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 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 only in the inner mitochondrial membrane, is responsible for establishing the cristae architecture and optimizing the function of the electron transport chain for ATP generation.4

Dysfunctional mitochondria produce less ATP and increased unhealthy levels of reactive oxygen species, or ROS, which leads to oxidative stress.2 Although low levels of ROS are normal and important for the cell, high levels of ROS can damage cardiolipin, thereby disrupting the structure of the inner mitochondrial membrane and triggering 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 characterizes numerous inherited rare diseases – collectively known as primary mitochondrial diseases – that arise from over 250 different genetic mutations.6 These include primary mitochondrial myopathy, Barth syndrome, and Leber’s hereditary optic neuropathy.7-8 Mitochondrial dysfunction is also involved in a wide range of common age-related diseases, such as dry age related macular degeneration.9-10

As the body’s main source of energy production, mitochondria are critical for normal organ function, particularly with respect to high energy demanding organ systems such as skeletal muscle, eye, brain, heart and kidney.10-12 Patients with mitochondrial disease often experience functional deficit in three or more of these organ systems.11-12

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 the 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—primary mitochondrial myopathy, Barth syndrome and Leber’s hereditary optic neuropathy – as well as an earlier stage clinical study in dry age-related macular degeneration.

Stealth BioTherapeutics Clinical Development

Programs

MMPOWER-3 (Primary Mitochondrial Myopathy)

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Primary (inherited) mitochondrial myopathy, or PMM, is characterized by debilitating skeletal muscle weakness and exercise intolerance.12 It is estimated that approximately 70,000 individuals in the United States are diagnosed with this syndrome.20 There are no therapies approved by the U.S. Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of primary mitochondrial myopathy.12 We have received Fast Track designation and Orphan Drug designation from the FDA for the development of elamipretide in this indication.

MMPOWER-3 is a phase 3 randomized, double-blind, parallel-group, placebo-controlled trial to evaluate the efficacy and safety of daily subcutaneous injections of elamipretide in subjects with primary mitochondrial myopathy (PMM) followed by an open-label treatment extension.21

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

ReSIGHT (Leber’s Hereditary Optic Neuropathy)

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Leber’s hereditary optic neuropathy, or LHON, 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

ReCLAIM (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 Dry AMD is a disease estimated to impact more than 1.7 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.30-33

ReCLAIM is an open-label, phase 1 study to evaluate the safety and tolerability of 24 weeks’ treatment with daily subcutaneous injections of elamipretide in patients with intermediate dry AMD.34

Pipeline

Stealth BioTherapeutics continues to expand our broad knowledge of mitochondrial biology and novel chemistries, and 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.

Our second product candidate, SBT-20, and 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 Alzheimer’s and Parkinson’s disease, rare mitochondrial diseases, such as Leigh’s syndrome and Freidrich’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 at: discovery@stealthbt.com

Resources

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