Lessons Learned from Discontinued Clinical Developments in Duchenne Muscular Dystrophy.

Theodora Markati,Laurent Servais,Urlike Schara-Schmidt,Liesbeth De Waele

doi:10.3389/fphar.2021.735912

Abstract

Duchenne muscular dystrophy (DMD) is an X-linked condition caused by a deficiency of functional dystrophin protein. Patients experience progressive muscle weakness, cardiomyopathy and have a decreased life expectancy. Standards of care, including treatment with steroids, and multidisciplinary approaches have extended the life expectancy and improved the quality of life of patients. In the last 30 years, several compounds have been assessed in preclinical and clinical studies for their ability to restore functional dystrophin levels or to modify pathways involved in DMD pathophysiology. However, there is still an unmet need with regards to a disease-modifying treatment for DMD and the attrition rate between early-phase and late-phase clinical development remains high. Currently, there are 40 compounds in clinical development for DMD, including gene therapy and antisense oligonucleotides for exon skipping. Only five of them have received conditional approval in one jurisdiction subject to further proof of efficacy. In this review, we present data of another 16 compounds that failed to complete clinical development, despite positive results in early phases of development in some cases. We examine the reasons for the high attrition rate and we suggest solutions to avoid similar mistakes in the future.

Highlights

Duchenne muscular dystrophy (DMD) is an X-linked condition caused by deficiency of functional dystrophin protein
By searches of relevant databases, we identified 16 compounds that had been in clinical development in the DMD population (Table 1)
Upstream treatments aim to treat the cause of the disease, namely the deficiency of functional dystrophin

Summary

Introduction

Duchenne muscular dystrophy (DMD) is an X-linked condition caused by deficiency of functional dystrophin protein. Dystrophin deficiency causes increased susceptibility of the sarcolemma to mechanical stress and results in high intracellular calcium levels, mitochondrial dysfunction, and increased production of reactive oxygen species that lead to a cycle of loss of muscle fibres, chronic inflammation, and decreased muscle regenerative capacity. Muscle fibres are replaced by connective and adipose tissue resulting in muscle dysfunction. Patients experience progressive weakness in skeletal muscles and cardiomyopathy. Several isoforms of dystrophins are expressed in the central nervous system, and a large proportion of patients have cognitive involvement ranging from mild attention deficit to severe autism (Doorenweerd, 2020). DMD patients lose ambulation and have a shortened life expectancy. For a detailed review of DMD pathophysiology, we refer

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