Moving towards clinical trials for mitochondrial diseases

Abstract

Primary mitochondrial diseases represent some of the most common and severe inherited metabolic disorders, affecting ~1 in 4,300 live births. The clinical and molecular diversity typified by mitochondrial diseases has contributed to the lack of licensed disease‐modifying therapies available. Management for the majority of patients is primarily supportive. The failure of clinical trials in mitochondrial diseases partly relates to the inefficacy of the compounds studied. However, it is also likely to be a consequence of the significant challenges faced by clinicians and researchers when designing trials for these disorders, which have historically been hampered by a lack of natural history data, biomarkers and outcome measures to detect a treatment effect. Encouragingly, over the past decade there have been significant advances in therapy development for mitochondrial diseases, with many small molecules now transitioning from preclinical to early phase human interventional studies. In this review, we present the treatments and management strategies currently available to people with mitochondrial disease. We evaluate the challenges and potential solutions to trial design and highlight the emerging pharmacological and genetic strategies that are moving from the laboratory to clinical trials for this group of disorders.

The Dimensions of Primary Mitochondrial Disorders

“…Many early attempts at therapy development have sought to improve the function of the respiratory chain, by administering cofactor supplements such as carnitine, niacin, and thiamine (Pfeffer et al, 2013). With the exception of a few of these deficiencies in the biosynthesis or transport of cofactors and vitamins (Koch et al, 2017), the majority of patients still receive only symptomatic and supportive treatments, such as exercise, hearing aids, or reduction of toxic metabolites (Distelmaier et al, 2017;Hirano et al, 2018;Pitceathly et al, 2020). Thanks to technological advances, however, the knowledge of mitochondrial diseases is improving.…”

Seeking impact: Global perspectives on outcome measure selection for translational and clinical research for primary mitochondrial disorders

“…A plethora of emerging therapeutic trials are exploring pharmacological and genetic therapies for PMDs. 32,33 9 | REGULATORY AGENCY INVOLVEMENT Regulatory agencies, including the FDA, have become actively engaged in clinical trial design and therapeutic development for rare diseases, facilitated by the 1983 US Orphan Drug Act, which has also been adopted by Japan and the European Union. A series of key meetings have brought together clinicians, scientists, patients, caregivers, industry participants, and PAGs.…”

“…A plethora of emerging therapeutic trials are exploring pharmacological and genetic therapies for PMDs. 32,33 The FDA has generated specific advice for rare orphan disorders as above, given the typical framework for clinical trials, which are notably difficult in rare disease populations. Traditionally, the four Clinical Research Phases for each step of clinical trials are each designed for a different purpose.…”

“…Selecting optimal outcome measures in the context of designing an ideal clinical trial needs to be based on preclinical studies, genotype, available natural history studies, and management strategies based on known pathomechanisms of disease. A plethora of emerging therapeutic trials are exploring pharmacological and genetic therapies for PMDs 32,33 …”

“…The heterogeneous and rare nature of PMDs, together with the lack of validated outcome measures, impedes the ability to conduct robust clinical trials 32 . As new clinical trials are designed and implemented for mitochondrial disease, we can continue to make critical improvements in terms of utilization of outcome measures.…”