Reducing clinical trial risk in multiple sclerosis

Gasperis-Brigante, Cassandra De; Parker, Jayson L.; O’Connor, Paul; Bruno, Tania

doi:10.1016/j.msard.2015.11.007

Cited by 8 publications

(10 citation statements)

References 18 publications

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“…Over the last two decades, clinical trials in MS have established a success rate of 27%, defined as passing phase I, II, III and United States Food and Drug Administration (US FDA) approval, almost tripling the overall industry rate of 10%. 1 As a result of now having 15 approved disease-modifying therapies (DMTs) for relapsing–remitting MS (RRMS), there is a greater challenge to improve the existing options and to achieve prolonged remission. The increased availability of treatment along with revisions in the diagnostic criteria have changed the clinical trial population and restricted the implementation of placebo-controlled trials.…”

Section: Introductionmentioning

confidence: 99%

Evolution of clinical trials in multiple sclerosis

Zhang

Salter

Wallström³

et al. 2019

Ther Adv Neurol Disord

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Clinical trials have advanced the treatment of multiple sclerosis (MS) by demonstrating the safety and efficacy of disease-modifying therapies (DMTs). This review discusses major changes to MS clinical trials in the era of DMTs. As treatment options for MS continue to increase, patients in modern MS trials present earlier and with milder disease compared with historic MS populations. While placebo-controlled trials for some questions may still be relevant, DMT trials in relapsing–remitting MS (RRMS) are no longer ethical. The replacement of the placebo arm by an active comparator arm in trials have raised the cost of trials by requiring larger sample sizes to detect on-study changes in treatment effects. Efforts to improve trial efficiency in RRMS have focused on exploring adaptive designs and relying on sensitive magnetic resonance imaging measures of disease activity. In trials for progressive forms of MS (PMS), the lack of sensitive outcome measures that can be used in shorter-term trials have delayed the development of effective treatments. Recent shifting of the focus to advancing trials in PMS has identified paraclinical outcome measurements with improved potential, and the testing of agents for neuroprotection and remyelination is in progress.

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Section: Introductionmentioning

confidence: 99%

Evolution of clinical trials in multiple sclerosis

Zhang

Salter

Wallström³

et al. 2019

Ther Adv Neurol Disord

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“…The integral role played by mTOR in the myelination process and neuronal plasticity can hence limit the use of general mTOR inhibitors, and may require specific timing and cell-specific targeting to avoid interference with processes of remyelination and axonal regeneration that occur after initial damage. For instance, on a translational level, phase II clinical trials of the rapamycin analogue CCl-779 (Temsirolimus) for RRMS were completed but failed to progress to phase III (NCT00228397) [ 153 , 154 ]. In the future, it will be advantageous to test the impact of exercise specifically in such immune cell nutrient sensing pathways in MS patients.…”

Section: Exercise As a Regulator Of Immunometabolismmentioning

confidence: 99%

Impact of Exercise on Immunometabolism in Multiple Sclerosis

Afzal

Dowling

McCoy

2020

JCM

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Multiple Sclerosis (MS) is a chronic, autoimmune condition characterized by demyelinating lesions and axonal degradation. Even though the cause of MS is heterogeneous, it is known that peripheral immune invasion in the central nervous system (CNS) drives pathology at least in the most common form of MS, relapse-remitting MS (RRMS). The more progressive forms’ mechanisms of action remain more elusive yet an innate immune dysfunction combined with neurodegeneration are likely drivers. Recently, increasing studies have focused on the influence of metabolism in regulating immune cell function. In this regard, exercise has long been known to regulate metabolism, and has emerged as a promising therapy for management of autoimmune disorders. Hence, in this review, we inspect the role of key immunometabolic pathways specifically dysregulated in MS and highlight potential therapeutic benefits of exercise in modulating those pathways to harness an anti-inflammatory state. Finally, we touch upon current challenges and future directions for the field of exercise and immunometabolism in MS.

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“…We expanded our research to provide a short overview of 'commercial' failures, defined as a compound that met the pSE but failed to progress to a subsequent clinical trial because of pharmaceutical companies' decisions. Of note, all of the following commercial failures relate to phase I studies and are more common than clinical failures in phase I/II in MS research [1]. While most of the reviewed failures revealed promising mechanisms, the companies selected to further develop the agents for treating other autoimmune diseases (e.g., the human antibody to GM-CSF otilimab, MOR103, developed by the biotechnology company MorphoSys).…”

Section: Commercial Failurementioning

confidence: 99%

“…The past decade has been marked by an overall decrease in the successful development of new drugs. Clinical trials in multiple sclerosis (MS) are regarded as an exception to this trend [1]. In this context, MS trials have a 27% success rate, defined as passing phases I, II, and III and receiving approval from the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA), almost tripling the average industry rate of 10% [1].…”

Section: Introductionmentioning

confidence: 99%

“…Clinical trials in multiple sclerosis (MS) are regarded as an exception to this trend [ 1 ]. In this context, MS trials have a 27% success rate, defined as passing phases I, II, and III and receiving approval from the United States Food and Drug Administration (FDA) or European Medicines Agency (EMA), almost tripling the average industry rate of 10% [ 1 ]. Therapeutic options for patients with MS have developed from solely steroids to 13 approved disease-modifying therapies (DMT), ranging from injectable biologics to the more recently approved small molecule drugs [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

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Failed, Interrupted, or Inconclusive Trials on Immunomodulatory Treatment Strategies in Multiple Sclerosis: Update 2015–2020

et al. 2020

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In the past decades, multiple sclerosis (MS) treatment has experienced vast changes resulting from major advances in disease-modifying therapies (DMT). Looking at the overall number of studies, investigations with therapeutic advantages and encouraging results are exceeded by studies of promising compounds that failed due to either negative or inconclusive results or have been interrupted for other reasons. Importantly, these failed clinical trials are informative experiments that can help us to understand the pathophysiological mechanisms underlying MS. In several trials, concepts taken from experimental models were not translatable to humans, although they did not lack a well-considered pathophysiological rationale. The lessons learned from these discrepancies may benefit future studies and reduce the risks for patients. This review summarizes trials on MS since 2015 that have either failed or have been interrupted for various reasons. We identify potential causes of failure or inconclusiveness, looking at the path from basic animal experiments to clinical trials, and discuss the implications for our current view on MS pathogenesis, clinical practice, and future study designs. We focus on anti-inflammatory treatment strategies, without including studies on already approved and effective DMT. Clinical trials addressing neuroprotective and alternative treatment strategies are presented in a separate article. Key Points Failed or inconclusive multiple sclerosis (MS) trials are invaluable to our understanding of the pathophysiology and treatment of MS. Trial failure present in relapsing-remitting study populations unveiled, among other things, the complexity of B-cell involvement in MS pathophysiology, that higher selectivity can probably imply lower efficacy, and that current animal models are useful tools but are not able to completely mimic the complexity of human disease.

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Reducing clinical trial risk in multiple sclerosis

Abstract: Overall, MS enjoys almost triple the clinical trial success rates of other disease areas. In addition, small molecules are superior to biologics in MS and novel drugs are superior to drugs with a previous FDA approval history outside MS.

Cited by 8 publications

References 18 publications

Evolution of clinical trials in multiple sclerosis

Evolution of clinical trials in multiple sclerosis

Impact of Exercise on Immunometabolism in Multiple Sclerosis

Failed, Interrupted, or Inconclusive Trials on Immunomodulatory Treatment Strategies in Multiple Sclerosis: Update 2015–2020

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