Programs & Pipeline

Stealth’s lead investigational product candidate, elamipretide, is a peptide compound that readily penetrates cell membranes, and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin.¹³ In preclinical or clinical studies, we have observed that elamipretide increases mitochondrial respiration, improves electron transport chain function and ATP production and reduces formation of pathogenic ROS levels.^13-19 This elamipretide-cardiolipin association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function.¹³ Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress.¹³ We are investigating elamipretide in late stage clinical studies in ophthalmic diseases entailing mitochondrial dysfunction, such as dry AMD, rare neuromuscular disorders, such as primary mitochondrial myopathy and Duchenne muscular dystrophy, and rare cardiomyopathies, such as Barth syndrome. We are evaluating our second-generation clinical-stage candidate, SBT-272, for rare neurological disease indications, such as amyotrophic lateral sclerosis.

Healthy & Unhealthy

Programs

Barth Syndrome

Barth syndrome, or Barth, is characterized by skeletal muscle weakness, delayed growth, fatigue, varying degrees of physical disability, heart muscle weakness, or cardiomyopathy, low white blood cell count, or neutropenia (which may lead to an increased risk for bacterial infections), and methylglutaconic aciduria (which is an increase in an organic acid that results from abnormal mitochondria function).^22-24 The incidence of Barth is estimated to be between one in 300,000 to 400,000 births.²²

There are no therapies approved by the FDA or the EMA for treating Barth.²⁴ We have received Fast Track and Orphan Drug designation from the FDA for the development of elamipretide in this indication. The U.S. Food and Drug Administration (“FDA”) is currently reviewing a New Drug Application (“NDA”) for elamipretide for the treatment of Barth syndrome with a user fee act date in early 2025.

NuPOWER (nuclear DNA mutations nPMD) —

The NuPOWER is a fully enrolled Phase 3 clinical trial designed from the clinical experience on the prespecified subgroup of patients with nPMD who appeared to respond to elamipretide therapy in the Company’s MMPOWER-3 trial. The nPMD subgroup of patients demonstrated a meaningful efficacy signal of improvement in the 6-minute walk test (6MWT), while the mtDNA subgroup did not show the same degree of benefit. For more information on the NuPOWER trial, please visit https://clinicaltrials.gov/ct2/show/NCT05162768

ReNEW (Dry Age-Related Macular Degeneration)

ReNEW is a Phase 3 global clinical trial evaluating the efficacy and safety of once-daily subcutaneous injections of elamipretide in participants with dry AMD. The primary endpoint for the trial is the rate of change in the macular area of photoreceptor loss assessed by spectral domain-optical coherence tomography and ellipsoid zone mapping. In the ReNEW trial, 360 patients will be randomized 2:1 to either elamipretide or placebo for 96 weeks with the option for participants to enroll in the open-label extension trial, ReTAIN. To learn more about the ReNEW trial, please visit https://dry-amdclinicaltrials.com/.

Bevemipretide (SBT-272)

Bevemipretide is a novel investigational small molecule that targets cardiolipin, a phospholipid within the inner mitochondrial membrane that is essential for mitochondrial structure and function. Bevemipretide has demonstrated mitochondria- and neuro-protective effects across preclinical models of alpha-synucleinopathy, amyotrophic lateral sclerosis, fronto temporal dementia, Huntington’s disease, and ischemic stroke. Bevemipretide-mediated improvements in functional assessments, lifespan, inflammation, and reduction of protein aggregates have been observed in these preclinical models. Data from a Phase 1 study evaluating subcutaneous Bevemipretide in healthy volunteers supports further clinical development.

Pipeline (SBT-255 and 580 series)

SBT-255 is a novel follow-on compound to our lead product candidate elamipretide. SBT-255 has a similar cardiolipin binding mechanism of action but has been clearly differentiated from other compounds across pre-clinical studies. It is currently being evaluated in several different models of cardiac and muscle myopathy including hypertrophic cardiomyopathy (HCM), idiopathic cardiomyopathy, Duchenne muscular dystrophy (DMD) and aging cardiac and skeletal muscle.

The SBT-580 series of compounds are promising novel molecules, with a unique mechanism of action, that acts on mitochondrial pathways essential for cellular health and energy production. The lead candidate in the series, SBT-589, has been studied in Friedreich’s ataxia (FA) patient-derived cells, isolated heart mitochondria, and an aggressive mouse model of FA cardiomyopathy. SBT-589 has been shown to improve bioenergetics in FA patient-derived cells and mitochondria and display significantly reduced cardiac hypertrophy. It has also been shown to delay the onset of mortality in mouse models.

Pipeline

Stealth BioTherapeutics continues to expand our broad knowledge of mitochondrial biology and novel chemistries, enabling us to advance our mitochondrial platform of late-stage clinical programs and pipeline candidates.

We have an active discovery and development program focused on the development of novel therapeutic compounds using proprietary new approaches to optimize absorption, distribution, metabolism and excretion properties. We have a growing compound library of small molecules and novel peptides that we are actively screening to broaden our existing mitochondrial product candidate portfolio.

Select pipeline compounds are being studied for neurodegenerative indications involving mitochondrial dysfunction. Mitochondrial dysfunction has been implicated as a factor in age-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, rare mitochondrial diseases, such as Leigh’s syndrome and Friedreich’s ataxia, and other rare diseases, such as ALS.

We are also developing a Mitochondrial Carrier Technology (MCT) platform to utilize the unique ability of our proprietary compounds to deliver biologically active cargo to mitochondria. Preliminary data demonstrates the ability of our carrier compounds to direct the distribution of biologically active cargo to mitochondria. This approach shows promise for mitochondrial localization of small molecules, and may also have the potential to deliver peptides, proteins and oligonucleotides.

For more information on Stealth BioTherapeutics’ Research and Discovery, please contact us discovery@stealthbt.com

Resources

For more information about clinical trials, please visit clinicaltrials.gov.