What Have Failed, Interrupted, and Withdrawn Antibody Therapies in Multiple Sclerosis Taught Us?

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 However, a remarkable number of mAbs failed due to negative study results were withdrawn because of unexpected serious adverse events (SAEs) or due to studies being halted for other reasons.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review summarizes MS mAbs that have either failed in phase II–III trials, have been interrupted for various reasons, or withdrawn from the market since 2015.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.

Receptor-mediated drug delivery of bispecific therapeutic antibodies through the blood-brain barrier

“…Therapeutic antibodies that target receptors within the CNS and behind the BBB are not expected to be effective in the treatment of MS, owing to lack of antibody transport across the BBB. This is illustrated in the failed clinical trial of opicinumab in MS, even at the very high dose of 100 mg/kg ( Kramer and Wiendl, 2022 ). This antibody inhibits leucine-rich repeat and immunoglobulin-like domain-containing Nogo receptor-interacting protein 1 (LINGO1), a protein that is selectively expressed on oligodendrocytes and neurons in brain ( Kramer and Wiendl, 2022 ), which are behind the BBB.…”

Heterogeneity of antibody-secreting cells infiltrating autoimmune tissues

“…Nevertheless, atacicept failure might not have been directly due to BAFF/APRIL antagonism, since a new trial with telitacicept is ongoing in MS ( 14 ). BAFF-only treatment with tabalumab gave no significant results ( 156 ). As of today, the disease has never been transferred in an animal with the systemic injection of antibodies directed against myelin-associated products ( 157 ).…”

Bioavailable central nervous system disease-modifying therapies for multiple sclerosis

“…Fingolimod treatment, however, did not slow disease progression compared with placebo in a phase 3 clinical trial of participants with primary progressive MS, suggesting that this antiinflammatory therapy for relapse-onset MS is less likely to be effective in primary progressive disease, and other treatment approaches may be needed for these patients (106). In addition, other putative remyelination-promoting therapies, including opicinumab, MD-1003, and elezanumab failed to meet their study endpoints in MS clinical trials; lack of efficacy may have been due to the studied dose, time of treatment initiation, proof of concept study endpoints, or patient selection (107)(108)(109)(110). The impact of centrally acting DMTs on brain volume, cognition, and/or disability contrasts with the lack of observed efficacy of remyelinating therapies and warrants further investigation.…”

“…Assessing the therapeutic response in the CNS may be accomplished with biomarkers (e.g., neurofilament light chain and glial fibrillary acidic protein), monitoring SELs and/or paramagnetic rim lesions, myelin measurements (e.g., MTR/MWF and ultrashort echo time MRI), P100 latency using multifocal or fullfield visual evoked potential, optical coherence tomography, or in vivo imaging techniques (e.g., positron emission tomography imaging of microglia). The reliability of these techniques for determining direct effects within the CNS remains under investigation (110,(151)(152)(153)(154)(155)(156)(157). Well-designed clinical trials that consider these approaches are needed to substantiate new treatment modalities for MS that may include combining BBB-penetrating DMTs with peripherally acting monoclonal antibodies to limit disease progression and improve treatment outcomes through promoting immunomodulation, remyelination, and neuroprotection (158,159).…”