Subcutaneously Administered Ofatumumab in Rheumatoid Arthritis: A Phase I/II Study of Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics

Abstract

Objective.To investigate the safety and tolerability of a single subcutaneous (SC) dose of ofatumumab, a fully human anti-CD20 monoclonal antibody, in patients with rheumatoid arthritis (RA) taking background methotrexate (MTX). Secondary objectives included characterizing pharmacokinetics and pharmacodynamics.Methods.In this single-blind, phase I/II study, 35 patients with RA were randomized in 5 cohorts to receive a single subcutaneous (SC) ofatumumab dose ranging from 0.3 to 100 mg, or placebo, following premedication with oral acetaminophen and antihistamine. Patients were followed for 24 weeks with extended followup to monitor B cell and immunoglobulin recovery for up to 2 years if required.Results.Thirty-five patients received the following treatment: 0.3 mg, n = 4; 3 mg, n = 6; 30 mg, n = 8; 60 mg, n = 6; 100 mg, n = 3; placebo, n = 8. The most common adverse events in the combined ofatumumab groups were headache, nausea, and upper respiratory tract infection. Because of tolerability concerns, only 3 patients were given 100 mg. For the 30–100 mg doses, median maximum plasma concentration values ranged from 4.02 to 4.49 days. Mean elimination half-life values ranged from 5.20 to 6.83 days. Increasing peripheral median B cell depletion was observed from 0.3 mg up to 30 mg, and full target B cell depletion was achieved with 30 mg, 60 mg, and 100 mg.Conclusion.Treatment of RA patients with SC ofatumumab doses of 30 mg or higher resulted in profound and prolonged B cell depletion in blood. Single doses up to 60 mg were tolerated without glucocorticoid premedication. (ClinicalTrials.gov identifier NCT00686868)

Next-generation anti-CD20 monoclonal antibodies in autoimmune disease treatment

“…As an alternative to the IV route and to eliminate the need for premedication with glucocorticoids, a SC formulation was investigated with the rationale that SC ofatumumab could achieve a slower rate of absorption and B cell depletion and potentially improve safety and tolerability. The sponsors began testing a SC formulation of ofatumumab in a 24-week phase I/II, single-blind trial with extended follow-up for up to 2 years to evaluate its safety and tolerability in RA patients who failed MTX [ 19 ]. Patients received a single SC injection of ofatumumab at 0.3, 3, 30, 60, or 100 mg doses or placebo with oral antihistamine and acetaminophen premedication.…”

“…Due to the high rate of IRRs with IV ofatumumab and the favorable safety profile demonstrated by a phase I/II trial for SC ofatumumab in RA patients [ 19 ], a study of SC ofatumumab in MS was conducted. The MIRROR trial was a 24-week phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study in RRMS in which ofatumumab was administered as SC injections [ 26 ].…”

“…A SC formulation of rituximab has already been developed and approved in Europe in 2014 for use in patients with follicular lymphoma and NHL, and in 2016 for CLL. Ofatumumab is also being developed as a SC formulation for use in RA and RRMS, and a SC formulation of veltuzumab was in development for RA patients with plans to start a new trial after the protocol is redesigned [ 19 , 26 ]. SC rituximab is administered over 5 min, and the patient needs to be monitored for IRRs for at least 15 min after the injection.…”

Biologicals in rheumatoid arthritis: current and future

“…A trial with subcutaneous ofatumumab in patients with RA on background MTX showed profound and prolonged B cell depletion without required glucocorticoid premedication. 41 …”

Safety of Repeated Open-Label Treatment Courses of Intravenous Ofatumumab, a Human Anti-CD20 Monoclonal Antibody, in Rheumatoid Arthritis: Results from Three Clinical Trials

“…Results of the initial dose-ranging study [ 13 ] and the 24-week, double-blind, placebo-controlled period of the Phase III study in biologic-naive MTX-refractory patients [ 14 ] indicated that the short-term efficacy and safety of intravenous ofatumumab in RA was similar overall to that observed with other anti-CD20 therapies [ 8 , 15 ]. Furthermore, consistent with the high potency of ofatumumab, a single-blind phase I/II trial in RA patients on background MTX demonstrated that even single subcutaneous formulation doses of ofatumumab, as low as 30 mg, were able to induce profound and persistent peripheral B-cell depletion [ 16 ]. Based on the encouraging results of the subcutaneous study, the clinical development of the intravenous formulation of ofatumumab in RA was discontinued and the three ongoing RA trials were prematurely terminated in favour of initiating a clinical development programme to evaluate the effects of subcutaneously administered ofatumumab in autoimmune diseases instead.…”