Programs & Pipeline

Mitochondria, often described as the “powerhouse of the cell”, are responsible for approximately 90% of energy production in human cells.¹ These “powerhouses” are found in all human cells other than mature red blood cells.² Mitochondria produce energy through the conversion of food into adenosine triphosphate, or ATP.² This happens through a series of reactions, controlled by the electron transport chain, within the inner folds of the mitochondria.² In normal mitochondria, the inner mitochondrial membrane is highly folded, creating curves, called cristae.³ The cristae house the electron transport chain, which is composed of five protein complexes responsible for mitochondrial ATP production.³ Cardiolipin, a phospholipid found within the inner mitochondrial membrane, is responsible for establishing the cristae architecture and optimizing the function of ATP generating machinery, including the electron transport chain.⁴

Dysfunctional mitochondria can have an impaired ability to produce ATP and can generate increased levels of reactive oxygen species, or ROS, a major contributor to oxidative stress.² Although low levels of ROS can be important signaling molecules in the cell, high levels of ROS can damage proteins and membrane lipids within the cell. Cardiolipin in particular is highly susceptible to oxidative damage, which can result in disrupted mitochondrial structure and a cycle of increasing ROS generation that can lead to the inflammation, fibrosis, senescence and cell death implicated in many human diseases.⁵

Mitochondrial dysfunction is commonly observed across both common and rare diseases. Contributors to mitochondrial dysfunction can include genetic mutations, the aging process, environmental factors, or a combination thereof. These impairments can affect a number of different organ systems, especially those with high energetic demands such as heart, eye, brain, kidney, and skeletal muscle^10-12. Stealth is focused on mitigating mitochondrial dysfunction in rare diseases associated with cardiomyopathy, Barth syndrome, and Leber’s hereditary optic neuropathy^7-8, as well as a wide range of common age-related diseases, such as dry age related macular degeneration.^9-10

Healthy & Unhealthy

Our 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 three primary mitochondrial diseases — rare diseases with cardiomyopathy, Barth syndrome and Leber’s hereditary optic neuropathy – as well as a clinical study in dry age-related macular degeneration.

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Programs

TAZPOWER (Barth Syndrome)

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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 in abnormal mitochondria function).^22-24 It is estimated the incidence of Barth 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.

TAZPOWER is a randomized, double-blind, placebo-controlled phase 2/3 crossover study to evaluate the safety, tolerability and efficacy of 12 weeks’ treatment with daily subcutaneous injections of elamipretide in individuals with genetically confirmed Barth syndrome followed by an open-label treatment extension.²⁵

ReCLAIM-2 (Age-Related Macular Degeneration)

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Dry age-related macular degeneration, or dry AMD, is characterized by symptoms such as distorted vision, reduction in low luminance visual acuity, reduced overall visual acuity and blurred vision.^30-31 AMD is a disease estimated to impact more than 10 million individuals in the United States and the leading cause of blindness among older adults in the developed world, for which there are no FDA or EMA approved treatments.^30-33Mitochondrial dysfunction is believed to be a significant contributor to the progression of dry AMD³⁸, making the mitochondrial network an attractive target to improve retinal function and mitigate disease burdens in this patient population.

ReCLAIM-2 is a phase 2, randomized, double-masked, placebo-controlled clinical study to evaluate the safety, efficacy and pharmacokinetics of subcutaneous injections of elamipretide in subjects with dry AMD with geographic atrophy.

ReSIGHT (Leber’s Hereditary Optic Neuropathy)

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Leber’s hereditary optic neuropathy, or LHON, is a mitochondrial disease that affects the eyes and is characterized by central vision loss.²⁶ We estimate that approximately 10,000 individuals in the United States are diagnosed with LHON.²⁷ There are no therapies approved by the FDA for the treatment of LHON.²⁸ We have received Fast Track and Orphan Drug designation from the FDA for the development of elamipretide in this indication.

ReSIGHT is a randomized, double-masked, vehicle-controlled study to evaluate the safety, tolerability and efficacy of 52 weeks’ treatment with twice-daily topical eye drop formulation of elamipretide to treat patients with LHON, the most common mitochondrial optic neuropathy.²⁹

SBT-272 Phase 1

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SBT-272 is a novel peptidomimetic being developed for the treatment of neurodegenerative diseases involving mitochondrial dysfunction. SBT-272 has been shown to increase adenosine triphosphate (ATP) production and decrease levels of reactive oxygen species (ROS) in dysfunctional mitochondria in preclinical studies. SBT-272 demonstrates higher mitochondrial uptake, greater concentrations in the brain, and improved oral bioavailability relative to elamipretide, Stealth’s first-in-class lead compound. Treatment with SBT-272 was associated with a dose-dependent delay in the onset of neurological disease, a reduction in systemic markers of neurodegeneration and prolonged lifespan in a mouse model of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease characterized by motor neuron deterioration and muscle atrophy. The compound is currently being evaluated in another ALS preclinical model, as well as in a preclinical model indicative of activity in multiple system atrophy (MSA), a neurological disorder leading to parkinsonism, cerebellar ataxia, dysautonomia and other motor and non-motor symptoms. Mitochondrial dysfunction is believed to contribute to the progression of ALS and MSA, as well as other neurodegenerative diseases including Parkinson’s, Huntington’s and Alzheimer’s.

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 mitotrials.com or clinicaltrials.gov.