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Link to original content: http://pubmed.ncbi.nlm.nih.gov/35794296/
What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us? - PubMed Skip to main page content
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Review
. 2022 Apr;19(3):785-807.
doi: 10.1007/s13311-022-01246-3. Epub 2022 Jul 6.

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

Julia Krämer  1 , Heinz Wiendl  2
Affiliations
Review

What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

Julia Krämer et al. Neurotherapeutics. 2022 Apr.

Abstract

In the past two decades, monoclonal antibodies (mAbs) have revolutionized the treatment of multiple sclerosis (MS). However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons. While trials with positive outcomes are usually published in prestigious journals, negative trials are merely published as abstracts or not at all. This review summarizes MS mAbs that have either failed in phase II-III trials, have been interrupted for various reasons, or withdrawn from the market since 2015. The main conclusions that can be drawn from these 'negative' experiences are as follows. mAbs that have been proven to be safe in other autoimmune conditions, will not have the same safety profile in MS due to immunopathogenetic differences in these diseases (e.g., daclizumab). Identification of SAEs in clinical trials is difficult highlighting the importance of phase IV studies. Memory B cells are central players in MS immunopathogenesis (e.g., tabalumab). The pathophysiological mechanisms of disease progression are independent of leukocyte 'outside-in' traffic which drives relapses in MS. Therefore, therapies for progressive MS must be able to sufficiently cross the blood-brain barrier. Sufficiently long trial duration and multicomponent outcome measures are important for clinical studies in progressive MS. The success of trials on remyelination-promoting therapies mainly depends on the sufficient high dose of mAb, the optimal readout for 'proof of concept', time of treatment initiation, and appropriate selection of patients. Failed strategies are highly important to better understand assumed immunopathophysiological mechanisms and optimizing future trial designs.

Keywords: Antibody therapy; Clinical trials; Drug development; Failure; Monoclonal antibodies; Multiple sclerosis.

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Conflict of interest statement

Julia Krämer received honoraria for lecturing from Biogen, Novartis, Sanofi Genzyme, Mylan, Merck, and Teva and financial research support from Sanofi Genzyme and Amicus Therapeutics. Heinz Wiendl received grants from German Ministry for Education and Research (BMBF), Deutsche Forschungsgesellschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, the European Union, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme, Consulting fees from Abbvie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, and Sanofi-Aventis; support for travel to meetings for other purposes from Abbvie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, and Sanofi-Aventis; fees for participation in review activities such as data monitoring boards from PSI CRO Deutschland GmbH, Swiss Multiple Sclerosis Society, Payment for lectures from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche Ltd., Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, TEVA, and WebMD Global; and honorarium for expert testimony from Alexion, Biogen, Merck Serono, Novartis, and Genzyme outside the submitted work. He has filed patent nos. SEP-103.323–1/08, EP2769223, WO2013057092 (A1), and 15001186.4–1402.

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