CN117813328A - Offatuzumab for the treatment of childhood MS - Google Patents

Abstract

The present invention relates to ofatuzumab for use in the treatment or prevention of childhood Multiple Sclerosis (MS). According to the invention, the ofatuzumab is administered during the loading dose regimen on weeks 0, 1, 2 of the dose regimen; and the administration of the ofatuzumab is continued once every six weeks after starting from the eighth week of the dosage regimen during the maintenance dosage regimen.

Description

Offatuzumab for the treatment of childhood MS

Technical Field

The present invention relates to ofatumumab for use in the treatment of childhood Multiple Sclerosis (MS). According to the invention, the ofatuzumab is administered during the loading dose regimen on weeks 0, 1, 2 of the dose regimen; and the administration of the ofatuzumab is continued once every six weeks after starting from the eighth week of the dosage regimen during the maintenance dosage regimen.

Background

Child MS places a heavy burden on the patient and his home. Childhood MS patients may repeatedly experience acute inflammatory activity and neurological abnormalities that severely impact their quality of life. Childhood episodic MS is associated with an impairment of brain development expected by childhood/adolescent early age, and brain atrophy from mid-pubertal to adulthood. Finally, childhood seizure MS patients have a poorer prognosis than adult seizure MS patients, are physically disabled, and have cognitive sequelae at a younger age. Unfortunately, current therapeutic approaches are very limited.

Thus, the unmet medical need for pediatric MS is high. To date, fingolimodIs the only therapy (based on PARADIGMS) which shows efficacy superior to interferon beta-1 a in terms of disease activity. After PARADIGMS, TERIKIIDS was performed on 166 pediatric patients to investigate the efficacy and safety of teriflunomide. However, the study did not reach the primary endpoint, i.e., statistical significance of the time to first clinical recurrence. Because ofHere, fingolimod is the only approved therapy for childhood MS in the united states. In the European Union (EU), interferon beta agents are available to pediatric patients (of different age ranges) according to the approval label of the drug. However, these eu-specific approvals are not based on prospective, randomized, control clinical studies such as PARADIGMS or teikids. Thus, treatment options are not only limited, but lack sufficient clinical study support and data.

In addition to limited treatment options, the lack of data is also a problem when the treatment is interrupted or changed. In this case, the pediatric MS patient is particularly fragile, and it is therefore necessary to reduce or minimize this vulnerability. Importantly, interrupting or altering the treatment is not uncommon in the treatment of pediatric patients. Causes of treatment disruption or change include adverse reactions, treatment failure, disease progression, disease regression, complications, physiological and metabolic changes (such as menstruation), and changing patient preferences.

Thus, there is a need for drugs that are effective and safe for pediatric MS patients.

Monoclonal antibodies (mabs), e.g., anti-CD 20 antibodies, such as ofatuzumab, orelizumab (ocrel izumab) and rituximab (rituximab) against proteins expressed by B cells are highly effective Disease Modification Therapies (DMT) with an overall good safety profile (D' Amico et al 2019).

Ofatuzumab (OMB 157) is a human IgG1 kappa mAb that targets CD20 expressed on subsets of B cells and T cells, and unlike other anti-CD 20 mabs, ofatuzumab binds to a unique epitope on CD20 molecules, which are cell surface antigens presented on pre-B lymphocytes and mature B lymphocytes, thereby inducing efficient B cell lysis and depletion. After binding of the cell surface to B lymphocytes, ofatuzumab causes antibody-dependent cell lysis and complement-mediated lysis.

OffatuzumabApproved in the united states and europe for treatment of adult-relapsing MS, including clinically isolated syndrome, relapse remissionType disease and active secondary progressive disease.

Disclosure of Invention

According to the present invention, it has unexpectedly been found that the ofatuzumab therapy is beneficial for pediatric MS patients as well as MS patients with low body weight of up to 40 kg.

Accordingly, the present invention provides ofatuzumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40kg and/or aged between 5 and 17 years.

The invention also provides ofatuzumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40kg.

The invention also provides an afatomumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40kg and aged between 5 and 17 years.

Detailed Description

The present invention provides ofatuzumab for use in the treatment or prophylaxis, preferably in the treatment of multiple sclerosis in a patient weighing up to 40kg and/or aged between 5 and 17 years.

In a preferred embodiment, the patient has a weight of at most 40kg. In another preferred embodiment, the patient's weight is at least 25kg, preferably the patient's weight is at least 25kg and at most 40kg.

In a preferred embodiment, the patient is a pediatric patient. In a preferred embodiment, the patient is a child. In another preferred embodiment, the patient is an adolescent.

Preferably, the child patient is between 5 and 17 years old, more preferably 10 to 17 years old, i.e. 10 to <18 years old. In another embodiment, the child patient is between 10 and 12 years old. In another embodiment, the child patient is between 5 and 14 years old, preferably between 10 and 14 years old. In another embodiment, the child patient is 15 to 17 years old, i.e., >14 to <18 years old.

In a preferred embodiment, the pediatric patient has a weight of up to 40kg. Further preferred, the child patient has a weight of at least 25kg, more preferred the child patient has a weight of at least 25kg and at most 40kg.

In a further preferred embodiment, the child patient is between 5 and 17 years old, preferably 10 and <18 years old, and has a body weight of at most 40kg, preferably between 25 and 40kg.

In a preferred embodiment of the invention, the ofatuzumab is administered at a dose of 20mg every 6 weeks, which is also referred to as a maintenance dose.

Preferably, the afatomu is administered parenterally, for example by epicutaneous, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, intratendinous, transtracheal, subcutaneous, subcuticular, intra-articular, subcapsular, subarachnoid, intraspinal, intracranial, intrathoracic, epidural or intrasternal injection or infusion. The preferred route of administration is subcutaneous injection (sc).

In a preferred embodiment of the invention, the ofatuzumab is administered in a loading dose. The term loading dose is defined as follows. In a preferred embodiment, three loading doses are preferably administered at weeks 0 and 1 and 2 after the onset of the ofatuzumab therapy. This means that the first loading dose at week 0 is considered the beginning of the therapy. In an alternative preferred embodiment, three loading doses are administered on days 1, 5-9, preferably 7 and 12-16, preferably 14 after initiation of the ofatuzumab therapy. This means that the first loading dose on day 1 is considered the start of therapy.

According to the invention, the ofatuzumab is administered at weeks 0, 1, 2 of the dosage regimen during a loading dosage regimen, which preferably comprises 20mg of ofatuzumab; and the administration of the ofatuzumab is started from week 8 of the dosage regimen during a maintenance dosage regimen, which preferably comprises 20mg of ofatuzumab, and thereafter continued once every six weeks.

Thus, in a preferred embodiment, the ofatuzumab is administered according to the following dosage regimen:

a) The ofatuzumab is administered at weeks 0, 1, 2 of the dosage regimen in a loading dose, which preferably comprises subcutaneous injection of 20mg of ofatuzumab; and

b) The afatomumab is administered at a maintenance dose, preferably comprising subcutaneous injection of 20mg of afatomumab, starting at week 8 of the dosage regimen, and continuing every six weeks thereafter.

It is entirely surprising that this dosage regimen provides a safe and effective treatment for patients, especially pediatric patients, as defined in the claims. This is because there are age-related changes associated with monoclonal antibody (mAb) distribution and/or absorption, turnover, and/or elimination.

First, according to recent reports, several processes that undergo age-related changes and are related to mAb distribution, the biological distribution of mabs appears to be affected by developmental changes. Thus, there is a well known difference in tissue moisture content in pediatric patients as compared to adults. Thus, for hydrophilic macromolecules such as monoclonal antibodies (mabs), a higher systemic volume fraction available for distribution in pediatric patients is expected. Furthermore, the perfusion rate of pediatric patient tissue is generally higher than that of adult counterpart tissue. In addition, pediatric patients have a larger capillary surface area per unit tissue volume, a greater proportion of "leaky" organs and tissues (e.g., liver, kidney, and spleen), and increased capillary permeability relative to their body size. In summary, pediatric patients are expected to have a faster extravasation rate and a lower concentration differential between the blood vessel and the extravascular space than adults. Based on the increased extracellular fluid volume in pediatric patients compared to adults, and the higher perfusion rates (about 0.2% plasma flow rate) that plasma and lymph fluid are assumed to be equally affected, pediatric patients are expected to have increased absorption of mAb.

Second, the efficiency of recovery processes (such as those involving the IgG receptor FcRn) and the general age-related differences in lysosomal protein turnover may be a source of mAb-elimination differences in pediatric patients versus adults after correction for body conformation differences. In this case, it must be noted that the protein turnover (i.e. catabolism in general) appears to be significantly higher in pediatric patients compared to adults. The effect of child age on these processes is expected to achieve clinically detectable differences in mAb elimination.

For these reasons, it is expected that age-related dose adjustments are necessary for the claimed patient, especially a pediatric patient. Thus, the fact that the claimed dosage regimen is similar to that of an adult human is entirely unexpected.

Furthermore, it is surprising that the claimed dosage regimen can be safely and effectively administered subcutaneously (s.c.). This is because Intravenous (IV) and to a lesser extent Intramuscular (IM) administration is generally preferred for pediatric patients.

Furthermore, unexpectedly, pediatric patients do not present serious problems in terms of immunogenicity and endogenous anti-drug antibodies (ADA).

It was unexpectedly found that the above determined dosage regimen achieved B cell depletion of 8 cells per microliter below the threshold. This is entirely surprising, as there is a significant difference between adult patients and pediatric patients. These differences are particularly relevant to physiology, metabolism and weight. In this case, it is also notable that the baseline B cell count is higher in children compared to adults, and therefore, the claimed dosage regimen is not expected to be able to continuously deplete B cells in patients as defined in the claims.

Most changes in the B cell subpopulation occur during childhood. From 18 months old, the percentage and absolute number of naive B cells gradually decreased. On the other hand, memory B cells are increased. The memory-switching B cells expressing CD27 undergo somatic hypermutation and class switching recombination at the center of development. The percentage of CD27+ IgD-B cells increases until 18 years of age and into adulthood. The CD19+CD27+IgD+ cell population (commonly referred to as non-switching memory B cells) corresponds to circulating marginal zone B cells. These cells are involved in T cell independent responses and play a vital role in controlling infections caused by the enveloped bacteria. The percentage and absolute number of non-switching memory B cells gradually increased from childhood to adolescence. Without being bound by theory, it is believed that the ofatuzumab retains regulatory T or B cells, including (a subset of) border zone B cells. Thus, it seems reasonable that the claimed dosage regimen of ofatuzumab results in a safe and effective treatment of the patient as defined in the claims.

On the other hand, the subject matter defined in the claims is not to be expected based on the prior art. This is because age-related changes, such as those described above or those related to regulatory T cells and other T lymphocyte maturation, lead to the expectation that: there is a significant difference in the maturation of immune system functions between pediatric patients and adults, and thus in processes involving immune cells such as immunoreactivity. One exemplary process that may vary between pediatric patients and adults is "target-mediated drug treatment" (TMDD), which represents a pathway of elimination based on binding of mabs to their targets. Since the detection of these and other age-related differences and the assessment of their size is complex and unpredictable, there is no expectation of success when using the claimed dosage regimen.

The present invention relates generally to the treatment of multiple sclerosis. In one embodiment of the invention, the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS). In another embodiment of the invention, the multiple sclerosis is Primary Progressive Multiple Sclerosis (PPMS). In another embodiment of the invention, the multiple sclerosis is Secondary Progressive Multiple Sclerosis (SPMS). In another embodiment, the multiple sclerosis is Clinically Isolated Syndrome (CIS). RRMS is most preferred.

In another embodiment, progressive forms of MS, such as PPMS and SPMS, are not included.

In the completed PARADIGMS study, fingolimod was compared to Interferon (IFN) β -1a (Avonex). Participants treated with ifnβ -1a experienced 120 MS relapses in 163 participants with years of exposure, while participants receiving fingolimod treatment experienced 25 MS relapses in 180 participants with years of exposure. The Annual Relapse Rate (ARR) (i.e., the number of MS relapses per year) for the fingolimod group was 0.122, and the ifnβ -1a group was 0.675. This corresponds to an 81.9% decrease in ARR compared to IFN beta-1 a (p < 0.001) (Chitnis et al 2018).

In one embodiment of the invention, the afatomumab is not inferior to interferon in terms of annual recurrence rate, in particular in terms of maintenance of annual recurrence rate, preferably in terms of reduction of annual recurrence rate. In other words, the annual relapse rate under the treatment of ofatuzumab is at most the annual relapse rate under the treatment of interferon, i.e. the annual relapse rate of the average patient under the treatment of ofatuzumab is at most the annual relapse rate of the average patient under the treatment of interferon.

In a preferred embodiment, the afatomu mab is not inferior to interferon beta in terms of annual recurrence rate, in particular interferon beta selected from the group consisting of interferon-beta 1a, interferon-beta 1b and its pegylated form.

In particular, the Annual Relapse Rate (ARR) (i.e. the number of MS relapses per year) is less than 0.67, preferably less than 0.50, more preferably less than 0.25, even more preferably less than 0.15.

Preferably, the ofatuzumab causes at least 26% reduction in ARR compared to ifnβ -1a (p < 0.001), more preferably at least 63%, more preferably at least 78%, especially at least 82% reduction in ARR

In a preferred embodiment of the invention, the ofatuzumab is not inferior to fingolimod in terms of annual recurrence rate, in particular in terms of maintenance of annual recurrence rate, preferably in terms of reduction of annual recurrence rate. In other words, the annual relapse rate under the treatment of ofatuzumab is at most that of fingolimod, i.e., the annual relapse rate of the average patient under the treatment of ofatuzumab is at most that of the average patient under the treatment of fingolimod.

Preferably, the ARR is at most 0.12. Preferably, the ARR is less than 0.10, more preferably less than 0.08.

In another embodiment of the invention, the ofatuzumab is not inferior to cinnimod (s iponimod) in terms of annual recurrence rate, particularly in terms of maintaining annual recurrence rate, preferably in terms of reducing annual recurrence rate. In other words, the annual relapse rate under the treatment of ofatuzumab is at most the annual relapse rate under the treatment of cinnimod, i.e., the annual relapse rate of the average patient under the treatment of ofatuzumab is at most the annual relapse rate of the average patient under the treatment of cinnimod.

In one embodiment of the invention, for ARR, an nonderistic threshold of 2 is used, with the ofatuzumab not being worse (i.e., not worse) than fingolimod. The non-inferior efficacy was evaluated based on the estimated ARR ratio (ofatuzumab/fingolimod). In other words, the ARR ratio of ofatuzumab/fingolimod is below 2, preferably below 1.

In the PARADIGMS study, the ARR ratio (fingolimod/interferon) was 0.18 (95% CI:0.11; 0.30) (Chitnis et al 2018). With the upper confidence interval limit as a conservative estimate, the ARR of the interferon will be 3.3 times higher than fingolimod.

The threshold of 2 demonstrates that ofatuzumab is superior to interferon compared to fingolimod.

Optionally, as an additional criterion, the main objective can be met only if the ARR post-median of ofatuzumab is less than 0.3. This additional criterion prevents declaring non-inferior efficacy in cases where the ARR is not significantly lower than the interferon ARR, which might otherwise occur if the ARR of the comparator (fingolimod) is higher than expected.

Yet another embodiment of the invention is ofatuzumab for use in the treatment or prevention of multiple sclerosis, wherein ofatuzumab is not inferior to fingolimod in terms of annual T2 lesions rate, in other words wherein the annual T2 lesions rate under ofatuzumab is at most the annual T2 lesions rate under fingolimod, preferably wherein the annual T2 lesions rate under ofatuzumab is reduced compared to fingolimod.

Yet another embodiment of the invention is ofatuzumab for use in the treatment or prevention of multiple sclerosis, wherein ofatuzumab is not inferior to fingolimod in terms of the concentration of neurofilament light chain (NfL) in serum. In other words, the neurite damage under the treatment of ofatuzumab, as measured by a concentration of NfL in serum, is at most as severe as under the treatment of fingolimod, preferably the neurite damage under the treatment of ofatuzumab, as measured by a concentration of NfL in serum, is reduced compared to the treatment of fingolimod.

In a preferred embodiment, the invention relates to ofatuzumab for use in the treatment or prevention of multiple sclerosis, wherein the damage to the nerve axons as measured by NfL concentration in serum is reduced compared to fingolimod.

Another embodiment of the invention is ofatuzumab for the treatment or prevention of multiple sclerosis, wherein the ofatuzumab is not inferior to fingolimod in terms of safety and tolerability, as determined by at least one of the following criteria:

the frequency and severity of adverse events (TEAEs) occurring in the treatment,

a Columbia suicide severity rating scale (C-SSRS),

a 12-lead electrocardiogram is taken,

laboratory and ophthalmologic data are provided for the purpose of,

-a test of the function of the lung,

-vital signs.

Another embodiment of the invention relates to an afatomu for use in the treatment or prevention of multiple sclerosis, wherein the afatomu is not inferior to fingolimod in terms of immunogenicity and endogenous anti-drug antibodies (ADA).

In a preferred embodiment of the invention, the ofatuzumab for use in the treatment of MS is for long-term treatment. The term long term treatment indicates that the ofatuzumab is used for an extended period of time. For example, the ofatuzumab may be used for more than 2 years, 3 years, 4 years, 5 years, 10 years. The ofatuzumab may be used for up to 5 years, 10 years, 15 years, 20 years, or for life.

In a preferred embodiment of the invention, ofatuzumab is administered to a patient weighing up to 40kg or a patient weighing up to 40kg and aged between 5 and 17 years at a dose of 20mg every 6 weeks. When the patient reaches more than 40kg of body weight or when the patient is over 18 years old and the body weight reaches more than 40kg, the dosage regimen need only be changed to a dosage of 20mg every 4 weeks.

This allows MS treatment to continue with only slight modification of the treatment regimen, even if conditions such as age or weight gain change, without the need to replace disease modifying drugs. This is particularly advantageous because replacement of the disease modifying drug may require a wash out period and/or may be associated with the occurrence of adverse events.

In a preferred embodiment of the invention, a pre-drug is administered to the patient prior to administration of the first dose of ofatuzumab. Preferably, the pre-drug comprises a compound selected from the group consisting of acetaminophen, antihistamines and steroids. Methylprednisolone may be the preferred steroid. 100mg iv may be the preferred dose. Preferably, the pre-drug is administered 30 to 60 minutes prior to the injection of the ofatuzumab.

In a particularly preferred embodiment, no pre-drug is administered prior to the first dose of ofatuzumab.

In a preferred embodiment of the invention, ofatuzumab is administered as the sole active ingredient for the treatment of MS. In other words, the ofatuzumab is preferably the only disease-modifying drug administered.

In general, side effects and adverse events associated with B cell depletion therapies such as orexin Li Zhushan anti-therapies are reported to be associated with a reduction in immunoglobulins (e.g., igG). In the present invention, it has surprisingly been found that ofatuzumab therapy is advantageous compared to other B-cell depleting therapies, because it does not lead to a reduction in immunoglobulins (e.g., igG) in the long term, thus opening up a new route for patients receiving long-term treatment.

Thus, in a preferred embodiment of the invention, ofatuzumab is used to treat MS, wherein ofatuzumab is administered to a patient with a known risk factor for malignancy. In another preferred embodiment of the invention, ofatuzumab is used to treat MS, wherein ofatuzumab is administered to a patient who is actively monitoring for recurrence of a malignancy. In an alternative embodiment of the invention, ofatuzumab is used to treat MS, wherein ofatuzumab is administered to a patient suffering from a malignancy of known activity.

MSIS-29 (see definition below) is a clinically useful and scientifically sound metric for measuring the effects of MS from a patient's perspective, suitable for clinical and epidemiological studies. It is considered a reliable, effective and responsive PRO (patient report outcome) metric that can be supplemented with other disease severity indicators to improve our understanding of MS impact.

In the present invention, it was unexpectedly found that the administration of ofatuzumab resulted in an advantageous decrease of the MS influence scale MSIS-29 as defined below.

In this regard, another subject of the present invention is ofatuzumab for the treatment or prevention of relapsing multiple sclerosis, wherein ofatuzumab decreases the MSIS-29 score. Preferably, the ofatuzumab reduces the MSIS-29 score by at least 1.5, more preferably at least 2.0, still more preferably at least 2.5, within 24 months. The decrease may be as high as 3.0 or 3.5 or 4.0.

In one embodiment of the invention, the ofatuzumab composition is formulated according to conventional procedures as a pharmaceutical composition suitable for intravenous administration to humans. Typically, the composition for intravenous administration is a solution in a sterile isotonic aqueous buffer. The composition may also contain, where appropriate, a solubilizing agent and a local anesthetic, such as lidocaine, to reduce pain at the injection site. Generally, the ingredients are provided individually or mixed together in unit dosage form, for example as a dry lyophilized powder or anhydrous concentrate in a sealed container such as an ampoule or pouch that indicates the amount of active agent.

When the composition is administered by infusion, in particular by subcutaneous injection (s.c.), it may be dispensed with an infusion bottle containing sterile pharmaceutical grade water or saline.

When the composition is administered by injection, an ampoule of sterile injection water or saline may be provided so that the ingredients may be mixed prior to administration.

In one embodiment, a formulation of ofatuzumab can be formulated according to the formulation disclosed in WO 2009/009407.

In one embodiment, the ofatuzumab is formulated in an antibody formulation, wherein the ofatuzumab is present in an amount of about 20-300mg/mL, 50-300mg/mL, 100-300mg/mL, 150-300mg/mL, 200-300mg/mL, or 250-300mg/mL, preferably 50 mg/mL.

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

The preferred dosage regimen for ofatuzumab is:

Subcutaneous 20mg initial or loading dose at weeks 0, 1 and 2, then

From the eighth week of the dosage regimen, a subsequent or maintenance dose of 20mg is injected subcutaneously, after which it continues every six weeks.

If the injection of ofatuzumab is missed, it should preferably be injected as soon as possible, rather than waiting until the next predetermined dose. Subsequent doses should be administered at recommended intervals.

In one embodiment, the ofatuzumab formulation is provided in a pre-filled syringe or an auto-injector, preferably a single dose pre-filled syringe or a single dose pre-filled auto-injector. Preferably, a pre-filled auto-injector designed for subcutaneous administration is used.

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

In a preferred embodiment, the formulation of ofatuzumab is intended for self-administration by a patient, preferably by subcutaneous injection.

In a preferred embodiment, the formulation is administered subcutaneously in the abdomen, thigh or outer upper arm. In a preferred embodiment, the formulation is not applied to moles, scars or areas of soft, bruised, reddish, hard or incomplete skin.

In embodiments, the first injection of the ofatuzumab formulation may be performed under the direction of a healthcare professional. If an injection-related response occurs, symptomatic treatment is suggested. 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, prior to application. In a preferred embodiment, the invention of the preparation of ofatuzumab is a clear to slightly milky white and colorless to slightly yellowish brown solution, obtainable as follows:

injection solution: 20mg/0.4mL in a single dose prefilled pen, e.gIn pens

Injection solution: 20mg/0.4mL in a single dose prefilled syringe.

In a preferred embodiment of the invention, the administration of ofatuzumab is delayed in patients with active infections such as covd-19 until the infection is resolved. Alternatively, the ofatuzumab may be administered during an infection, for example during a covd-19 infection. Thus, the administration of ofatuzumab may continue during infection, e.g., during a covd-19 infection.

In another preferred embodiment of the invention, immunoglobulin levels at the beginning of, during and after treatment interruption of the ofatuzumab therapy are monitored as indicated clinically until B-cell supplementation. If the patient develops severe opportunistic infections or recurrent infections (in cases where immunoglobulin levels indicate immune impairment), it is considered to stop the afatomu therapy.

In one embodiment of the invention, the ofatuzumab is for a patient who has received a disease-modifying therapy other than ofatuzumab, wherein the drug of the early disease-modifying therapy is selected from the group consisting of orelizumab, rituximab, fingolimod, teriflunomide, interferon beta and glatiramer acetate.

Another subject of the invention is ofatuzumab for use in the treatment of childhood multiple sclerosis, wherein the treatment is a long-term treatment and wherein the serum IgG level is maintained within a range, wherein the range is substantially the same as the untreated patient.

In the context of the present invention, "untreated patient" refers to a pediatric patient diagnosed with MS or Clinically Isolated Syndrome (CIS) and not administered B-cell and/or T-cell inhibitors. In a preferred embodiment, untreated patients exhibit IgG levels in the range of 600 to 2500 mg/dl.

Another subject of the invention is ofatuzumab for use in the treatment of childhood multiple sclerosis, wherein a pediatric patient with reduced serum IgG levels is treated.

Yet another subject of the present invention is ofatuzumab for use in the treatment of multiple sclerosis, wherein a pediatric patient is treated with a risk factor associated with serum Ig levels, in particular serum IgG levels.

In an embodiment of the invention, the administration of ofatuzumab is not performed to pediatric patients suffering from active HBV infection, in particular suffering from active HBV infection as demonstrated by the positive results of the hepatitis b surface antigen [ HBsAg ] and anti-HBV test. The ofatuzumab may or may not be administered to pediatric patients who are HBsAg negative and hepatitis b core antibody positive [ hbcab+ ] or HBV carrier [ hbsag+ ].

In another embodiment of the invention, the afatomumab is not administered to pediatric patients suffering from acute or chronic hepatitis a, b, c and/or e infections.

In another embodiment of the invention, the pediatric patient who has received any live vaccine or attenuated live vaccine (including varicella zoster virus or measles vaccine) within 4 weeks prior to the intended first administration of the ofatuzumab is not administered the ofatuzumab.

Another subject of the invention is a method for treating multiple sclerosis comprising administering to a patient in need thereof, ofatuzumab, wherein said patient

i) Weight of at most 40kg, and/or

ii) between 5 and 17 years of age.

Another subject of the invention is a method for manufacturing a medicament for the above-mentioned treatment.

Definition of the definition

The term "treatment" or "treatment" may be defined as the application or administration of, for example, ofatuzumab to a patient, wherein the aim is to eliminate, reduce or alleviate the symptoms of a disease such as Multiple Sclerosis (MS). In particular, the term "treatment" includes achieving a clinically significant effect on a patient, such as achieving a clinically significant reduction in the rate of annual relapse in treating RMS. The term also includes MS that is prevented from becoming a progressive form.

The term "patient" preferably refers to a human patient, e.g. a patient suffering from or at risk of suffering from the disorders described herein. Preferably, the patient is a pediatric patient. According to the invention, the treatment described herein is suitable for individual patients as well as for patient populations.

The term "pediatric patient" encompasses patients under 18 years of age, thus including children and adolescents. Preferably, the child patient is between 5 and 17 years old, more preferably 10 to <18 years old (i.e. they have not yet had a birthday of 18 years old). More preferably, the child patient has a weight of at most 40kg. Further preferred, the child patient has a weight of at least 25kg, more preferred the child patient has a weight of at least 25kg and at most 40kg.

More preferably, the child patient is between 5 and 17 years old and weighs at most 40kg, preferably between 25 and 40 kg.

As used herein, the term "child" refers to individuals between 5 and 12 years of age, and the term "adolescent" refers to individuals between 13 and <18 years of age.

The term "adverse event" (AE) may relate to any adverse medical event occurring in a patient or clinical study in which a drug is administered to a subject that is not necessarily causally related to such treatment. Thus, an Adverse Event (AE) may be any adverse and unexpected sign (including abnormal laboratory findings), symptom, or disease that is temporally related to the use of a medical (research) product, whether or not related to the medical (research) product.

RRMS

Relapsing-remitting multiple sclerosis (RRMS) may be characterized by a relapse, defined as a new neurological deficit or exacerbation of neurological onset lasting longer than 24 hours, preferably without fever or infection.

During remission, the disease may not progress significantly. At various time points, RRMS may be further characterized as active (evidence of relapse and/or new MRI activity) or inactive, and worsening (increased confirmed disability over a specified period of time after relapse) or no worsening. Reference Lubl in, neurology.2014, 7 months 15 days; 83 (3):278-286.

RMS

The term RMS (relapsing multiple sclerosis) encompasses RRMS, SPMS and Clinically Isolated Syndrome (CIS).

Primary Progressive MS (PPMS)

PPMS is characterized by the onset of impaired neurological function (accumulation of disability) from the onset of symptoms, and no early recurrence or remission. PPMS can be further characterized as active (evidence of occasional relapse and/or new MRI activity) or inactive, and progressive (objective measure of disease progression over time, evidence of disease progression, with or without relapse or new MRI activity) or no progressive at different time points. Reference Lubl in2014.

Everyone experiences PPMS uniquely. PPMS may have a short period of disease stabilization, with or without relapse or new MRI activity, and a period of increased disability, with or without new relapse or MRI lesions.

Secondary Progressive MS (SPMS)

SPMS occurs after the initial course of relapse remission. Most people diagnosed with RRMS eventually transition to a secondary progressive course of disease, with progressive deterioration of neurological function (accumulation of disability) over time. SPMS can be further characterized as active (evidence of recurrence and/or new MRI activity) or inactive, and progressive (objective measure of change over time, evidence of disease progression, with or without recurrence) or not at various time points. Reference Lubl in2014.

Everyone experiences SPMS uniquely. SPMS occurs after relapsing remitting MS. Disability increases gradually over time, with or without evidence of disease activity (recurrence or MRI changes). In SPMS, recurrent events may occur occasionally, and stationary phases may also occur.

West Nimod under trade nameThe following is a selective sphingosine 1 phosphate receptor modulator for oral use for Multiple Sclerosis (MS).

Recurrence of

Recurrence may be defined as the onset of a new neurological deficit or neurological deterioration, preferably for a duration longer than 24 hours. In other words, recurrence may be considered as a discrete onset of neurological dysfunction (also referred to in the art as "attack", "burst" or "exacerbation"), preferably lasting at least 24 hours. In general, complete or partial recovery occurs after recurrence, and there is no symptom progression or accumulation of disability (remission) over a period of time.

The term "annual recurrence rate" (ARR) relates to the number of MS relapses per year, in particular to the number of MS relapses per year in average patients. As used herein, the term "mean patient" relates to the mean behavior of a population of patients receiving treatment.

B cells as used herein may relate to one type of white blood cell of a lymphocyte subtype. B cells play a role in the humoral immune portion of the adaptive immune system by secreting antibodies such as immunoglobulins (e.g., igG). In addition, B cells can present antigens and secrete cytokines. Unlike T cells and natural killer cells, B cells express B Cell Receptors (BCR) on the cell membrane. BCR allows B cells to bind to a specific antigen and initiate an antibody response against that antigen.

T cells as used herein may relate 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.

Clinically Isolated Syndrome (CIS):

clinically Isolated Syndrome (CIS) may refer to a single clinical attack of inflammatory demyelinating symptoms of the Central Nervous System (CNS), suggesting Multiple Sclerosis (MS). CIS performance may be monofocal or multifocal, and may generally involve the optic nerve, brain stem, cerebellum, spinal cord, or hemispheres of the brain. Reference is made to Miller et al, clinically isolated syndromes, lancet Neurol.2012;11:157-169.

Gd+ lesions

Gadolinium ("contrast agent") is a compound that is injected into a person's vein during an MRI scan. Gadolinium is generally unable to enter the brain or spinal cord from the blood stream due to the blood brain barrier. However, during active inflammation in the brain or spinal cord, such as during MS recurrence, the blood brain barrier may be disrupted, allowing gadolinium to pass. Gadolinium can then enter the brain or spinal cord and infiltrate the MS lesion, causing it to glow and form a highlighted spot on the MRI. Such MS lesions are referred to as gadolinium enhanced lesions or gd+ lesions.

Lesions of T1 and T2

T1 and T2 relate to different MRI methods for generating magnetic resonance images. In particular, T1 and T2 refer to the time taken between the magnetic pulse and the recorded image. These different methods are used to detect different structures or chemicals in the central nervous system. T1 and T2 lesions refer to whether lesions are detected using the T1 or T2 method. T1 MRI images provide information about current disease activity by highlighting areas of active inflammation. T2 MRI images provide information about disease burden or lesion burden (total amount of lesion area, including old and new).

The term "annual T2 lesion rate" relates to the number of new or newly enlarged T2 lesions on MRI per year.

EDSS

Extended Disability Status Scale (EDSS) is a method to quantify multiple sclerosis disability and monitor the change in disability level over time.

EDSS scales range from 0 to 10, increments of 0.5 units, representing higher levels of disability. The score is based on examination by the neurologist.

EDSS steps 1.0 to 4.5 refer to MS patients who can walk without any help and are based on injury measurements of eight Functional Systems (FS):

cone-muscle weakness or difficulty in limb movement

Cerebellar-ataxia, imbalance, coordination or tremors

Brainstem-speech, swallowing and nystagmus problems

Sensory-numbness or loss of sensation

Bowel and bladder function

Visual function-vision problem

Brain function-thought and memory problems

Others.

The Functional System (FS) represents a network of neurons in the brain responsible for a particular task. Each FS scores ranged from 0 (no disability) to 5 or 6 (more severe disability). Reference is made to Kurtzke JF. Assessment of neurological damage to multiple sclerosis: extended Disability Status Scale (EDSS). Neurology.11, 1983; 33 (11):1444-52.

Multiple sclerosis influence scale (MSIS-29)

MSIS-29 version 2 is a 29-item self-filling questionnaire comprising 2 fields: physiological and psychological. Reactions were on a 4-point scale, ranging from 1 (no at all) to 4 (very), with higher scores reflecting greater impact on daily life. MSIS-29 takes about 5 minutes to complete and the problem aims to determine the patient's opinion of the effect of MS on his daily life during the last 2 weeks. Reference is made to Hobart J and Cano S (2009), "Improving the evaluation of therapeutic intervent ions in multiple scleros is: the role of new psychometric methods", health Technol Assess;13 (12) iii, ix-x,1-177.NS RO to Hobart J,Lamping D,Fi tzpatrick R et al (2001), "The Multiple Scleros is Impact Scale (MSIS-29): a new pat kit-based outcome measure", brain;124 (Pt 5) 962-73.

Ofatuzumab:

the ofatuzumab is a human monoclonal antibody directed against the CD20 protein. The ofatuzumab specifically binds to the small extracellular loop and the large extracellular loop of CD20 molecules. The Fab domain of ofatuzumab can bind to the CD20 molecule, and the Fc domain mediates immune effector functions, resulting in B cell lysis in vitro. In particular, ofatuzumab is a recombinant human monoclonal immunoglobulin G1 (IgG 1) antibody that binds to human CD20 expressed on, for example, B cells. The ofatuzumab was produced in the murine NS0 cell line and consisted of two IgG1 heavy chains and two kappa light chains, with a molecular weight of about 146kDa.

Altrastuzumab is described in EP 1 558 648 B1 and EP 3 284 753 B1. Further reference is made to the descriptions in drug bank ca, accession numbers DB06650 and WHO Drug Informat ion, volume 20, phase 1, 2006. In embodiments, the protein has the formula C ₆₄₈₀ H ₁₀₀₂₂ N ₁₇₄₂ O ₂₀₂₀ S ₄₄ And the average protein weight was about 146100Da. In the united states, ofatuzumab is under the trade nameAnd (5) selling downwards.

The metabolic pathway of ofafatomumab can be degraded into small peptides and amino acids by ubiquitous proteolytic enzymes. The ofatuzumab may be eliminated in two ways: the same target independent pathway as other IgG molecules and the target mediated pathway associated with B cell binding.

The half-life of ofatuzumab at steady-state can be about 16 days, particularly after repeated subcutaneous administration of 20mg doses.

The ofatuzumab preferably does not share a common clearance pathway with chemical drugs metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Preferably, the ofatuzumab is not involved in the modulation of drug metabolizing enzyme expression.

Loading dose

The loading dose is an initial dose of drug, preferably an initial higher dose that may be administered at the beginning of the treatment (e.g., DMT) before transitioning to the maintenance dose, preferably lower than the loading dose or at longer time intervals than the loading dose.

Disease Modification Therapy (DMT)

The term "disease modifying therapy" is used because there is no cure for Multiple Sclerosis (MS), but a variety of Disease Modifying Drugs (DMD) have been approved for MS. Generally, RMS-directed DMT can reduce the frequency and/or severity of relapse. Thus, DMT does not cure RMS patients, but can reduce the number of patient relapses and their severity. DMT includes, but is not limited to, treatment with DMD such as interferon beta, glatiramer acetate, teriflunomide, mitoxantrone, dimethyl fumarate, cladribine, fingolimod, cinnimod, brimod, alemtuzumab (alemtuzumab), daclizumab (daclizumab), natalizumab (natalizumab), ofatuzumab, orexin Li Zhushan, and rituximab.

Examples

Phase III clinical study comparing efficacy and safety of ofatuzumab and cilnimod with fingolimod in pediatric patients with multiple sclerosis

The purpose and rationale of this study was to demonstrate the efficacy of ofatuzumab and cinnimod relative to fingolimod in pediatric Multiple Sclerosis (MS) patients (ages 10 to <18 years) and evaluate their safety/tolerability.

Target object

The primary objective was to demonstrate the non-inferior efficacy of ofatuzumab and/or cinimamod compared to fingolimod, as assessed by the Annual Recurrence Rate (ARR) of target pediatric MS participants treated for up to 2 years.

Secondary objectives include, inter alia, demonstrating superiority of ofatuzumab and/or cinnimod compared to historical interferon β -1a data, assessed by annual recurrence rate (ARR confirming recurrence).

The secondary objectives also include:

evaluation of the effect of ofatuzumab and/or cinimamod on the number of new or newly enlarged T2 lesions compared to fingolimod, by annual MRI of the number of new or newly enlarged T2 lesions (annual T2 lesion rate)

-evaluating the effect of ofatuzumab and/or cinnimod on the concentration of neurofilament light chain (NfL) compared to fingolimod, assessed by the concentration of neurofilament light chain (NfL) in serum

Evaluation of Pharmacokinetic (PK) properties of ofatuzumab and cilnimod (and its metabolite M17) in pediatric MS patients, by evaluation of afatuzumab and cilnimod and (metabolite M17) plasma concentrations

Evaluation of immunogenicity (ofatuzumab) by proportion of participants with anti-ofatuzumab antibodies

Evaluation of safety and tolerability of ofatuzumab and cinnimod by adverse events, columbia suicide severity rating scale (C-SSRS), electrocardiogram, laboratory and ophthalmic data, pulmonary function tests and vital signs

Study design

The study randomized about 180 participants at a 1:1:1 randomized distribution ratio (60 participants randomized to subcutaneous ofatuzumab, 60 participants randomized to oral cinnimod, and 60 participants randomized to oral fingolimod). This includes at least 5 participants with a Body Weight (BW). Ltoreq.40 kg and at least 5 participants between 10 and 12 years of age targeted into the group in each of the ofatuzumab and cinnimod groups.

The study consisted of three parts:

-a core part comprising a screening phase and a double blind treatment phase

-an extension part comprising a transition period of double blind processing

-followed by an open label treatment period

-a post-treatment follow-up portion.

Analysis

Efficacy assessment will include the following:

-MS recurrence

-EDSS

-MRI

Concentration of neurofilament light chain (NfL) in serum

Symbolic digital pattern test (SDMT)

-B cells

The primary endpoint of this study was the Annual Recurrence Rate (ARR), which is defined as the average number of recurrences confirmed each year (i.e., total number of recurrences confirmed divided by total study days multiplied by 365.25).

Endpoints of secondary targets include annual recurrence rate (ARR confirming recurrence), number of new or newly enlarged T2 lesions on annual MRI (annual T2 lesions), concentration of neurofilament light chain (NfL) in serum, afatomu and cinnimod and (metabolite M17) plasma concentrations, proportion of participants with anti-afatomu antibodies, adverse events, golombian suicide severity rating scale (C-SSRS), electrocardiogram, laboratory and ophthalmic data, pulmonary function tests and vital signs.

ARR was analyzed using bayesian primary analysis model, confirming only recurrence.

Analysis of secondary endpoints includes efficacy and/or pharmacodynamic endpoints such as comparison to historical interferon data, new/newly enlarged rates of aging of T2 lesions.

Alzhitumumab and cinnimod PK/PD relationship

Exploratory PK/PD analysis was performed on absolute B cell counts if correlation was considered after evaluation of the primary outcome of the study.

No evidence of disease activity

Cross-sectional analysis was performed on the proportion of participants without clinical and MRI disease activity (no evidence of disease activity; NEDA-3) in logistic regression models at years 1 and 2, adjusting treatment, T2 lesion volume and baseline age. NEDA-3 is defined as no 3mCDW, no confirmed MS recurrence and no new or enlarged T2 lesions in any MRI scan compared to baseline. The analysis only considers those participants who follow up the time point of the assessment in the analysis (e.g., participants who follow up for 12 months or more in a 12 month disease-free assessment only, etc.). Intermediate loss values (e.g., due to missing MRI assessments) are not considered to be disease-free.

3 months confirm worsening disability

The 3 month confirmation of worsening disability (3 mCDW) was defined as an increase in EDSS over baseline lasting at least 3 months. This means that after a scheduled or unscheduled visit in which the patient meets the disability deterioration criteria, all EDSS assessments (scheduled or unscheduled) also need to meet the deterioration criteria until deterioration ("event") can be confirmed in the first scheduled visit 3 months or later after the start of deterioration. Screening occurred in all participants who did not experience a 3mCDW event in the study (screening also occurred in those who had worsened "temporary" disability due to early interruption or any other reason. The censoring time is defined as the time from the first dose to the last available EDSS evaluation.

Further evaluating the results reported by the subject, comprising:

children health utilities 9D (CHU 9-D)

Quality of life scale for children (PedsQL)

PedsQL multidimensional fatigue scale

The invention also features the following embodiments:

1. ofatuzumab for use in the treatment or prevention of multiple sclerosis i) in a patient having a body weight of at most 40kg, and/or

ii) between 5 and 17 years of age.

2. An ofatuzumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40 kg.

3. Ofatuzumab for use in the treatment or prevention of multiple sclerosis i) in a patient having a body weight of at most 40kg, and

ii) between 5 and 17 years of age.

4. The ofatuzumab for use according to any one of the preceding embodiments, wherein the patient is a pediatric patient.

5. The ofatuzumab for use according to any one of the preceding embodiments, wherein the patient is between 10 and 17 years of age.

6. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is administered according to the following dosage regimen:

a) The ofatuzumab is administered at the loading dose at weeks 0, 1, 2 of the dosage regimen; and

b) The afatomu mab was administered at a maintenance dose starting from the eighth week of the dose regimen and continuing every six weeks thereafter.

7. The ofatuzumab for use according to embodiment 6, wherein the loading dose and the maintenance dose comprise subcutaneous injections of 20mg of ofatuzumab.

8. The ofatuzumab for use according to any one of the preceding embodiments, wherein the treatment or prevention achieves B cell depletion below a threshold of 8 cells per microliter.

9. The ofatuzumab for use according to any one of the preceding embodiments, wherein the multiple sclerosis is relapsing-remitting multiple sclerosis (RRMS).

10. The ofatuzumab for use according to any one of the preceding embodiments, wherein the multiple sclerosis is Clinically Isolated Syndrome (CIS).

11. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in terms of annual recurrence rate.

12. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in maintaining the annual recurrence rate, preferably in reducing the annual recurrence rate

13. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to interferon in terms of annual recurrence rate.

14. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to interferon in maintaining the annual recurrence rate, preferably in reducing the annual recurrence rate.

15. The ofatuzumab for use according to embodiment 13 or 14, wherein the interferon is interferon beta, in particular interferon beta selected from the group consisting of interferon-beta 1a, interferon-beta 1b and pegylated forms thereof.

16. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to cinnimod in terms of annual recurrence rate.

17. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to cilnimod in maintaining the annual recurrence rate, preferably in reducing the annual recurrence rate.

18. The ofatuzumab for use according to any one of the preceding embodiments, wherein the annual recurrence rate of average patients is less than 0.67.

19. The ofatuzumab for use according to any one of the preceding embodiments, wherein the annual recurrence rate of the average patient is at most 0.12.

20. The ofatuzumab for use according to any one of the preceding embodiments, wherein the reduction in ARR compared to interferon is at least 26%, more preferably the reduction in ARR is at least 63%, more preferably at least 78%, in particular at least 82%.

21. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is for a patient who has received a disease-modification therapy other than ofatuzumab, wherein the medicament of the early disease-modification therapy is selected from the group consisting of orelizumab, rituximab, fingolimod, teriflunomide, interferon beta and glatiramer acetate.

22. The ofatuzumab for use according to any one of the preceding embodiments, wherein the treatment is a chronic treatment.

23. The ofatuzumab for use according to any one of the preceding embodiments, wherein a pre-drug is administered to the patient prior to administration of the first dose of ofatuzumab.

24. The ofatuzumab for use according to any one of the preceding embodiments, wherein the pre-dose comprises acetaminophen, an antihistamine and/or a steroid.

25. The ofatuzumab for use according to any one of the preceding embodiments, wherein the pre-drug is administered 30 to 60 minutes prior to the injection of the ofatuzumab.

26. The ofatuzumab for use according to any one of the preceding embodiments, wherein no pre-drug is administered prior to the first dose of ofatuzumab.

27. The ofatuzumab for use according to any one of the preceding embodiments, wherein the patient is treated for acute or previous infection with covd-19.

28. The ofatuzumab for use according to any one of the preceding embodiments, wherein the treatment is continued during a covd-19 infection.

29. The ofatuzumab for use according to any one of the preceding embodiments, wherein the treatment is discontinued during the covd-19 infection and continued after the infection is resolved.

30. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in terms of annual T2 lesion rate.

31. The ofatuzumab for use according to any one of the preceding embodiments, wherein the rate of annual T2 shift is reduced compared to fingolimod.

32. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in terms of concentration of neurofilament light chain (NfL) in serum.

33. The ofatuzumab for use according to any one of the preceding embodiments, wherein the neurite damage measured by NfL concentration in serum is reduced compared to fingolimod.

34. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in terms of safety and tolerability, as determined by at least one of the following criteria:

the frequency and severity of adverse events (TEAEs) occurring in the treatment,

a Columbia suicide severity rating scale (C-SSRS),

a 12-lead electrocardiogram is taken,

laboratory and ophthalmologic data are provided for the purpose of,

-a test of the function of the lung,

-vital signs.

35. The ofatuzumab for use according to any one of the preceding embodiments, wherein the average number of Gd-enhanced T1 lesions per year is reduced compared to fingolimod.

36. The ofatuzumab for use according to any one of the preceding embodiments, wherein the risk of worsening disability (3 mCDW) is confirmed for 3 months as compared to fingolimod.

37. The ofatuzumab for use according to any one of the preceding embodiments, wherein the risk of worsening disability (6 mCDW) is confirmed for 6 months as compared to fingolimod.

38. The ofatuzumab for use according to any one of the preceding embodiments, wherein the ofatuzumab is not inferior to fingolimod in terms of immunogenicity and endogenous anti-drug antibodies (ADA)

39. A method for treating multiple sclerosis, the treatment comprising administering ofatuzumab to a patient in need thereof, wherein the patient

i) Weight of at most 40kg, and/or

ii) between 5 and 17 years of age.

40. A method for manufacturing a medicament for the treatment of multiple sclerosis, wherein a patient to be treated

i) Weight of at most 40kg, and/or

ii) between 5 and 17 years of age.

Claims (15)

1. An ofatuzumab for use in treating or preventing multiple sclerosis in a patient:

i) Weight of at most 40kg, and/or

ii) between 5 and 17 years of age.

2. An ofatuzumab for use in the treatment or prevention of multiple sclerosis in a patient weighing up to 40 kg.

3. An ofatuzumab for use in treating or preventing multiple sclerosis in a patient:

i) Weight of at most 40kg, and

ii) between 5 and 17 years of age.

4. The ofatuzumab for use of any one of the preceding claims, wherein the patient is a pediatric patient.

5. The ofatuzumab for use of any one of the preceding claims, wherein the patient is between 10 and 17 years of age.

6. The ofatuzumab for use of any one of the preceding claims, wherein the ofatuzumab is administered according to the following dosage regimen:

c) The ofatuzumab is administered at the loading dose at weeks 0, 1, 2 of the dosage regimen; and

d) The afatomu mab was administered at a maintenance dose starting from the eighth week of the dose regimen and continuing every six weeks thereafter.

7. The ofatuzumab for use of claim 6, wherein the loading dose and the maintenance dose comprise subcutaneous injections of 20mg of ofatuzumab.

8. The ofatuzumab for use according to any one of the preceding claims, wherein the ofatuzumab is not inferior to fingolimod, cinnimod or interferon β in terms of maintaining a yearly recurrence rate, preferably in terms of reducing the yearly recurrence rate.

9. The ofatuzumab for use according to any one of the preceding claims, wherein the annual recurrence rate of the average patient is less than 0.67, preferably at most 0.12.

10. The ofatuzumab for use according to any one of the preceding claims, wherein the reduction in ARR compared to interferon is at least 26%, more preferably the reduction in ARR is at least 63%, more preferably at least 78%, in particular at least 82%.

11. The ofatuzumab for use according to any one of the preceding claims, wherein ofatuzumab is for a patient who has been treated with a disease-modification therapy other than ofatuzumab, wherein the medicament of the early disease-modification therapy is selected from the group consisting of orelizumab, rituximab, fingolimod, teriflunomide, interferon beta and glatiramer acetate.

12. The ofatuzumab for use of any one of the preceding claims, wherein the treatment is a chronic treatment.

13. The ofatuzumab for use according to any one of the preceding claims, wherein the patient is treated for acute or previous infection with covd-19.

14. The ofatuzumab for use according to any one of the preceding claims, wherein the treatment is continued during a covd-19 infection.

15. The ofatuzumab for use of any one of the preceding claims, wherein the ofatuzumab is not inferior to fingolimod in terms of annual T1 lesion rate, in terms of T2 lesion rate, in terms of concentration of neurofilament light chain (NfL) in serum, in terms of immunogenicity and endogenous anti-drug antibodies (ADA) and/or in terms of safety and tolerability, as determined by at least one of the following criteria:

frequency and severity of adverse events (TEAE) occurring in the treatment, -Columbia suicide severity rating scale (C-SSRS), -12 lead electrocardiogram,

laboratory and ophthalmologic data are provided for the purpose of,

-a test of the function of the lung,

-vital signs.