KESIMPTA (Page 4 of 8)

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

KESIMPTA (ofatumumab) injection is a preservative-free, clear to slightly opalescent and colorless to slightly brownish-yellow solution for subcutaneous administration, which is supplied as follows:

KESIMPTA Sensoready Pen:

Carton of one 20 mg/0.4 mL single-dose prefilled Sensoready Pen NDC 0078-1007-68

KESIMPTA Prefilled Syringe:

Carton of one 20 mg/0.4 mL single-dose prefilled syringe NDC 0078-1007-69

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