with ocrelizumab (Ocrevus®) In clinical trials in patients receiving steroids, an increased number of malignancies (including breast cancer) have been observed. The Ocrevus SmPC provides an individual benefit / risk profile for aggressive treatment of recurrent malignancies. We recommend that this be considered in patients who are being monitored for known active malignancies. Patients with uterine tumors 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 It has been reported that leukemia is associated with a decrease in immunoglobulins (e.g., IgG). In the present study, ofatumumab therapy was shown to be effective against rheumatoid arthritis, as it was associated with prolonged immunoglobulin (e.g., It has advantages over other B cell depletion therapies because it does not cause a decrease in IgG. It was surprisingly discovered that this opens up new avenues for patients undergoing long-term treatment. .

[0064] Therefore, in a preferred embodiment of the invention, ofatumumab is used in the treatment of MS. In use, ofatumumab is administered to patients with known risk factors for malignancy. In another preferred embodiment of the invention, ofatumumab is used in the treatment of MS. ofatumumab is administered to patients who are actively monitored for recurrence of their malignant tumor. In an alternative embodiment of the invention, ofatumumab is used in the treatment of MS. ofatumumab is administered to patients with known active malignancies.

[0065] MSIS-29 (see definition below) is a patient-specific data set suitable for clinical and epidemiological studies. A clinically useful and scientifically valid measure of the impact of MS from the patient's perspective. It is a disease severity indicator used to improve our understanding of the impact of MS. Reliable, valid, and responsive patient-reported outcomes (PROs) that complement other indicators of disease severity cam) is considered to be an evaluation criterion.

[0066] In the present invention, the administration of ofatumumab is performed to evaluate the MS Impact Scale MSIS-2 as defined below. It was unexpectedly found that this leads to a beneficial reduction in 9. Reference is made to the Experimental section below.

[0067] In this regard, a further subject of the present invention is the use of hydroxybenzoates in the treatment or prevention of relapsing forms of multiple sclerosis. ofatumumab for use in reducing MSIS-29 scores Preferably, ofatumumab will improve MSIS-29 scores by at least 24 months. at least 1.5, more preferably at least 2.0, and even more preferably at least 2.5 The reduction can be up to 3.0 or 3.5 or 4.0.

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

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

[0070] When the composition is administered by injection, sterile injections are used so that the ingredients can be mixed prior to administration. An ampoule of injection water or saline may be provided.

[0071] In one embodiment, the formulation of ofatumumab is described in WO 2009 / 00940 It can be formulated according to the formulations disclosed in pamphlet No. 7.

[0072] In one embodiment, ofatumumab is administered at a dose of about 20-300 mg / mL. mL, 50~300mg / mL, 100~300mg / mL, 150~300mg / mL , 200 to 300 mg / mL, or 250 to 300 mg / mL, preferably 50 mg / The antibody formulation is present in an amount of 0.1 ml.

[0073] In one embodiment, ofatumumab is administered in a formulation containing 10 to 100 mM sodium acetate. 25-100 mM sodium chloride, 0.5-5% arginine free base, 0.02-0 Contains .2mM EDTA, 0.01-0.2% polysorbate 80, pH 5.0-7. 0. Preferably, the ofatumumab formulation is formulated into an antibody formulation adjusted to 50 m M sodium acetate, 51 mM sodium chloride, 1% arginine free base, 0.05 mM Contains EDTA, 0.02% polysorbate 80, and is adjusted to pH 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 preferably be waited until the next scheduled dose. The first dose should be administered as soon as possible without delay. Subsequent doses should be administered at the recommended intervals. should be given.

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

[0077] In a preferred embodiment, ofatumumab injection is sterile, preservative-free, for subcutaneous use. Preferably, each 20 mg / 0.4 mL prefilled pen or The pre-filled syringe delivers 0.4 mL of solution. Preferably, each 0.4 mL contains: 20 mg ofatumumab and arginine (4 mg), edetate disodium (0.0 07mg), Polysorbate 80 (0.08mg), Sodium acetate trihydrate (2.72mg) 2 mg), sodium chloride (1.192 mg), and water for injection having a pH of 5.5, Contains USP. Hydrochloric acid may be added to adjust the pH.

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

[0079] In a preferred embodiment, the formulation is administered subcutaneously in the abdomen, thigh, or outer upper arm. In a preferred embodiment, the preparation is applied to moles, scars, or tender skin. Do not administer to areas that are broken, red, hard, or not intact.

[0080] In one embodiment, the first injection of the ofatumumab formulation is administered under the supervision of a healthcare professional. If an injection-related reaction occurs, symptomatic treatment is recommended. Alternatively, the prefilled syringe is preferably removed from the refrigerator and left for, for example, about 15 to 30 minutes. In a preferred embodiment, the ofatumumab preparation of the present invention is The formulation is a clear to slightly opalescent and colorless to slightly brownish formulation that can be used as follows: The resulting yellow solution: Injectable solutions: in single-dose prefilled pens, e.g., Sensoready® pens 20 mg / 0.4 mL 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 is administered In this state, the concentration is about 400 to 550, more preferably 450 to 500, for example 483 mcg h / Mean AUC in mL tau and / or 1.0 to 2.5, more preferably 1.2 to 1 .7, e.g., a mean C of 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 was It 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 a preferred embodiment of the invention, ofatumumab is administered to patients with rheumatoid arthritis, preferably in adults. including first-episode syndrome, relapsing-remitting disease, and active secondary progressive disease; It is administered for the treatment of relapsing forms of multiple sclerosis (MS).

[0084] In a preferred embodiment of the invention, ofatumumab administration is administered to treat an active infection, such as CO In patients with VID-19, treatment is delayed until the infection has resolved. Tumors can be administered during an infection, such as during a COVID-19 infection. Administration of atatumumab may be continued for the duration of the infection, for example, for the duration of a COVID-19 infection.

[0085] In another preferred embodiment of the invention, at the time of initiation of treatment with ofatumumab Immunoglobulin levels during and after treatment are monitored until B cell repletion and clinically indicated. If the patient develops a severe opportunistic or recurrent infection, If immunoglobulin levels indicate immune deficiency, discontinue ofatumumab treatment. is taken into consideration.

[0086] A further subject of the present invention is a method for treating multiple sclerosis, said treatment comprising: (a) providing a patient in need thereof with, optionally and preferably, a B-cell and / or anti-cancer agent other than ofatumumab; and / or administering a T cell inhibitor; (b) monitoring serum Ig levels, in particular serum IgG levels; (c) If serum IgG levels decrease, administer ofatumumab to B and / or T cells. Selecting and administering as a cell inhibitor and / or The treatment comprises: (a) providing a patient in need thereof with, optionally and preferably, a B-cell and / or anti-cancer agent other than ofatumumab; and / or administering a T cell inhibitor; (b) assessing the patient's predisposition to an increased risk of infection; (c) If a predisposition to an increased risk of infection is identified, administer ofatumumab to B-cell and / or or a 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 a long-term treatment. , serum IgG levels are maintained throughout treatment.

[0088] 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, A patient with a bell is treated.

[0089] 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, and measuring serum Ig levels, in particular Patients with risk factors associated with serum IgG levels are treated.

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

[0091] definition The terms "treatment" or "treating" are used when the purpose is to treat a disease, such as multiple sclerosis (MS). Eliminate, reduce, or alleviate symptoms in patients, e.g., ofatumumab In particular, the term "treatment" can be defined as the application or administration of a Achieving a clinically meaningful response, e.g., a clinically meaningful annual relapse rate when treating RMS This involves achieving a certain reduction.

[0092] As used herein, a patient is defined as a person who has suffered a medical condition due to such treatment. A person may "need" treatment if they would benefit financially or in terms of quality of life. .

[0093] As used herein, the term "patient" refers to a mammal, e.g., a primate, preferably a are higher primates, particularly preferably humans (e.g., those at risk as described herein). The patient may be a patient at risk of having the disorder. Preferably, the patient is an adult. This includes elderly patients, however, patients between the ages of 18 and 60 are preferred. As used herein, the terms "administering" or "administration" ofatumumab The term can mean providing ofatumumab to a patient in need of treatment. Administration "in combination with" multiple further therapeutic agents can occur in any order and via any administration route. This includes simultaneous (concurrent) and sequential administration in the same route.

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

[0095] The term "adverse event" (AE) does not necessarily have a causal relationship with this treatment. any untoward events in patients or in clinical trials in which subjects are administered a pharmaceutical product An adverse event (AE) can be related to a medical occurrence. Therefore, an adverse event (AE) is an event that is related to a medical (investigational) product. Any undesirable use of a medical (investigational) product, whether or not it is The abnormality may be an unexpected and unintended sign (including abnormal laboratory findings), symptom, or disease.

[0096] The phrase "therapeutic regimen" refers to a treatment or therapy for the treatment of a disease state or condition. It can refer to the regimen used to prevent the onset of a disease, for example, the medication used. Therapeutic regimens may include induction regimens, loading regimens, and maintenance regimens.

[0097] RRMS Relapsing-remitting multiple sclerosis (RRMS) should be treated with steroids, preferably in the absence of fever or infection. as a new neurological deficit or episode of neurological deterioration lasting longer than 24 hours It may be characterized by defined recurrences.

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

[0099] RMS The term RMS (relapsing multiple sclerosis) is used to refer to RRMS, SPMS, and first-episode multiple sclerosis. This includes the syndrome consisting of swords (CIS).

[0100] Primary progressive MS (PPMS) PPMS is characterized by early relapses or episodes of symptoms that lead to a deterioration of neurological function (physical function). PPMS may be characterized by an accumulation of physical impairments (e.g., schizophrenia, dizziness ... recurrence and / or new MRI evidence of disease) or inactivity, and progressive (with or without recurrence or new MRI activity, or changes over time) Further characterized as either no progression (evidence of disease worsening on objective criteria) or no progression Reference is made to Lublin 2014.

[0101] The experience of each person with PPMS will be unique. PPMS can occur in recurring or new Short periods of stable disease with or without MRI activity, as well as new There may be periods of increased disability with or without new relapses or lesions.

[0102] Secondary progressive MS (SPMS) SPMS follows an initial relapsing-remitting course. Most people diagnosed with RRMS People with secondary progressive dementia have progressive deterioration of neurological function over time (accumulation of disability). SPMS may be active (relapses and / or with new MRI evidence of activity) or inactivity, as well as progression ( Evidence of disease worsening or progression on objective measures of change over time, with or without recurrence These may be further characterized as either line-free or line-free. Reference is made to Lublin 2014.

[0103] The experience of each person with SPMS will be unique. SPMS is a type of relapsing-remitting MS. Disability is assessed with or without evidence of disease activity (relapse or MRI changes). SPMS is characterized by occasional relapses and periods of stability. You can.

[0104] recurrence Relapse is defined as a new neurological deficit or neurological deterioration lasting preferably longer than 24 hours. In other words, a recurrence can be defined as an episode of A discrete episode of neurological dysfunction lasting for a period of time (known in the art as a "seizure," "flare" or "insult"). A relapse can usually be followed by a complete relapse (also called a "relapse" or "exacerbation"). Complete or partial recovery, followed by a period of no progression of symptoms or accumulation of disability (remission) .

[0105] As used herein, a "B cell inhibitor" generally refers to a compound that abolishes biological B cell function. B-cell inhibitors can refer to any substance that increases, decreases, or weakens the activity of biological B cells. necessary for cellular function, e.g., cytokine secretion or response to cis and / or trans stimuli B cell inhibitors can disrupt the signal transduction pathway that is essential for the production of B cells from stem / progenitor cells. It may also interfere with the production of B cells or negatively affect their maturation. Inhibitors may act by blocking crosstalk with other cell populations, such as T cells Alternatively, B cell inhibitors may be secreted by sequestration (e.g., into lymphoid tissues such as the spleen) or or by lysis, e.g., through CDC, ADCC, phagocytosis, or other processes, of B cells. Some subsets of B cells can express CD20.

[0106] As used herein, B cells refer to one type of white blood cell of the lymphocyte subtype. B cells can secrete antibodies such as immunoglobulins (e.g., IgG) to B cells function in the humoral immune component of the adaptive immune system. Additionally, B cells present antigens and B cells are distinct from T cells and natural killer cells and can secrete cytokines. They express the B cell receptor (BCR) on their cell membrane. It is capable of binding to antigens, against which it initiates an antibody response.

[0107] As used herein, a T cell inhibitor is an agent that abolishes or reduces biological T cell function. T cell inhibitors may refer to any substance that inhibits and / or attenuates biological T cell function, e.g., required for cytokine secretion or response to cis and / or trans stimuli T cell inhibitors can disrupt signal transduction pathways. Furthermore, T cell inhibitors may interfere with or negatively affect their maturation. Alternatively, they may act by inhibiting crosstalk with other cell populations, such as B cells. In particular, T cell inhibitors can be expressed by sequestration (e.g., in lymphoid tissues such as the spleen) or by, for example, Depletion of T cells, for example by lysis through CDC, ADCC, phagocytosis, or other processes It is possible.

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

[0109] First-episode syndrome (CIS): First-episode syndrome (CIS) is a central symptom suggestive of multiple sclerosis (MS). It can refer to a single clinical episode of central nervous system (CNS) inflammatory demyelinating symptoms. CIS presentation is unifocal or multifocal, typically involving the optic nerves, brainstem, cerebellum, spinal cord, or cerebral hemispheres. Ru. Miller et al, Clinically isolated syndromes, Lancet Neurol. 2012;11:157-169 Reference is made to

[0110] Multiple Sclerosis Impact Scale (MSIS-29) The MSIS-29 Version 2 is a 29-item questionnaire covering two domains: physical and psychological. The questionnaire was self-administered. Responses were on a 4-point scale ranging from 1 (not at all) to 4 (extremely). It is captured on an ordinal scale of symptoms, with higher scores reflecting greater impact on daily life. The MSIS-29 takes about five minutes to complete and questions are asked about their daily routines over the past two weeks. Designed to assess patients' views of the impact of MS on their lives. Hobart J and C ano 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), "T he Multiple Sclerosis Impact Scale (MSIS-29): a new patient-based outcome measure e", Brain; 124(Pt 5):962-73.

[0111] Ofatumumab: Ofatumumab is a human monoclonal antibody directed against the CD20 protein. Fatima specifically binds 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 can bind to the immunoglobulin G. Mediates immune effector functions leading to B cell lysis in vitro. Mabs are recombinant human monoclonal antibodies that bind to human CD20 expressed on B cells, for example. Ofatumumab is an immunoglobulin G1 (IgG1) antibody. It has a molecular weight of approximately 146 kDa and consists of two IgG1 heavy chains and two It consists of kappa light chains.

[0112] Ofatumumab is disclosed in European Patent No. 1 558 648 and European Patent No. 3 28 4753. drugbank.ca, Accession No. DB0 6650 and further information in 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 The average protein weight is approximately 146,100 Da. In the United States, ofatumumab is sold under the trade name Kesimpta®. are.

[0113] The metabolic pathway of ofatumumab involves the degradation of small peptides and Ofatumumab can be broken down into amino acids in two ways: as with other IgG molecules, It can be eliminated in a target-independent pathway and in a target-mediated pathway that involves binding to B cells.

[0114] The steady-state half-life of ofatumumab is It could be the 16th.

[0115] Ofatumumab is preferably a chemical drug metabolized by the cytochrome P450 system. or other drug metabolizing enzymes. Tumorinib 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 a dose that is administered to a patient at the beginning of treatment (e.g., a steroid) before transitioning to a maintenance dose that is preferably lower than the loading dose. an initial dose of the drug, preferably an initial higher dose, that may be given at the beginning of the treatment (DMT, DMT) This is a small dose.

[0118] Immunoglobulins (Ig) and subtypes IgG, IgA, IgM, IgD, and I gE is generally known and is described, for example, in Berg / Tymoczko / Stryer "Biochemie", 5 th edition, pp. This application focuses on serum levels of IgG and IgM, particularly IgG. Match the dots.

[0119] Serum immunoglobulin (Ig) levels can be routinely determined in clinical practice. In the present application, serum Ig levels can be preferably determined by immunoturbidimetry. or the cobas® analyzer manufactured by Roche, in particular the cobas® analyzer In a preferred embodiment, the Ig level was measured using module c of the IgM analyzer. The level was determined by using the cobas® c 311 analyzer. IgG measurement can be performed according to the "IGG-2 Tina- quant IgG Gen.2, preferably version 11.0 dated February 2016 The IgM measurement was carried out as described in the leaflet "IGM-2 Tina-quan t IgM Gen.2", preferably as described in version 13.0 dated November 2018 It is more preferred that the method be carried out as described above.

[0120] Serum samples were preferably kept at 2-8°C before measurement. [Brief explanation of the drawings]

[0121] [Figure 1] It is a diagram depicting the setup of a clinical trial according to Example 1 and the measurement of IgG and IgM. [Figure 2] It is a diagram illustrating the change in serum IgG levels from baseline. [Figure 3] It is a diagram illustrating the change in serum IgM levels from baseline. [Figure 4] It is a diagram showing the proportion of patients with IgG levels <LLN and <50% of LLN (at least once during the post-baseline hospital visits). [Figure 5] It is a diagram showing the decrease in IgG levels after administration of a 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] It is a diagram 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]It is a figure illustrating the changes in serum IgM and IgG levels from the baseline. The average IgM and IgG levels remained well within the reference range over time. A decrease in IgM levels from the baseline was observed in both treatment groups in both studies (ASCLEPIOS I and II). A decrease in IgG levels from the baseline was observed up to week 36 in both treatment groups in both studies (ASCLEPIOS I and II), and then they recovered. In patients treated with ofatumumab, the IgG levels recovered to the highest baseline level by W72. [Figure 8] It is a figure showing the proportions 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] It is a figure showing the proportions of patients with IgM and IgG levels at ≧LLN, ≧10%LLN, and ≧20%LLN. At any time point after baseline, approximately 82 - 89% of patients in ofatumumab had IgM levels at or above LLN compared to teriflunomide (>90%), and >85% of patients in ofatumumab had IgG levels at or above LLN compared to teriflunomide (>77%). [Figure 10] It is a figure illustrating the occurrence of severe infections in relation to immunoglobulin levels. [Figure 11] It is a figure illustrating the occurrence of severe infections in relation to immunoglobulin levels. [Figure 12] It is a figure illustrating the change in serum IgG levels from the baseline. [Figure 13] It is a figure illustrating the change in serum IgM levels from the 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, is in Phase 3 ASC EC, which demonstrated superior efficacy compared to teriflunomide in the LEPIOS I / II trials See TRIMS Online Library. Hauser S. et al. 09 / 13 / 19; 279581; 336. MS patients on rituximab received Auba in the ASCLEPIOS I and II studies. 50% reduction in annualized relapse rate (ARR) compared with gio® (teriflunomide) had a 0.5% (0.11 vs. 0.22) and 58.5% (0.10 vs. 0.25) reduction in (p<0.001 in both studies). showed highly significant suppression of gadolinium (Gd) T1 lesions and reduced the incidence of new inflammatory activity. Ofatumumab demonstrated significant inhibition of gliomas-related leukemia in a prespecified pooled analysis. Compared to Aubagio®, 3-month confirmed disability progression (CDP) 34.4% (p=0.002) and 32.5% (p=0.012) of 6-month CDP ) showed a relative risk reduction.

[0123] the purpose Determine serum immunoglobulin (Ig) levels and compare IgG or IgM levels with new treatments To examine the relationship between options, patients with multiple sclerosis were treated with ofatumumab.

[0124] method ASCLEPIOS I and II are double-blind, double-dummy, active control This is a comparator-controlled, parallel-group, innovative, adaptive design, multicenter trial. ofatumumab 20 mg sc injection every 4 weeks (20 mg on days 1, 7, and 14) after an initial loading regimen of sc doses) or oral Terif once daily for up to 30 months Patients were randomized (1:1) to receive either 14 mg of flunomide or 14 mg of flunomide. A core treatment with flexible duration and termination blinded according to pre-specified criteria ≥1 recurrence in the past year or ≥2 recurrences in the past 2 years, or had a positive gadolinium-enhanced (Gd+) MRI scan within the year prior to randomization, Expanded Disability Status Scale (EDS) score of 0 to 5.5 at screening Patients were assessed by EDSS score (according to Kurtzke, Neurology. 1983, Nov; 33(11): 1444-52). Patients aged 18 to 55 years were included.

[0125] Serum IgG / IgM levels were measured at baseline, week 4 (W), W12, and 12 weeks. See Figure 1. The lower limit of normal (LLN) was IgG, 7 g / The outcome was defined as significantly low IgG / IgM levels. The proportion of patients with HIV infection and the relationship between significantly low IgG / IgM levels and the incidence of infection Includes related.

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

[0127] By week 12, nearly all patients (99.3%) had CD19+ B lymphomas below the LLN. CD19+ B cell depletion was observed in >96% of patients throughout treatment The median CD19+ B cell count was zero from week 2 onwards. Up to 4.5% of patients in the flunomide group had B-cell tumors below the LLN throughout the study treatment period. Median CD19+ B-cell counts were significantly higher than those in the LLN at all time points up to 120 weeks. It was above.

[0128] [Table 1]

[0129] b) Ig levels

[0130]

Table 2

[0131] The change in serum IgG level from baseline is shown in Figure 2. The change in blood serum IgM level from baseline is 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 of IgG < LLN: Ofatumumab N = 134: 61 (45.5%) Teriflunomide N = 214: 78 (36.4%)

[0134] conclusion In ofatumumab-treated patients, there was no decrease in IgG levels at week 72 and thereafter. Furthermore, there was a turning point at week 36 where the trend of decreasing IgG levels reversed, ultimately resulting in a net increase in IgG starting from around week 72. Therefore, long-term MS therapy was provided without unduly affecting the serum levels of immunoglobulins. The absence or improvement of negative effects on Ig, particularly IgG levels, and hence on the

[0135] [Example 2] method In a differential analysis, the results of Example 1 were compared with those obtained by Derfuss et al.

[0136] ​​​ ) led to a roughly 5% decrease in IgG levels, while ofatumumab reduced it by about 3%. This has led to an increase in the number of cases. See Figure 6.

[0137] conclusion Ofatumumab sustained and even increased IgG levels over the long term, while octamer Lelizumab 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 : Anti-CD20 monoclonal antibody (mAb) for relapsing multiple sclerosis (RM) B cell depletion in patients with S) is associated with increased annual relapse rates and magnetic resonance imaging findings. Reduces inflammatory lesion activity and delays time to confirmed disability progression. The mAbs ocrelizumab and rituximab are administered by intravenous infusion in the clinic. ofatumumab is delivered in a prefilled syringe or self-injector to facilitate self-administration. It is administered subcutaneously using an anti-injection (AI) pen.

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

[0140] method Approximately 100 adults with RMS will be enrolled at 10-20 centers in the United States. Eligible patients were treated with intravenous ocrelizumab or rituximab (other anti-CD20 mAbs) Previously treated with 2-5 consecutive courses of steroids (excluding b) at baseline Other inclusion criteria were a ≥5.5 or ≥9 months post-screening. had a lower Total Disability Scale score and 1% more severe than baseline anti-CD20 therapy. CD19 B cells depleted to suboptimal response to anti-CD20 therapy in the past 6 months Patients with a satisfactory response (recurrence, ≥2 active gadolinium-enhancing [Gd+] lesions, any new new / growing T2 lesions, clinical deterioration), or severe infusion-related reactions or recurrent infections Patients who discontinued anti-CD20 therapy for any reason or who had progressive disease will be excluded. All participants received AI pens on days 1, 7, and 14, then monthly from months 1 to 12. Patients will receive 20 mg ofatumumab subcutaneously administered by bolus injection. The primary endpoint is a 12-month follow-up period. The secondary endpoints were a stable or decreased number of Gd+ lesions at 6 months. and participant retention and changes in immune biomarkers, treatment satisfaction, and at 12 months. Safety and tolerability. There is a 6-month interim analysis.

[0141] result : The study is aimed at evaluating AI in patients previously treated with ocrelizumab or rituximab Efficacy maintenance, retention, and satisfaction data based on monthly subcutaneous drug delivery via a pen This will complement the ofatumumab Phase 3 program in RMS by generating

[0142] conclusion The study is aimed at developing a new drug for the treatment of RMS in patients transitioning from intravenous anti-CD20 therapy. Provide important data on the maintenance of efficacy of tumab.

[0143] [Example 4] Primary immunodeficiency The majority of patients with primary antibody deficiency suffer from recurrent otitis media, sinusitis, and pneumonic septicemia. presents with recurrent bacterial infections of the sino-pulmonary tract, including pulmonary edema (Gupta S 2017 In addition, up to 25% of these patients show signs of autoimmunity, including autoimmune lytic Hemolytic anemia and autoimmune thrombocytopenia are the most commonly observed disorders (Goldstein MF et al 2006. Selective IgM immunodeficiency: retrospective analysis of 36 adul t 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 in IgM defic Int Arch Allergy Immunol. 2009; 150(3):291-8). Recurrent infections are severe. combined, multi-sited, resistant to treatment, caused by atypical organisms If the condition is diagnosed or present in a family member, a primary immunodeficiency should be suspected. In their work, physicians treating MS patients are aware of the immunosuppressive effects of MS DMTs and the risk of infection and Know the associated risk of MS and therefore have a medical history or screening Patient immune status should be assessed using a cytotoxicity test.

[0144] Secondary immunoglobulin deficiency and risk of infection Decline and progression of serum immunoglobulins in patients with MS treated with anti-CD20 therapy and risk of infection have been reported. Rates vary depending on the measurement device used, the population setting (e.g., outpatient or inpatient, sociodemographic characteristics), and study design (e.g., immunoglobulin linear assay, normal value, frequency of monitoring, etc.), or may vary according to the method used to indicate or counter can vary according to the method used.

[0145] > 14,816 PY (Patient - Years) with over 1246 patients having > 5 years of follow - up Among 3595 patients treated with rituximab over 11 years with 14,816 PY (Patient - Years 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%) had developed < LLN IgM for at least 4 months, while 143 / 3595 (4%) had 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 severe infection rate in patients who developed low IgG levels was higher than the corresponding proportion in patients who did not develop low IgG both before and after the development of low IgG levels, and higher than that 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 determined by low IgG, and higher than that in all exposed populations, suggesting that these patients may have a higher intrinsic risk of developing severe infection events than the corresponding proportion in patients who did not develop low IgG both before and after the development of low IgG levels, and higher than that in all exposed populations, suggesting that these patients may have a higher intrinsic risk of developing severe infection events than the corresponding proportion in patients who did not develop low IgG both before and after the development of low IgG levels, and higher than that in all exposed populations, suggesting that these patients may have a higher intrinsic risk of developing severe infection events RF, Fleischmann RM, Furst DE, Lacey S, Lehane PB. Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Globa l Clinical Trial Program over 11 Years. J Rheumatol. 2015;42(10):1761-1766. doi: 10.3899 / jrheum.15005).

[0146] Severe infections and hypogammaglobulinemia during therapy in rheumatic and musculoskeletal diseases A single-center study of 700 patients treated with rituximab to assess the impact of the disease Another study showed similar results regarding the association between Ig and infection risk. The rate of severe infection was significantly higher in patients with low baseline IgM (10.6 / 100PY) ), patients who had low IgM before treatment (9.8 / 100PY), and patients with normal IgM The results were similar in those with and without PD (9.2 / 100PY) (Md Yusof MY, et al. Prediction ng Severe Infection and Effects of Hypogammaglobulinemia During Therapy With Rit uximab in Rheumatic and Musculoskeletal Diseases. Arthritis Rheumatol. 2019;71(1 1):1812-1823). However, the rate of severe infection was significantly higher in those with normal IgG (9.7 / 10 patients with low IgG at baseline (16.4 / 100PY) compared with patients with 0PY and those who developed low IgG during or after rituximab (RTX) treatment (21 This was higher in the period 2002-2010 (.3 / 100PY). A single-center retrospective study of 177 patients with multisystem autoimmune diseases who received ximab Supported by a review of the literature, the proportion of patients affected by the infection differs according to IgM levels. (normal IgM 37% vs. low IgM 43%) (Marco H, Smith RM, Jones R B, et al. The effect of rituximab therapy on immunoglobulin levels in patients w ith multisystem autoimmune disease. BMC Musculoskelet Disord. 2014;15:178. Publi shed 2014 May 25. doi:10.1186 / 1471-2474-15-178).

[0147] However, gamma globulin levels in patients with rheumatoid arthritis using rituximab have not been reported. Factors known to be associated with decreased performance include background chronic corticosteroid use and high 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 a baseline for multiple sclerosis patients treated with other anti-CD20 therapies. The characteristics are significantly different compared to the original.

[0148] In patients treated with ocrelizumab for multiple sclerosis, a 5.5-year clinical study With overtreatment, the association with infection was strongest for IgG (6.50 / 100PY vs. 2 .11 / 100PY), and less so for IgM (3.66 / 100PY It was revealed that it is important to note that the ary.ectrims-congress.eu / ectrims / 2019 / stockholm / 279399 / tobias.derfuss.serum.immun oglobulin.levels.and.risk.of.serious.infecti).

[0149] Therefore, in patients treated with anti-CD20 therapy, the decline in IgG is related to the decline in IgM. It can be assumed that this is more clinically meaningful than

[0150] Pharmacological differences between Kesimpta, Ocrevus, and Rituxan Pharmacologically, ofatumumab is different from other anti-CD2 antibodies, such as rituximab or ocrelizumab. All of these antibodies have distinct mechanisms of action when compared to B Although it binds to the CD20 receptor on cells, preclinical data suggest that some ofatumumab The ADCC activity of ofatumumab compared to ocrelizumab is related to No significant differences were observed, whereas rituximab was less active [Synopsis of Clinical Pharmacology (S CP) - Figure 12]. In addition, B-cell binding studies demonstrated that ofatumumab is more potent than rituximab. exhibited a slower off-rate (i.e., dissociation rate of the antibody from the CD20 receptor) than the antibody , which is functionally important [Non-clinical review].

[0151] Both ocrelizumab and rituximab were administered at doses of 600 mg and 2000 mg, respectively. g of these drugs are administered intravenously in high doses, so that they eventually reach the lymphatic system. Before it can reach the bloodstream, it must pass through the circulatory system and organs, including the liver and spleen. Ofatumumab, administered subcutaneously at a dose of 20 mg, is delivered via the indirect route via the lymphatics. enters the systemic circulation via the IV route (Richter et al. 2012), which is significantly more potent than the high-dose intravenous route. Equivalent clinical efficacy, better tolerability, and lower clinical risk (i.e., (i.e., no low IgG, no neutropenia, more rapid repletion of CD20) Clinically, ofatumumab has demonstrated clinical efficacy as measured by: It differs from other anti-CD20 mAbs in its functional characteristics: As expected with CD20 therapy, treatment with ofatumumab resulted in some level of Although this was associated with a decline in IgM in the LLN, the majority of patients remained above LLN. The attenuation of M was predominantly noted only in the first 48 weeks. In contrast to ocrelizumab, ofatumumab (O MB)-treated patients had a mean serum IgG level of 2.2% from baseline to week 96 An increase of 0.249 g / L was observed in the teriflunomide group. A 4.1% decrease in mean IgG levels (-0.421 g / L) from baseline was observed at 96 weeks. It was. The lack of risk of neutropenia is associated with ofatumumab treatment in patients with MS. Note that mean and median neutrophil counts remained within the normal range, and baseline neutrophil counts were Particle counts were summarized by visit window in both the G2301 and G2302 studies. Based on the statistics, no decay was expected over the course of the study. In Pool C2, study treatment was discontinued and 48 weeks after the last dose was reached Twenty-eight of 40 patients (70.0%) in the ofatumumab group were treated with teriflunomide. showed B-cell repletion compared with 22 of 35 patients (62.9%) in the LLN or or had B cells at or above baseline). At approximately 48 weeks into the study, all but one subject It was filled with B cells [OMS115102-section 8.2.3]. As per Ocrevus USPI, in 51 patients from an MS clinical study, B-cell The median time for recovery of counts to either baseline or LLN was 10 days after the last Ocrevus injection. 72 weeks after injection (range 27-175 weeks) and within 2.5 years of the last injection, Cell counts rose to either baseline or LLN in 90% of patients. As per the Rituxan label, the majority of patients with rheumatoid arthritis receive at least 6 months of A small proportion of patients (approximately 4%) showed peripheral B-cell depletion for more than 3 years after a single course of treatment. had prolonged peripheral B-cell depletion that lasted longer than that of the control group.

[0152] Serum immunoglobulins and ofatumumab in MS research In pool C2, serum immunoglobulin results showed that mean serum IgM levels increased over time. Within the reference range (reference range for patients >19 years of age: 0.40-2.30 g / L) The results demonstrated that the patient's condition remained adequately stable from baseline to week 48 (Figures 12 and 13). A 30.9% decrease in mean IgM levels (-0.420 g / L) was noted at week 96. The slope of mean IgM decay among completers was lower compared with the first 48-week completers (3 8.8%, -0.537 g / L). In both completers at week 48 and week 96, the mean serum IgM levels remained well within the reference range.

[0153] Immunoglobulin leading to discontinuation Serum IgG and / or serum IgM below the LLN are exclusion criteria for studies G2301 and G2302, but protocols for significantly low levels of IgG / M for treatment discontinuation recommend levels 20% below the LLN for IgG and 10% below the LLN for IgM. From the perspective of clinical practice, these protocols specify thresholds that can be considered quite conservative. Overall, 167 (17.7%) patients out of 944 treated with ofatumumab reported

[0154] IgM below the 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 decreased IgG / M.

[0155] In chronic diseases such as MS and due to the nature of double - blinding in clinical studies, treatment The physician in question was unable to continue the study treatment interruption by protocol call in order to avoid any risk of disease activity and potential recurrence. Therefore, the discontinuation rate 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) with 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 patients (17.7%) treated with ofatumumab reported IgM below the LLN at any time after baseline. Of the 167 patients: · 124 patients (74.3%) with at least one episode of <LLN IgM temporarily interrupted ofatumumab treatment according to the protocol; · The majority of patients continued treatment with ofatumumab in ongoing clinical studies and did not discontinue study treatment; [[ID=3②]] · 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 in patients who had infections from 1 month before to 1 month after a decrease in <LLN IgM (2 patients, 1.

[0158] In patients who maintained IgM > LLN (18 patients, 2.3%) compared to those with IgM < LLN (2%, note was taken of both severe infections (upper respiratory tract infection, urinary tract infection) in the IgM < LLN group, which were not opportunistic in nature and were typically expected in MS patients; · The most frequently reported infection adverse events (AE, ≥ 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 using 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 < LLN at any time after baseline visit was lower in the ocrelizumab group (14.2%; 134 / 944) compared to the teriflunomide group (22.9%; 214 / 934). Among completers at week 96, no patients were reported with 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]. Overall, no cases of PML or hepatitis B reactivation were identified in any MS clinical trial using ocrelizumab, ​​​​​​​​​​​​​​​​In contrast, the data do not indicate an increased risk of any malignancies.

[0160] [Table 3-1]

[0161] [Table 3-2]

[0162] overview Kesimpta (ofatumumab) is considered under the umbrella class of B-cell depleting antibodies. However, data from preclinical safety and efficacy studies, including immunoglobulin and infectious AEs, are available. and comprehensive analysis of clinical trial data. 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 infection noted with IgM decay appears to be related to the absence of any decay of immunoglobulins. The majority of patients had non-severe grade 1 or 2 disease and were treatment-limited. It was not on target; No cytopenias were noted during ofatumumab therapy Based on these findings, it is possible that ofatumumab may have distinct mechanisms and mechanisms of action compared to other anti-CD20 therapies. It was revealed that it exhibits clinical efficacy.

[0163] As seen in the section on immune globulin, low subcutaneous doses on a monthly schedule Kesimpta is given as an intravenous regimen in high doses every six months. It is different from other CD20 antibodies.

[0164] These major differences may be seen as positive externalities in terms of their impact on immunoglobulin levels. Set the value to

[0165] [Example 5] long term study Patients were placed on long-term treatment. Patients received ofatumumab 20 mg sc injections every 4 weeks. received (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 is especially important for the lower quartile, see Figure 15.

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

[0175] [Example 6] Characteristics of COVID-19 in patients with relapsing multiple sclerosis receiving ofatumumab Signs and outcomes Objective: Patients with MS (pwMS) who received ofatumumab 20 mg subcutaneously every 4 weeks To report the clinical characteristics of COVID-19 infection in people.

[0176] method: COV in patients receiving ofatumumab in the open-label extension study ALITHIOS Confirmed or suspected cases of ID-19 infection were reviewed (data cutoff: 202 December 21, 0).

[0177] If a positive SARS-CoV2 test result is available or the patient has a history of COVID If a person reports having been diagnosed with COVID-19, they are considered a confirmed COVID-19 case. was classified as.

[0178] In the absence of a positive SARS-CoV2 test or a confirmed diagnosis, suspected COVID-19 cases Cases with this finding were classified as suspected.

[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 are reporting criteria established by ICH for regulatory reporting purposes. Based on regulations, the definition of fatal, life-threatening, hospitalization, and medically significant.

[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. Over 90% (614 / 677) of patients in the newly switched group received oncolytic therapy for 1 to 2 years. Fatumumab exposure.

[0181] [Table 6]

[0182] Results: COVID-19 Case Overview As of December 21, 2020, 35 of 1703 patients were receiving ofatumumab In the ongoing open-label, extension ALITHIOS clinical trial for confirmed COVID-19 had D-19 infection and / or COVID-19 pneumonia (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 one patient had a COVID-1 Nine outcomes were fatal (details below).

[0183] Associated risk factors* (*associated risk factors such as chronic lung conditions, diabetes, hypertension, or malignancies) A 48-year-old patient with no known comorbidities reported COPD approximately 3 years and 7 months after ofatumumab treatment. The patient reported symptoms of VID-19 (pneumonia, fever, weakness, cough, and difficulty breathing). 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 Six severe cases of COVID-19 in patients receiving ofatumumab were characterized below. are listed below.

[0186] [Table 8]

[0187] Conclusion: Of the total 1,703 patients in the ongoing ALITHIOS study, 1,703 were COVID-1 9 infections and / or 35 confirmed cases of COVID-19 pneumonia have been reported There was a complete recovery in 34 cases; one case had a fatal outcome. There were no cases suspected to be due to medical reasons.

[0188] Based on a review of reported cases, C in pwMS during ofatumumab therapy The clinical presentation and outcome of OVID-19 cases are related to the MS population (Richadson S, et al JAMA. 2020;323:2052-2059;Sormani MP, et al. Lancet Neurol. 2020 Jun; 19(6):48 1-482;Montero-Escribano P, et al. Mult Scler Relat Disord. 2020;42:102185;Safa vi F, et al. Mult Scler Relat Disord. 2020;43:102195;Barzegar M, et al. Mult Sc ler Relat Disord. 2020;45:102276) and in the general population (Bchetnia M, et al. JI Infect Public Health. 2020;13(11):1601-1610) This was similar to other reports.

[0189] New cases will be screened according to local guidelines for SARS-CoV2 testing. Therapy with atumumab may be initiated.

Claims

1. A pharmaceutical composition comprising ofatumumab, for use in a method of treating multiple sclerosis in a patient who is being administered ocrelizumab as disease-modifying therapy and whose serum IgG levels are monitored and found to be decreasing during ocrelizumab administration, wherein the method comprises continuing treatment of multiple sclerosis with ofatumumab as disease-modifying therapy.

2. The pharmaceutical composition according to claim 1, wherein the patient is identified as having a predisposition to increased infection risk after administration of ocrelizumab.

3. The pharmaceutical composition according to claim 1 or 2, wherein, during administration of ocrelizumab, the patient's serum IgG level is found to decrease at an average rate of 3-4% per year.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the patient has been administered ocrelizumab for at least two years.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein it has been found that the patient's serum IgG level decreased to less than 80% of the patient's serum IgG level at the start of ocrelizumab treatment.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein it has been found that the serum IgG level of the patient has decreased to less than 900 mg / dl.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein it has been found that the serum IgG level of the patient has decreased to less than 700 mg / dl.

8. A pharmaceutical composition comprising ofatumumab, for use in both the treatment of multiple sclerosis in a patient and the acquisition of an increase in serum IgG levels in the said patient.

9. The pharmaceutical composition according to claim 8, wherein the patient has a predisposition to increased risk of infection.

10. The pharmaceutical composition according to claim 8 or 9, wherein the patient has risk factors related to serum IgG levels.

11. The pharmaceutical composition according to claim 10, wherein the risk factor is obesity, metabolic syndrome, alcohol consumption, or smoking.

12. The pharmaceutical composition according to any one of claims 8 to 11, wherein the increase is relative to the patient's serum IgG level at the start of treatment with ofatumumab.

13. The pharmaceutical composition according to any one of claims 8 to 12, wherein the patient has a serum IgG level of less than 900 mg / dl at the start of treatment with ofatumumab.

14. The pharmaceutical composition according to any one of claims 8 to 13, wherein an increase in serum IgG levels is achieved in the patient 72 weeks after treatment with ofatumumab.

15. The pharmaceutical composition according to any one of claims 8 to 14, wherein an increase in serum IgG levels is achieved in the patient at 96 weeks of treatment with ofatumumab.

16. The pharmaceutical composition according to any one of claims 8 to 15, wherein the patient is being administered a B cell and / or T cell inhibitor other than ofatumumab.

17. The pharmaceutical composition according to claim 16, wherein the B cell and / or T cell inhibitor other than ofatumumab is ocrelizumab.

18. The pharmaceutical composition according to any one of claims 1 to 17, wherein the multiple sclerosis is relapsing multiple sclerosis (RMS), relapsing-remitting multiple sclerosis (RRMS), secondary progressive multiple sclerosis (SPMS), primary progressive multiple sclerosis (PPMS), or progressive relapsing multiple sclerosis (PRMS).

19. The pharmaceutical composition according to any one of claims 1 to 18, wherein ofatumumab is administered subcutaneously.

20. The pharmaceutical composition according to any one of claims 1 to 19, wherein ofatumumab is administered in a dose of 10 to 30 mg every four weeks.

21. The pharmaceutical composition according to any one of claims 1 to 20, wherein ofatumumab is administered in a dose of 20 mg every four weeks.

22. The pharmaceutical composition according to claim 20 or 21, wherein ofatumumab is administered in a dose of 20 mg during weeks 0, 1 and 2 of treatment, prior to the administration of the aforementioned dose of ofatumumab every four weeks.

23. The pharmaceutical composition according to any one of claims 1 to 22, wherein the pharmaceutical composition further comprises 10 to 100 mM sodium acetate, 25 to 100 mM sodium chloride, 0.5 to 5% arginine free base, 0.02 to 0.2 mM EDTA, and 0.01 to 0.2% polysorbate 80, and is adjusted to a pH of 5.0 to 7.

0.

24. The inventions described herein.

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