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Pharmacodynamics: B-cell Depletion: For B-cell counts, assays for CD19+ B-cells are used because the presence of BONSPRI interferes with the CD20 assay. In Study 1 and Study 2, BONSPRI 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 Recommended Dosage under Dosage & Administration and Clinical Studies as follows]. 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 BONSPRI 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.
Clinical Studies: The efficacy of BONSPRI 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 BONSPRI, 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 BONSPRI (n = 465) or teriflunomide (n = 462). Of those randomized to BONSPRI, 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 BONSPRI (n = 481) or teriflunomide (n = 474). Of those randomized to BONSPRI, 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, BONSPRI significantly lowered the ARR compared to teriflunomide.
BONSPRI significantly reduced the risk of 3-month confirmed disability progression compared to teriflunomide.
BONSPRI 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 1 and figure. (See Table 1 and figure).
Click on icon to see table/diagram/imageClick on icon to see table/diagram/imageA similar effect of BONSPRI 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.
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 BONSPRI 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 BONSPRI 20 mg injections. The half-life at steady state was estimated to be approximately 16 days following subcutaneous administration of repeated BONSPRI 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 BONSPRI and other medicinal products have not been investigated in formal studies.
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.
