The Development of Ofatumumab, a Fully Human Anti-CD20 Monoclonal Antibody for Practical Use in Relapsing Multiple Sclerosis Treatment.

Autor: Hauser SL; UCSF Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA. Stephen.Hauser@ucsf.edu., Kappos L; Research Center for Clinical Neuroimmunology and Neuroscience Basel (RC2NB) and MS Center, and Departments of Medicine, Clinical Research, Biomedicine and Biomedical Engineering, University Hospital of Basel, University of Basel, Basel, Switzerland., Bar-Or A; Center for Neuroinflammation and Experimental Therapeutics and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA., Wiendl H; Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany., Paling D; Sheffield Institute of Translational Neuroscience, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK., Williams M; Joi Life Wellness Multiple Sclerosis Neurology Center, Atlanta, GA, USA., Gold R; Department of Neurology, St Josef-Hospital/Ruhr-University Bochum, Bochum, Germany., Chan A; Department of Neurology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland., Milo R; Department of Neurology, Barzilai Medical Center, Ashkelon/Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel., Das Gupta A; Novartis Pharma AG, Basel, Switzerland., Karlsson G; Novartis Pharma AG, Basel, Switzerland., Sullivan R; Novartis Pharma AG, Basel, Switzerland., Graham G; Novartis Pharma AG, Basel, Switzerland., Merschhemke M; Novartis Pharma AG, Basel, Switzerland., Häring DA; Novartis Pharma AG, Basel, Switzerland., Vermersch P; Univ. Lille, INSERM U1172 LilNCog, CHU Lille, FHU Precise, 59000, Lille, France.
Jazyk: angličtina
Zdroj: Neurology and therapy [Neurol Ther] 2023 Oct; Vol. 12 (5), pp. 1491-1515. Date of Electronic Publication: 2023 Jul 14.
DOI: 10.1007/s40120-023-00518-0
Abstrakt: The importance of B cells in multiple sclerosis (MS) has been demonstrated through the advent of B-cell-depleting anti-CD20 antibody therapies. Ofatumumab is the first fully human anti-CD20 monoclonal antibody (mAb) developed and tested for subcutaneous (SC) self-administration at monthly doses of 20 mg, and has been approved in the US, UK, EU, and other regions and countries worldwide for the treatment of relapsing MS. The development goal of ofatumumab was to obtain a highly efficacious anti-CD20 therapy, with a safety and tolerability profile that allows for self-administration by MS patients at home and a positive benefit-risk balance for use in the broad relapsing MS population. This development goal was enabled by the unique binding site, higher affinity to B cells, and higher potency of ofatumumab compared to previous anti-CD20 mAbs; these properties of ofatumumab facilitate rapid B-cell depletion and maintenance with a low dose at a low injection volume (20 mg/0.4 ml). The high potency in turn enables the selective targeting of B cells that reside in the lymphatic system via subcutaneous (SC) administration. Through a comprehensive dose-finding program in two phase 2 studies (one intravenous and one SC) and model simulations, it was found that safety and tolerability can be further improved, and the risk of systemic injection-related reactions (IRRs) minimized, by avoiding doses ≥ 30 mg, and by reaching initial and rapid B-cell depletion via stepwise weekly administration of ofatumumab at Weeks 0, 1, and 2 (instead of a single high dose). Once near-complete B-cell depletion is reached, it can be maintained by monthly doses of 20 mg/0.4 ml. Indeed, in phase 3 trials (ASCLEPIOS I/II), rapid and sustained near-complete B-cell depletion (largely independent of body weight, race and other factors) was observed with this dosing regimen, which resulted in superior efficacy of ofatumumab versus teriflunomide on relapse rates, disability worsening, neuronal injury (serum neurofilament light chain), and imaging outcomes. Likely due to its fully human nature, ofatumumab has a low immunogenic risk profile-only 2 of 914 patients receiving ofatumumab in ASCLEPIOS I/II developed anti-drug antibodies-and this may also underlie the infrequent IRRs (20% with ofatumumab vs. 15% with the placebo injection in the teriflunomide arm) that were mostly (99.8%) mild to moderate in severity. The overall rates of infections and serious infections in patients treated with ofatumumab were similar to those in patients treated with teriflunomide (51.6% vs. 52.7% and 2.5% vs. 1.8%, respectively). The benefit-risk profile of ofatumumab was favorable compared to teriflunomide in the broad RMS population, and also in the predefined subgroups of both recently diagnosed and/or treatment-naïve patients, as well as previously disease-modifying therapy-treated patients. Interim data from the ongoing extension study (ALITHIOS) have shown that long-term treatment with ofatumumab up to 4 years is well-tolerated in RMS patients, with no new safety risks identified. In parallel to the phase 3 trials in which SC administration was carried out with a pre-filled syringe, an autoinjector pen for more convenient self-administration of the ofatumumab 20 mg dose was developed and is available for use in clinical practice.
(© 2023. The Author(s).)
Databáze: MEDLINE
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