KESIMPTA: Package Insert and Label Information (Page 2 of 4)

7 DRUG INTERACTIONS

7.1 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

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 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 Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

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 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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

Contraception

Females of childbearing potential should use effective contraception while receiving KESIMPTA and for 6 months after the last treatment of KESIMPTA [see Warnings and Precautions (5.4) and Clinical Pharmacology (12.3)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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

11 DESCRIPTION

Ofatumumab is a recombinant human monoclonal immunoglobulin G1 (IgG1) antibody that binds to human CD20 expressed on B-cells. Ofatumumab is produced in a murine NS0 cell line and consists of two IgG1 heavy chains and two kappa light chains with a molecular weight of approximately 146 kDa.

KESIMPTA (ofatumumab) injection is a sterile, preservative-free solution for subcutaneous use.

Each 20 mg/0.4 mL KESIMPTA Sensoready pen or prefilled syringe delivers 0.4 mL of solution. Each 0.4 mL contains 20 mg of ofatumumab, and arginine (4 mg), disodium edetate (0.007 mg), polysorbate 80 (0.08 mg), sodium acetate trihydrate (2.722 mg), sodium chloride (1.192 mg), and Water for Injection, USP with a pH of 5.5. Hydrochloric acid may have been added to adjust pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which ofatumumab exerts its therapeutic effects in multiple sclerosis 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.

12.2 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 RMS clinical studies indicate B-cell recoveries over the LLN in at least 50% of patients in 24 to 36 weeks post treatment discontinuation. Modeling and simulation for B-cell repletion corroborates these data, predicting median time to B-cell recovery of 40 weeks post treatment discontinuation.

12.3 Pharmacokinetics

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

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 in two ways: a target-independent route as with other IgG molecules and a target-mediated route that is related to binding to B-cells. Higher baseline B-cell count results in greater component of target-mediated elimination clearance and shorter ofatumumab half-life at the start of therapy. 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.

Specific 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.

Patients with Renal/Hepatic Impairment

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

Drug Interaction Studies

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.

13 NONCLINICAL TOXICOLOGY

13.1 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.

14 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
a 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.b Prospective pooled analysis of Studies 1 and 2. Proportion of patients with 3-month confirmed disability progression refers to Kaplan-Meier estimates at Month 24.
Study 1 Study 2
Endpoints KESIMPTA20 mg(n = 465)Teriflunomide14 mg(n = 462)KESIMPTA20 mg(n = 481)Teriflunomide14 mg(n = 474)
Clinical Endpoints
Annualized relapse rate (Primary Endpoint)0.110.220.100.25
Relative Reduction51% (p < 0.001)59% (p < 0.001)
Proportion of Patients with 3-month Confirmed Disability Progressiona,b Relative Risk Reduction10.9% KESIMPTA vs 15.0% teriflunomide34.4% (p = 0.002)
MRI Endpoints
Mean number of T1 Gd-enhancing lesions per MRI scan0.010.450.030.51
Relative Reduction98% (p < 0.001)94% (p < 0.001)
Number of new or enlarging T2 lesions per year0.724.000.644.15
Relative Reduction82% (p < 0.001)85% (p < 0.001)

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

Figure 1: Time to First 3-month Confirmed Disability Progression by Treatment Full Analysis Set
(click image for full-size original)

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.

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