Inactive
Elamipretide (Brand Name FORZINITY™ for Barth Syndrome)
Children’s Hospital of Philadelphia
Inactive
Elamipretide (aka SS31), brand name FORZINITY™ for Barth Syndrome, is a tetrapeptide compound developed by Stealth Therapeutics. It targets the inner mitochondrial membrane where it binds reversibly to cardiolipin. In preclinical or clinical studies, elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production, and reduces formation of pathogenic reactive oxygen species (ROS) levels. Functional benefit is achieved through improvement of ATP production as well as interruption and potential reversal of damaging oxidative stress.
The FDA granted elamipretide Orphan Drug Designation for the treatment of patients with Friedreich’s ataxia. FORZINITY™ (elamipretide HCl) has been granted accelerated approval based on improved muscle strength in adult and pediatric patients with Barth syndrome.
HOW DOES A DRUG GET DEVELOPED?
INACTIVE: Stages of Development for Elamipretide
The drug development process can be thought of as a series of stages, and drugs must successfully pass through each stage to become available to patients. This treatment has been evaluated, and the program has been discontinued. Thus, it is not in the pipeline.
Elamipretide came out of a chance discovery of a family of compounds (Szeto–Schiller (SS) peptides) that selectively target the mitochondrial ETC to optimize efficiency of electron transport and restore cellular bioenergetics in aging and diverse disease models without any effect on the normal healthy organism. Originally named SS-31 (also named MTP-131 and Bendavia) it entered clinical development for a variety of complex diseases. Studies in isolated mitochondria and cells demonstrated that elamipretide improved electron transport, decreased mitochondrial generation of reactive oxygen species and elevated ATP generation.
In mouse experiments, treatment with elamipretide prevented the increase in mitochondrial oxidative stress and muscle wasting associated with disuse atrophy in hindlimb and diaphragm. In aging mice, a single IP injection of elamipretide increased ATP, levels, oxidative phosphorylation, and reduced muscle fatigue Longer term treatment with elamipretide demonstrated similar increases in mitochondrial energetics and decreases in muscle fatigue
Stealth BioTherapeutics obtained regulatory approval for the first in human studies with elamipretide (then known as MTP-131). The first trials in 2015 were small, open label phase I trials in other diseases. The regulatory filings for the FA Investigator Initiated Study (IIS) With Elamipretide were in 2021.
The Children’s Hospital of Philadelphia (CHOP) conducted a Phase 1/2 clinical trial evaluating safety, tolerability, and potential for efficacy of elamipretide in addressing the vision loss in FA. Two doses were compared; high dose (40-60mg) vs low dose (20-30mg) over 104 Weeks.
All participants had genetically confirmed diagnosis of FA and symptoms of vision loss and evidence of cardiac disease. The goal was to evaluate the effect of elamipretide in addressing some of the later stage symptoms of FA.
The complete results are posted on clinicaltrials.gov
Main findings include:
- Participants who received high dose elamipretide progressed less/improved more over essentially all the outcomes, including the primary outcome visual acuity.
- There was a significant withdrawal rate (~50%) in the study which makes comparisons between groups and statistics problematic (n=9 with measurable data at week 104).
- Both Clinician Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) showed improvement in the subjects who remained in the study. In addition, patient reported outcome measures of vision function revealed a mild- moderate subjective beneficial response across majority of subjects remaining in study.
- Elamipretide was generally safe and well-tolerated. There were no drug-related serious adverse events. There were injection site reactions that were believed to be drug-related. They were not serious.
- Clinical trials in advanced FA are challenging as it is difficult for the participants to travel to the study site multiple times and it is also difficult for them to perform some of the clinical assessments. For example,
- None of the included subjects perceived any letters on low contrast acuity charts.
- OCT images of poor quality (difficulty in OCT in advanced subjects with abnormal eye movements)
- Cardiac MRI was usually unable to be performed: technical aspects including positioning difficulties.