KESIMPTA is indicated for the treatment of relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults.

KESIMPTA should be initiated by a physician experienced in the management of neurological conditions.

4.2.1  Assessments Prior to First Dose of KESIMPTA

Hepatitis B Virus Screening

Prior to initiating KESIMPTA, perform Hepatitis B virus (HBV) screening. KESIMPTA is contraindicated in patients with active HBV confirmed by positive results for Hepatitis B surface antigen [HBsAg] and anti-HBV tests. For patients who are negative for HBsAg and positive for Hepatitis B core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with KESIMPTA (see section Special warnings and precautions for use).

Serum Immunoglobulins

Prior to initiating KESIMPTA, perform testing for quantitative serum immunoglobulins (see section Special Warnings and Precautions for use). For patients with low serum immunoglobulins, consult immunology experts before initiating treatment with KESIMPTA.

Vaccinations

Because vaccination with live-attenuated or live vaccines is not recommended during treatment and after discontinuation until B-cell repletion, administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines (see section Special warnings and precautions for use).

Posology

The recommended dosage of KESIMPTA is:

•           initial dosing of 20 mg by subcutaneous injection at Weeks 0, 1, and 2, followed by

•           subsequent dosing of 20 mg by subcutaneous injection once monthly starting at Week 4.

Missed Doses

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

Special populations

Elderly (aged 65 years and over)

No studies have been performed in elderly MS patients. Ofatumumab was studied in patients with RMS aged 18 to 55 years. Results from population pharmacokinetics suggest that dose adjustment is not required in elderly patients (see section Pharmacokinetic properties).

Renal impairment

No specific studies of ofatumumab in patients with renal impairment have been performed.

Patients with mild renal impairment were included in clinical studies. There is no experience in patients with moderate and severe renal impairment. However, as ofatumumab is not excreted via urine it is not expected that patients with renal impairment require dose modification (see section Pharmacokinetic properties).

Hepatic impairment

No studies of ofatumumab in patients with hepatic impairment have been performed.

Since hepatic metabolism of monoclonal antibodies such as ofatumumab is negligible, hepatic impairment is not expected to impact its pharmacokinetics. Therefore, it is not expected that patients with hepatic impairment require dose modification (see section Pharmacokinetic properties).

Paediatric population

The safety and efficacy of Kesimpta in children aged 0 to 18 years have not yet been established. No data are available.

Method of administration

Administer by subcutaneous injection only.

KESIMPTA is intended for patient self-administration by subcutaneous injection.

Administer KESIMPTA in the abdomen, thigh, or outer upper arm subcutaneously. Do not give injection into moles, scars, stretch marks or areas where the skin is tender, bruised, red, scaly or hard.

The first injection of KESIMPTA should be performed under the guidance of a healthcare professional (see section special Warnings and Precautions for use).

KESIMPTA Sensoready® pens and syringes are for one-time use only and should be discarded after use.

4.4     Special warnings and precautions for use

Infections

Serious, including life-threatening or fatal, bacterial, fungal, and new or reactivated viral infections have been observed during and following completion of treatment with anti-CD20 B-cell depleting therapies.
In KESIMPTA Study 1 and Study 2 [see Clinical Studies (14)], the overall rate of infections and serious infections in patients treated with KESIMPTA was similar to patients who were treated with teriflunomide (51.6% vs 52.7%,
and 2.5% vs 1.8%, respectively). The most common infections reported by KESIMPTA-treated patients in the randomized clinical relapsing MS (RMS) trials included upper respiratory tract infection (39%) and urinary tract infection (10%). Delay KESIMPTA administration in patients with an active infection until the infection is resolved

Possible Increased Risk of Immunosuppressant Effects with Other Immunosuppressants

When initiating KESIMPTA after an immunosuppressive therapy or initiating an immunosuppressive therapy after KESIMPTA, consider the potential for increased immunosuppressive effects (see section Interaction with other medicinal products and other forms of interaction and Pharmacodynamics). KESIMPTA has not been studied in combination with other MS therapies.

Hepatitis B Virus

Reactivation

There were no reports of HBV reactivation in patients with MS treated with KESIMPTA. However, HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, has occurred in patients being treated with ofatumumab for chronic lymphocytic leukemia (CLL) (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment) and in patients treated with other anti-CD20 antibodies.

Infection

KESIMPTA is contraindicated in patients with active hepatitis B disease. Fatal infections caused by HBV in patients who have not been previously infected have occurred in patients being treated with ofatumumab for CLL (at higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). HBV screening should be performed in all patients before initiation of treatment with KESIMPTA. At a minimum, screening should include Hepatitis B surface antigen (HBsAg) and Hepatitis B Core Antibody (HBcAb) testing. These can be complemented with other appropriate markers as per local guidelines. For patients who are negative for HBsAg and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment with KESIMPTA. These patients should be monitored and managed following local medical standards to prevent HBV infection or reactivation.

Progressive Multifocal Leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs in patients who are immunocompromised, and that usually leads to death or severe disability.

Although no cases of PML have been reported for KESIMPTA in the RMS clinical studies, PML resulting in death has occurred in patients being treated with ofatumumab for CLL (at substantially higher intravenous doses than the recommended dose in MS but for a shorter duration of treatment). In addition, JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies. At the first sign or symptom suggestive of PML, withhold KESIMPTA and perform an appropriate diagnostic evaluation. Magnetic reasonance imaging (MRI) findings may be apparent before clinical signs or symptoms. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes.

If PML is confirmed, treatment with KESIMPTA should be discontinued.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of KESIMPTA for live or live-attenuated vaccines, and whenever possible, at least 2 weeks prior to initiation of KESIMPTA for inactivated vaccines.

KESIMPTA may interfere with the effectiveness of inactivated vaccines.

The safety of immunization with live or live-attenuated vaccines following KESIMPTA therapy has not been studied. Vaccination with live or live-attenuated vaccines is not recommended during treatment and after discontinuation until B-cell repletion (see section Pharmacodynamics).

Vaccination of Infants Born to Mothers Treated with KESIMPTA During Pregnancy

In infants of mothers treated with KESIMPTA during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

Inactivated vaccines may be administered, as indicated, prior to recovery from B-cell depletion, but an assessment of vaccine immune responses, including consultation with a qualified specialist, should be considered to determine whether a protective immune response was mounted.

Treatment of severely immunocompromised patients

KESIMPTA should not be given to patients in a severely immunocompromised state (e.g. significant neutropenia or lymphopenia).

Injection-Related Reactions and Hypersensitivity Reactions

KESIMPTA can result in systemic injection-related reactions and hypersensitivity reactions, which may be serious or life-threatening.

In Study 1 and Study 2, systemic and local injection reactions were reported in 21% and 11% of patients treated with KESIMPTA compared to 15% and 6% of patients treated with teriflunomide who received matching placebo injections, respectively (see section Undesirable effects and Pharmacodynamic properties)

Injection-related reactions with systemic symptoms observed in clinical studies occurred most commonly within 24 hours of the first injection, but were also observed with later injections. Symptoms observed included fever, headache, myalgia, chills, and fatigue, and were predominantly (99.8%) mild to moderate in severity. There were no life-threatening injection reactions in the RMS clinical studies.

In the post-marketing setting, additional systemic injection-related reactions and hypersensitivity reactions have been reported, including anaphylaxis, angioedema, pruritus, rash, urticaria, erythema, bronchospasm, throat
irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, dizziness, nausea, and tachycardia. Most cases were non-serious and occurred with the first injection. Most serious cases resulted in
permanent discontinuation of KESIMPTA.

Symptoms of systemic injection-related reactions may be clinically indistinguishable from acute hypersensitivity reactions. A hypersensitivity reaction may occur with any injection. New or more severe symptoms compared to
those experienced with previous injections should prompt consideration of a potential hypersensitivity reaction.

Only limited benefit of premedication with corticosteroids, antihistamines, or acetaminophen was observed in RMS clinical studies. The first injection of KESIMPTA should be performed under the guidance of an appropriately
trained healthcare professional. If systemic injection-related reactions occur, initiate appropriate therapy. Patients who experience symptoms of systemic injection-related reactions or hypersensitivity reactions with KESIMPTA
should be instructed to seek immediate medical attention.

If a hypersensitivity reaction or life-threatening systemic injection-related reaction occurs, immediately and permanently discontinue KESIMPTA [see Section Contraindications]. If restarting KESIMPTA after a severe (but
not life-threatening) systemic injection-related reaction or other event after which rechallenge is considered appropriate, administer the next KESIMPTA injection under clinical observation. If a mild to moderate injectionrelated
reaction occurs, consider rechallenge under clinical observation.

Local injection-site reaction symptoms observed in clinical studies included erythema, swelling, itching, and pain. If local injection-related reactions occur, symptomatic treatment is recommended.

Reduction in Immunoglobulins 

As expected with any B-cell depleting therapy, decreased immunoglobulin levels were observed. Decrease in immunoglobulin M (IgM) was reported in 7.7% of patients treated with KESIMPTA compared to 3.1% of patients treated with teriflunomide in RMS clinical trials (see section Undesirable effects)Treatment was discontinued because of decreased immunoglobulins in 3.4% of patients treated with KESIMPTA and in 0.8% of patients treated with teriflunomide. No decline in immunoglobulin G (IgG) was observed at the end of the study. Monitor the levels of quantitative serum immunoglobulins during treatment, especially in patients with opportunistic or recurrent infections, and after discontinuation of therapy until B-cell repletion. Consider discontinuing KESIMPTA therapy if a patient with low immunoglobulins develops a serious opportunistic infection or recurrent infections, or if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins. 

Fetal Risk

Based on animal data, KESIMPTA can cause fetal harm due to B-cell lymphopenia and reduce antibody response in offspring exposed to KESIMPTAin utero. Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 B-cell depleting antibodies during pregnancy. Advise females of reproductive potential to use effective contraception while receiving KESIMPTA and for at least 6 months after the last dose (see section Interaction with other medicinal products and other forms of interaction).

Ofatumumab does not share a common clearance pathway with chemical drugs that are metabolized by the cytochrome P450 system or other drug metabolizing enzymes. Additionally, there is no evidence that CD20 monoclonal antibodies are involved in the regulation of the expression of drug metabolizing enzymes. Interactions between KESIMPTA and other medicinal products have not been investigated in formal studies.

Immunosuppressive or Immune-Modulating Therapies

Concomitant usage of KESIMPTA with immunosuppressant drugs, including systemic corticosteroids, may increase the risk of infection. Consider the risk of additive immune system effects when coadministering immunosuppressive therapies with KESIMPTA.

When switching from therapies with immune effects, the duration and mechanism of action of these therapies should be taken into account because of potential additive immunosuppressive effects when initiating KESIMPTA.

Pregnancy/ Contraception in males and females

Females of childbearing potential should use effective contraception while receiving KESIMPTA and for 6 months after the last treatment of KESIMPTA (see section special Warnings and Precautions for use and Pharmacokinetic properties)

Risk Summary

There are no adequate data on the developmental risk associated with the use of KESIMPTA in pregnant women. Ofatumumab may cross the placenta and cause fetal B-cell depletion based on findings from animal studies [see section Interaction with other medicinal products and other forms of interaction (Data)].

Transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. B-cell levels in infants following maternal exposure to KESIMPTA have not been studied in clinical trials. The potential duration of B-cell depletion in infants exposed to ofatumumab in utero, and the impact of B-cell depletion on the safety and effectiveness of vaccines, are unknown. Avoid administering live vaccines to neonates and infants exposed to KESIMPTA in utero until B-cell recovery occurs (see section special Warnings and Precautions for use and Pharmacodynamics).

Following administration of ofatumumab to pregnant monkeys, increased mortality, depletion of B-cell populations, and impaired immune function were observed in the offspring, in the absence of maternal toxicity, at plasma levels substantially higher than that in humans  [see section Interaction with other medicinal products and other forms of interaction (Data)].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.  

Data

Animal Data

Intravenous administration of ofatumumab (weekly doses of 0, 20, or 100 mg/kg) to pregnant monkeys during the period of organogenesis (gestations days 20 to 50) resulted in no adverse effects on embryofetal development; however, B-cell depletion was observed in fetuses at both doses when assessed on gestation day 100. Plasma exposure (Cave) at the no-effect dose (100 mg/kg) for adverse effects on embryofetal development was greater than 5000 times that in humans at the recommended human maintenance dose of 20 mg. A no-effect dose for effects on B-cells was not identified; plasma exposure (Cave) at the low-effect dose (20 mg/kg) was approximately 780 times that in humans at the recommended human maintenance dose (RHMD) of 20 mg/month. 

Intravenous administration of ofatumumab (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg) to pregnant monkeys throughout pregnancy resulted in no adverse effects on the development of the offspring. However, postnatal death, B-cell depletion, and impaired immune function were observed in the offspring at the high dose. The deaths at the high dose were considered secondary to B-cell depletion. Plasma exposure (Cave) in dams at the no-effect dose (100/20 mg/kg) for adverse developmental effects was approximately 500 times that in humans at RHMD. A no-effect level for  mortality and immune effects in offspring was not established because of the limited number of evaluable offspring at the low dose.

Breast‑feeding

Risk Summary

There are no data on the presence of ofatumumab in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Human IgG is excreted in human milk, and the potential for absorption of ofatumumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for KESIMPTA and any potential adverse effects on the breastfed infant from KESIMPTA or from the underlying maternal condition.

Impairment of Fertility

No effects on reproductive parameters, including hormones, menstrual cycle, sperm analysis, or histopathological evaluation of reproductive organs, were observed in male or female monkeys administered ofatumumab by intravenous injection (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg). Plasma exposures (Cave) at the high dose tested in monkey are greater than 500 times that in humans at the recommended human maintenance dose of 20 mg/month.

Kesimpta expected to have no or negligible influence on the ability to drive and use machines

a.Summary of the safety profile

The following clinically significant adverse reactions are discussed in greater detail elsewhere in the labeling:

·         Infections (see section Special warnings and precautions for use)

·         Injection-Related Reactions and Hypersensitivity Reactions (see section Special warnings and precautions for use)

·          Reduction in Immunoglobulins (see section Special warnings and precautions for use)

4.8.1  Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Approximately 1500 patients with RMS received KESIMPTA in clinical studies. In Study 1 and Study 2, 1882 patients with RMS were randomized, 946 of whom were treated with KESIMPTA for a median duration of 85 weeks; 33% of patients receiving KESIMPTA were treated for up to 120 weeks (see section Pharmacodynamic properties). The most common adverse reactions occurring in greater than 10% of patients treated with KESIMPTA and more frequently than in patients treated with teriflunomide were upper respiratory tract infections, injection-related reactions (systemic), headache, and injection-site reactions (local). The most common cause of discontinuation in patients treated with KESIMPTA was low immunoglobulin M (3.3%), defined in trial protocols as IgM at 10% below the lower limit of normal (LLN).

b.Tabulated list of adverse reactions

Table 1 summarizes the adverse drug reactions that occurred in Study 1 and Study 2.

Table 1: Adverse Reactions in Patients with RMS with an Incidence of at Least 5% with KESIMPTA and a Greater Incidence Than Teriflunomide (Pooled Study 1 and Study 2)

c.Description of selected adverse reactions

Injection-Related Reactions and Injection-Site Reactions

The incidence of injection-related reactions (systemic) was highest with the first injection (14.4%), decreasing with subsequent injections (4.4% with second, less than 3% with third injection). Injection-related reactions were mostly (99.8%) mild to moderate in severity. Two (0.2%) patients treated with KESIMPTA reported serious injection-related reactions. There were no life-threatening injection-related reactions. Most frequently reported symptoms (2% or greater) included fever, headache, myalgia, chills, and fatigue.

In addition to systemic injection-related reactions, local reactions at the administration site were very common. Local injection-site reactions were all mild to moderate in severity. The most frequently reported symptoms (2% or greater) included erythema, pain, itching, and swelling [see section special Warnings and Precautions for use).

Laboratory Abnormalities

Immunoglobulins

In Study 1 and Study 2, a decrease in the mean level of IgM was observed in KESIMPTA-treated patients but was not associated with an increased risk of infections (see section special Warnings and Precautions for use). In 14.3% of patients in Study 1 and Study 2, treatment with KESIMPTA resulted in a decrease in a serum IgM that reached a value below 0.34 g/dL. KESIMPTA was associated with a decrease of 4.3% in mean IgG levels after 48 weeks of treatment and an increase of 2.2% after 96 weeks.

4.8.2  Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medication, and the underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other ofatumumab products may be misleading.

Treatment induced anti-drug antibodies (ADAs) were detected in 2 of 914 (0.2%) KESIMPTA-treated patients; no patients with treatment enhancing or neutralizing ADAs were identified. There was no impact of positive ADA titers on PK, safety profile or B-cell kinetics in any patient; however, these data are not adequate to assess the impact of ADAs on the safety and efficacy of KESIMPTA.

--To reports any side effect(s):

·    Saudi Arabia:

·    Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

• To report any complaint(s) :complaints.ksa@novartis.com

·    Other GCC States:

-- Please contact the relevant competent authority.

4.8.3 Postmarketing Experience
The following adverse reactions have been identified during post approval use of KESIMPTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
their frequency or establish a causal relationship to drug exposure.

Immune System: Hypersensitivity reactions [see Section Special warnings and precautions for use]

No cases of overdose have been reported in RMS clinical studies.

Pharmacotherapeutic group: selective immunosuppressants, ATC code: L04AG12

Mechanism of action

The precise mechanism by which ofatumumab exerts its therapeutic effects in MS is unknown, but is presumed to involve binding to CD20, a cell surface antigen present on pre-B and mature B lymphocytes. Following cell surface binding to B lymphocytes, ofatumumab results in antibody-dependent cellular cytolysis and complement-mediated lysis.

Pharmacodynamics

B-cell Depletion

For B-cell counts, assays for CD19+ B-cells are used because the presence of KESIMPTA interferes with the CD20 assay. In Study 1 and Study 2, KESIMPTA administered as recommended, resulted in a reduction of CD19+ B-cells to below the LLN in 77.0% and 78.8% of patients, respectively, one week after treatment initiation, and in 95.0% and 95.8% of patients, respectively, two weeks after treatment initiation [see Dosage and Administration (2.2) and Clinical Studies (14)]. In Study 1 and Study 2, at Week 12, 99.3% to 99.5% of patients had CD19+ B-cell counts below LLN. The CD19+ B-cell counts remained below LLN for approximately 97% of patients in Study 1 and 92% of patients in Study 2 from 12 weeks through 120 weeks while on KESIMPTA treatment.

In a study of bioequivalence using the same dosing regimen as in Study 1 and Study 2, before initiation of the maintenance phase, total CD19+ B-cell levels below the defined threshold of 10 cells/µL were achieved in 94% of patients starting at Week 4 and 98% of patients at Week 12.

B-cell Repletion

Data from Studies 1 and 2 indicate a median time to B-cell recovery to either LLN or baseline value of 24.6 weeks posttreatment discontinuation. Pharmacokinetics and pharmacodynamics modeling and simulation for B-cell repletion
corroborate these data, predicting median time to B-cell recovery to LLN of 23 weeks post-treatment discontinuation

Clinical studies

The efficacy of KESIMPTA was demonstrated in two randomized, double-blind, double-dummy, active comparator-controlled clinical trials of identical design, in patients with relapsing forms of MS [Study 1 (NCT02792218) and Study 2 (NCT02792231)]. Both studies enrolled patients with at least one relapse in the previous year, 2 relapses in the previous 2 years, or the presence of a T1 gadolinium-enhancing (GdE) lesion in the previous year. Patients were also required to have an Expanded Disability Status Scale (EDSS) score from 0 to 5.5. 

Patients were randomized to receive either KESIMPTA, 20 mg subcutaneously on Days 1, 7, and 14, followed by 20 mg every 4 weeks thereafter starting at Week 4 with a daily oral placebo, or the active comparator, teriflunomide, at a dose of 14 mg orally once daily with a placebo administered subcutaneously on Days 1, 7, 14, and every 4 weeks thereafter. The treatment duration for an individual patient was variable based on when the end of study criteria were met. The maximal duration of treatment for an individual patient was 120 weeks. Neurologic evaluations were performed at baseline, every 3 months during blinded treatment, and at the time of a suspected relapse. Brain MRI scans were performed at baseline, 1 and 2 years.

The primary endpoint of both trials was the annualized relapse rate (ARR) over the treatment period. Additional outcome measures included: 1) the time to 3-month confirmed disability progression for the pooled populations, 2) the number of T1 GdE lesions per scan at Weeks 24, 48, and 96, and 3) the annualized rate of new or enlarging T2 MRI lesions. Disability progression was defined as an increase in EDSS of at least 1.5, 1, or 0.5 points in patients with a baseline EDSS of 0, 1 to 5, or 5.5 or greater, respectively.

In Study 1, a total of 927 patients were randomized to receive KESIMPTA (n = 465) or teriflunomide (n = 462). Of those randomized to KESIMPTA, 90% completed the study; of those randomized to teriflunomide, 81% completed the study. Demographics and disease characteristics were balanced across treatment arms. The mean age was 38 years, 89% were White, and 69% were female. The mean time since MS diagnosis was 5.7 years and the median EDSS score at baseline was 3.0; 60% had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the previous year was 1 and the mean number of T1 GdE lesions on MRI scan was 1.5.

In Study 2, a total of 955 patients were randomized to receive KESIMPTA (n = 481) or teriflunomide (n = 474). Of those randomized to KESIMPTA, 83% completed the study; of those randomized to teriflunomide, 82% completed the study. Demographics and disease characteristics were balanced across treatment arms. The mean age was 38 years, 87% were White, and 67% were female. The mean time since MS diagnosis was 5.5 years and the median EDSS score at baseline was 2.5; 61% had been treated with a non-steroid therapy for MS. At baseline, the mean number of relapses in the previous year was 1.3, and the mean number of T1 GdE lesions on MRI scan was 1.6.

In both studies, KESIMPTA significantly lowered the ARR compared to teriflunomide.

KESIMPTA significantly reduced the risk of 3-month confirmed disability progression compared to teriflunomide.

KESIMPTA significantly reduced the number of T1 GdE lesions and the rate of new or enlarging T2 lesions in both studies.

Key results for Study 1 and Study 2 are presented in Table 2 and Figure 1.

Table 2: Key Clinical and MRI Endpoints From Study 1 and Study 2

Figure 1 : Time to First 3-month Confirmed Disability Progression by Treatment Full Analysis Set

A similar effect of KESIMPTA on the key efficacy results compared to teriflunomide was observed across the two
studies in exploratory subgroups defined by sex, age, body weight, prior non-steroid MS therapy, and baseline
disability and disease activity.

Absorption

A subcutaneous dose of 20 mg every 4 weeks leads to a mean AUCtau of 483 mcg h/mL and a mean Cmax of 1.43 mcg/mL at steady state.

After subcutaneous administration, ofatumumab is believed to be predominantly absorbed via the lymphatic system similarly to other therapeutic monoclonal antibodies.

Distribution

The volume of distribution at steady-state was estimated to be 5.42 L following subcutaneous administration of repeated KESIMPTA 20 mg dose.

Elimination

Biotransformation/metabolism

Ofatumumab is a protein for which the expected metabolic pathway is degradation to small peptides and amino acids by ubiquitous proteolytic enzymes.

Excretion

Ofatumumab is eliminated by both linear catabolic pathways and a non-linear B-cell mediated pathway, resulting
in non-constant elimination half-life. Initially, a higher baseline B-cell count results in greater B-cell-mediated
elimination and shorter ofatumumab half-life. As the B-cells are depleted, the catabolic pathway predominates,
resulting in a relatively longer ofatumumab half-life compared to earlier in therapy when both elimination pathways
were available.
Following B cell depletion, clearance was estimated to be 0.34 L/day following repeated subcutaneous
administration of KESIMPTA 20 mg injections. The half-life at steady state was estimated to be approximately 16
days following subcutaneous administration of repeated KESIMPTA 20 mg dose.
Ofatumumab, a monoclonal antibody, is not likely to undergo renal excretion.

Special populations

The following population characteristics do not have a clinically meaningful effect on the pharmacokinetics of ofatumumab: body weight, sex, age, race, or baseline B-cell count.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of KESIMPTA did not include sufficient numbers of geriatric patients to determine whether they respond differently from younger subjects.

Patients with Renal/Hepatic Impairment

Pharmacokinetics of ofatumumab in patients with renal or hepatic impairment have not been studied.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No carcinogenicity studies have been conducted to assess the carcinogenic potential of ofatumumab.

Mutagenesis

No studies have been conducted to assess the mutagenic potential of ofatumumab. As an antibody, ofatumumab is not expected to interact directly with DNA.

Impairment of Fertility

No effects on reproductive parameters, including hormones, menstrual cycle, sperm analysis, or histopathological evaluation of reproductive organs, were observed in male or female monkeys administered ofatumumab by intravenous injection (5 weekly doses of 0, 10, and 100 mg/kg, followed by biweekly doses of 0, 3, and 20 mg/kg). Plasma exposures (Cave) at the high dose tested in monkey are greater than 500 times that in humans at the recommended human maintenance dose of 20 mg/month.

L-arginine 4mg/0.4ml

Sodium acetate trihydrate 2.722mg/0.4ml

Sodium chloride 1.192 mg/0.4ml

Polysorbate 80 0.080 mg/0.4ml

Disodium edetate dihydrate 0.007 mg/0.4ml

Hydrochloric acid (for pH adjustment) QS

Water for injections up to 408ml

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

Kesimpta 20 mg solution for injection in pre-filled pen

Store in refrigerator at (2ºC to 8ºC).

Keep the product in the original carton to protect from light.

Do not freeze.

Do not shake.

Kesimpta 20 mg solution for injection in pre-filled pen

is supplied in a single-use glass syringe, equipped with a stainless steel needle, a plunger stopper and a rigid needle shield, containing 0.4 ml solution. The syringe is assembled into an auto-injector (SensoReady pen).

Kesimpta is available in unit packs containing 1 pre-filled SensoReady pen and in multipacks containing 3 (3 packs of 1) pre-filled SensoReady pens.

Not all pack sizes may be marketed.

The KESIMPTA “Instructions for Use” for each presentation contains more detailed instructions on the preparation of KESIMPTA.

Before administration, remove KESIMPTA Sensoready pen or KESIMPTA prefilled syringe from the refrigerator and allow KESIMPTA to reach room temperature for about 15 to 30 minutes. DO NOT remove the needle cover while allowing the prefilled syringe to reach room temperature.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if the liquid contains visible particles or is cloudy.