Elamipretide (DB11981): A Comprehensive Monograph on a First-in-Class Mitochondrial-Targeted Tetrapeptide

Executive Summary

Elamipretide (DrugBank ID: DB11981) is an investigational, first-in-class, mitochondria-targeted therapeutic agent representing a novel paradigm in addressing diseases rooted in cellular bioenergetic failure. A synthetic aromatic-cationic tetrapeptide, Elamipretide was engineered to selectively target and interact with cardiolipin, a phospholipid unique to the inner mitochondrial membrane that is critical for maintaining mitochondrial structure and function. Its mechanism of action is fundamentally restorative; by binding to and stabilizing cardiolipin, Elamipretide improves the integrity of the electron transport chain, enhances adenosine triphosphate (ATP) production, and reduces the generation of damaging reactive oxygen species (ROS). This action is most pronounced in dysfunctional mitochondria, with minimal effect on healthy organelles, conferring a favorable safety profile.

The therapeutic rationale for Elamipretide is exceptionally broad, leading to an ambitious and complex clinical development program spanning multiple indications. These include ultra-rare genetic disorders such as Barth syndrome (BTHS) and primary mitochondrial myopathy (PMM), as well as common, age-related diseases like dry age-related macular degeneration (dry AMD) and heart failure. Across these varied conditions, the clinical trial results have been mixed. While the drug has consistently demonstrated excellent safety and tolerability, it has often failed to meet primary endpoints in large, heterogeneous patient populations. A recurring theme in its development has been the post-hoc identification of responsive patient subgroups or alternative endpoints that have justified continued, more targeted investigation.

The regulatory journey of Elamipretide, particularly for Barth syndrome in the United States, has been a protracted and challenging case study. It has highlighted the inherent friction between the U.S. Food and Drug Administration's (FDA) rigorous evidentiary standards and the practical impossibilities of conducting traditional large-scale, placebo-controlled trials for ultra-rare diseases. Despite an initial "refusal to file" and a subsequent Complete Response Letter, a positive recommendation from an FDA Advisory Committee and persistent advocacy have forged a potential path toward accelerated approval based on a surrogate endpoint, contingent on a post-marketing confirmatory study.

Developed by Stealth BioTherapeutics, Elamipretide serves as the lead asset for a broader platform focused on mitochondrial medicine. The company is leveraging the knowledge gained from Elamipretide's development to advance a pipeline of next-generation molecules and a proprietary mitochondrial drug delivery platform. The ultimate regulatory and commercial success of Elamipretide remains to be determined, but its journey has already significantly advanced the scientific understanding of mitochondrial therapeutics and has set important precedents for the development and review of drugs for ultra-rare diseases.

Introduction: Targeting Mitochondrial Dysfunction as a Therapeutic Strategy

The Centrality of Mitochondria in Health and Disease

Mitochondria are indispensable organelles that perform essential metabolic and energetic functions critical to cellular activity and survival. While widely recognized as the primary sites of ATP synthesis through oxidative phosphorylation (OXPHOS), their role extends far beyond energy production.[1] Mitochondria are central hubs for regulating cellular calcium homeostasis, orchestrating the intrinsic pathway of apoptosis (programmed cell death), and managing the production and detoxification of reactive oxygen species (ROS).[1]

Consequently, mitochondrial dysfunction is not a niche pathological curiosity but a fundamental mechanism implicated in a vast and diverse spectrum of human diseases.[1] This includes rare, inherited genetic disorders caused by mutations in either mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) that encode mitochondrial proteins, such as Barth syndrome, primary mitochondrial myopathies, and Leber's hereditary optic neuropathy.[3] Furthermore, accumulating evidence has established a causal link between mitochondrial decline and the pathophysiology of many common, complex, and age-related conditions, including heart failure, neurodegenerative diseases like Alzheimer's and Parkinson's disease, metabolic syndrome, and age-related macular degeneration.[1] In these conditions, chronic oxidative stress and other cellular insults lead to damage of mitochondrial components, impairing energy production, increasing ROS generation, and promoting cell death, thereby driving disease progression.[1]

The Emergence of Mitochondria-Targeted Therapeutics

Given the central role of mitochondrial failure in disease, these organelles represent a highly attractive target for therapeutic intervention.[2] However, the development of drugs that can effectively and selectively act within mitochondria has historically faced significant challenges. A primary obstacle has been the double-membrane structure of the mitochondrion, which presents a formidable barrier to the entry of many molecules.[5] Furthermore, identifying specific molecular targets within the complex machinery of the mitochondrion to safely restore function without disrupting normal cellular processes has proven difficult.[5] Elamipretide represents a leading example of a new class of therapeutics specifically designed to overcome these hurdles, employing a unique chemical architecture to achieve selective accumulation and action at the inner mitochondrial membrane.[1]

Elamipretide (SS-31): From Discovery to Clinical Investigation

Elamipretide originated from the serendipitous discovery of a family of cell-permeable antioxidant peptides known as the Szeto-Schiller (SS) peptides.[7] The 31st compound in this series, SS-31, was found to selectively target the mitochondrial electron transport chain, optimizing its efficiency and restoring cellular bioenergetics.[11] Originally designated SS-31 and later known by codes such as MTP-131 and the brand name Bendavia, the compound was eventually given the generic name Elamipretide.[11]

The development of Elamipretide was undertaken by Stealth Peptides, a company founded in 2006 to advance intellectual property licensed from several universities. The company later changed its name to Stealth BioTherapeutics.[12] Under its stewardship, Elamipretide has progressed through extensive preclinical and clinical investigation. The therapeutic strategy for Elamipretide is exceptionally broad, targeting the common denominator of mitochondrial dysfunction across a wide array of diseases. This approach positions the drug as a potential disease-modifying agent for conditions that are etiologically distinct but share a final common pathway of bioenergetic collapse. This breadth is both a significant opportunity and a major developmental challenge, necessitating a multifaceted clinical program and complex regulatory interactions, which have come to define the drug's trajectory.

Molecular Profile and Physicochemical Characteristics

Systematic Identification

Elamipretide is an investigational small molecule drug that is unambiguously identified by a consistent set of chemical and regulatory identifiers.

• Generic Name: Elamipretide [12]
• DrugBank ID: DB11981 [13]
• CAS Number: 736992-21-5 (for the free base form) [12]
• Synonyms and Development Codes: The compound has been referred to by numerous names throughout its development, including SS-31, MTP-131, Bendavia, and RX-31. Its chemical shorthand is often written as H-D-Arg-Tyr(2,6-diMe)-Lys-Phe-NH2 or D-Arg-Dmt-Lys-Phe-NH2.[11]

Chemical Structure and Composition

Elamipretide is classified as a small molecule and, more specifically, as an oligopeptide, containing a sequence of four amino acid residues.[12]

• Classification: Tetrapeptide [4]
• Amino Acid Sequence: The sequence is D-Arginyl-2,6-dimethyl-L-tyrosyl-L-lysyl-L-phenylalaninamide.[12] The structure incorporates several key features essential to its function: a D-amino acid (D-Arginine) at the N-terminus, which confers resistance to proteolysis; a synthetically modified tyrosine residue (2,6-dimethyl-L-Tyrosine, Dmt); and a C-terminal amidation (phenylalaninamide).
• IUPAC Name: (2S)-6-Amino-2-amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-hexanamide.[12]
• Molecular Formula: C32​H49​N9​O5​.[12]
• Molecular Weight: The calculated average molecular weight is approximately 639.80 g·mol⁻¹ (or 639.79 g·mol⁻¹), with a monoisotopic mass of approximately 639.3857 g·mol⁻¹.[12]

Physicochemical Properties and Formulation

The physicochemical properties of Elamipretide are uniquely tailored to its mechanism of action, leading to a profile that deviates from conventional orally available drugs. Although the free base is described as insoluble in water and soluble in DMSO [18], it is also referred to as a "water-soluble" peptide in clinical contexts, indicating that it is formulated as a salt for administration.[4] Various salt forms, including hydrochloride and acetate, have been developed.[13]

An analysis of Elamipretide's chemical structure reveals a deliberate departure from traditional drug design principles. Its calculated properties, such as a high polar surface area (264.56A˚2) and a large number of hydrogen bond donors and acceptors (10 each), result in a violation of Lipinski's Rule of Five.[13] For conventional drug development, such violations would predict poor oral bioavailability and membrane permeability. However, in the case of Elamipretide, these properties are not liabilities but functional necessities. The molecule's unique aromatic-cationic motif—comprising the positively charged D-Arginine and Lysine residues and the aromatic Phenylalanine and dimethyl-Tyrosine residues—is precisely what enables its high cell permeability and electrostatic attraction to the negatively charged inner mitochondrial membrane.[2] Thus, its "non-drug-like" characteristics are a direct consequence of its optimization for organelle targeting, a key principle in its rational design.

In clinical trials, Elamipretide has been administered through several routes, reflecting its intended use in systemic and localized diseases. These include intravenous infusion for acute conditions like heart failure, subcutaneous injection for chronic systemic administration in diseases like PMM and Barth syndrome, and a topical ophthalmic solution for localized treatment of LHON.[5]

Property	Value	Source(s)
Generic Name	Elamipretide	12
DrugBank ID	DB11981	13
CAS Number	736992-21-5 (free base)	12
IUPAC Name	(2S)-6-Amino-2-amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]amino]-N-hexanamide	12
Synonyms/Codes	SS-31, MTP-131, Bendavia, RX-31, D-Arg-Dmt-Lys-Phe-NH2	12
Molecular Formula	C32​H49​N9​O5​	12
Average Molar Mass	639.802 g·mol⁻¹	12
Monoisotopic Mass	639.385665714 g·mol⁻¹	13
Classification	Small Molecule, Oligopeptide (Tetrapeptide)	12
logP (Predicted)	-0.12 to -0.55	13
Polar Surface Area	264.56A˚2	13
Hydrogen Bond Donors	10	13
Hydrogen Bond Acceptors	10	13
Rotatable Bonds	19	13
Lipinski's Rule of Five	No (Violations: 2-3)	13
Physiological Charge	+3	13
Water Solubility (Predicted)	0.0155 mg/mL	13
Table 1: Key Identifiers and Physicochemical Properties of Elamipretide. This table consolidates the fundamental molecular and chemical data for Elamipretide, providing a comprehensive reference for its identity.

Mechanism of Action: Restoring Bioenergetics at the Inner Mitochondrial Membrane

The therapeutic activity of Elamipretide is predicated on a novel and highly specific mechanism of action that directly targets the root of mitochondrial dysfunction. It acts not as a conventional agonist or antagonist but as a molecular stabilizer, restoring the integrity and function of the mitochondrial machinery responsible for cellular energy production.

The Central Role of Cardiolipin

The primary molecular target of Elamipretide is cardiolipin (CL), a dimeric phospholipid with a unique structure containing four fatty acid chains.[1] CL is found almost exclusively within the inner mitochondrial membrane (IMM), where it plays several indispensable roles.[1] It is crucial for maintaining the highly curved architecture of the mitochondrial cristae, the folds of the IMM where oxidative phosphorylation occurs.[1] This structure is vital for optimizing the surface area available for energy production. Furthermore, CL acts as a molecular anchor for proteins of the electron transport chain (ETC), facilitating the assembly and stabilization of large multi-protein complexes known as respiratory supercomplexes (e.g., complexes I, III, and IV).[1] Under conditions of cellular stress and disease, CL is highly susceptible to oxidation by ROS. Oxidized CL loses its ability to properly organize the ETC, leading to supercomplex disruption, inefficient electron transport, increased electron leakage, further ROS production, and ultimately, impaired mitochondrial bioenergetics and the initiation of cell death pathways.[1]

Selective Targeting and Binding

Elamipretide is rationally designed to seek out and interact with CL. Its alternating aromatic-cationic amino acid sequence allows it to readily penetrate cell membranes and selectively accumulate at the IMM.[7] The IMM maintains a significant negative membrane potential, and the high concentration of negatively charged CL phosphate groups creates a strong electrostatic attraction for the positively charged arginine and lysine residues of Elamipretide.[2] This electrostatic interaction concentrates the peptide at its site of action. The binding is further stabilized by hydrophobic interactions between the peptide's aromatic residues (dimethyl-tyrosine and phenylalanine) and the acyl chains of CL.[10]

Stabilization of the Electron Transport Chain and Respiratory Supercomplexes

Once bound to CL, Elamipretide exerts a protective and restorative effect. It physically shields CL from peroxidation by ROS and stabilizes its interaction with key ETC components, most notably cytochrome c.[3] This elamipretide-cardiolipin association normalizes the structure of the IMM, promotes the proper assembly and stability of the respiratory supercomplexes, and improves the overall coupling and efficiency of the ETC.[5] This mechanism is fundamentally restorative rather than stimulatory. Evidence from studies on explanted human hearts demonstrates that Elamipretide improves mitochondrial function in failing cardiac tissue but has no discernible effect on the already normal function of mitochondria from non-failing hearts.[6] This pathology-dependent activity suggests that the therapeutic effect is contingent on the presence of mitochondrial stress and CL disorganization, explaining both its potential efficacy across diverse diseases and its favorable safety profile, as it does not appear to perturb normally functioning physiological pathways.

Downstream Bioenergetic and Cellular Effects

The stabilization of the IMM and ETC by Elamipretide triggers a cascade of beneficial downstream effects that collectively combat mitochondrial dysfunction:

• Enhanced ATP Production: By improving the efficiency of electron transport and OXPHOS, Elamipretide increases mitochondrial respiration and boosts the synthesis of ATP, restoring the cell's energy supply.[8]
• Reduction of Reactive Oxygen Species (ROS): A more tightly coupled ETC minimizes the leakage of electrons that react with oxygen to form superoxide and other harmful ROS. This action breaks the vicious cycle of oxidative stress, where ROS damages mitochondrial components, leading to more ROS production.[3]
• Restoration of Mitochondrial Architecture: The interaction with CL helps to normalize the morphology of mitochondrial cristae, which is often disrupted in mitochondrial diseases.[5]
• Anti-Apoptotic Effects: During apoptosis, CL translocates to the outer mitochondrial membrane, facilitating the release of cytochrome c, which activates the caspase cascade leading to cell death.[1] By stabilizing CL and preventing cytochrome c detachment, Elamipretide inhibits this key step in the intrinsic apoptotic pathway.[20]

Comprehensive Pharmacological Profile

The pharmacological profile of Elamipretide is characterized by a strong body of preclinical evidence demonstrating its cytoprotective and bioenergetic effects, which are supported by targeted pharmacodynamic findings in human studies. However, a comprehensive public profile of its systemic pharmacokinetics remains incomplete.

Pharmacodynamics (PD)

The pharmacodynamic effects of Elamipretide have been extensively documented in a wide range of preclinical models, establishing a robust scientific rationale for its clinical development. Studies have shown that Elamipretide can ameliorate myocardial infarction, improve renal function following ischemia-reperfusion injury, protect neurons from inflammatory and oxidative stress, and attenuate muscle wasting associated with disuse atrophy.[1]

These preclinical findings have been corroborated by direct evidence of pharmacodynamic activity in humans. A landmark study using freshly explanted failing human hearts demonstrated that ex vivo treatment with Elamipretide significantly improved mitochondrial oxygen flux and the function of respiratory supercomplexes (CI, CIII, and CIV).[6] This provided direct proof-of-principle for its mechanism in human cardiac tissue. Furthermore, a clinical trial in patients with heart failure with reduced ejection fraction (HFrEF) established a clear exposure-response relationship; the highest dose of infused Elamipretide resulted in favorable changes in left ventricular end-diastolic and end-systolic volumes that correlated significantly with peak plasma concentrations of the drug.[23] The FDA's own review of nonclinical data submitted for the Barth syndrome application concluded that the evidence supports the proposed mechanism of action related to the improvement of mitochondrial function and morphology.[28]

Pharmacokinetics (PK)

The pharmacokinetic profile of Elamipretide is defined more by its unique distribution characteristics than by traditional ADME parameters, for which there is a notable gap in publicly available information.

• Absorption and Distribution: As an aromatic-cationic peptide, Elamipretide is described as readily penetrating cell membranes and rapidly entering tissues within minutes of administration.[6] Its key feature is its selective localization to and concentration within the inner mitochondrial membrane, its site of action.[5] Preclinical evidence also suggests it is capable of crossing the blood-brain barrier.[30]
• Metabolism and Excretion: Detailed information regarding the metabolic pathways and route of elimination for Elamipretide is largely unavailable in the provided source materials. Major drug databases explicitly state that this information is "Not Available".[13] While its developer, Stealth BioTherapeutics, has stated a focus on optimizing ADME properties for its pipeline compounds, specific data for Elamipretide have not been widely published.[27]
• Human Pharmacokinetic Data: The most definitive human PK data comes from the Phase 2 trial in HFrEF patients. Following a single 4-hour intravenous infusion, peak plasma concentrations (Cmax​) were observed at the end of the infusion period. The drug was cleared from the plasma relatively quickly, becoming undetectable by 24 hours post-infusion.[23] This suggests a short plasma half-life, though its tissue and mitochondrial residence time may be longer.

The collective absence of detailed systemic ADME data represents a significant knowledge gap. For a drug that has undergone multiple Phase 3 trials and is under active NDA review, the lack of public information on its metabolism, clearance pathways, and potential for drug-drug interactions is conspicuous. This suggests that while intracellular pharmacodynamics have been the primary focus of its development story, its systemic disposition is a critical area that will undoubtedly be subject to intense regulatory scrutiny.

The Clinical Development Program: A Multi-Indication Analysis

The clinical development of Elamipretide has been ambitious, targeting a range of diseases linked by the common pathophysiology of mitochondrial dysfunction. This broad strategy has yielded a complex portfolio of clinical trials with varied outcomes, characterized by both significant setbacks and promising signals that have guided a progressively more refined development approach.

Barth Syndrome (BTHS)

Barth syndrome is an ultra-rare, X-linked genetic disorder caused by mutations in the TAZ gene, leading to defective cardiolipin remodeling. It is characterized by a triad of symptoms: cardiomyopathy, skeletal muscle weakness (myopathy), and neutropenia, accompanied by debilitating fatigue and growth delays.[4]

The pivotal study for this indication was the TAZPOWER trial, a Phase 2/3 study with a placebo-controlled crossover period followed by a long-term open-label extension.[31] While the initial crossover portion did not meet its primary endpoints, the open-label extension yielded compelling data that formed the basis of the New Drug Application (NDA). Key findings from the trial and its extension included a clinically meaningful increase in cardiac stroke volume (a 27% increase from baseline) and a substantial improvement in skeletal muscle strength, with knee extensor strength improving by over 45%.[31] Critically, this improvement in muscle strength was shown to be significantly correlated with gains in the 6-Minute Walk Test (6MWT), an FDA-recognized measure of clinical benefit, thereby linking the surrogate endpoint to functional improvement.[31]

Primary Mitochondrial Myopathy (PMM)

PMM is a heterogeneous group of genetic disorders that impair mitochondrial oxidative phosphorylation, resulting in pronounced muscle weakness, severe exercise intolerance, and fatigue.[5]

The development program in PMM began with the MMPOWER-1 and -2 trials, which were early-phase studies that provided promising initial signals. In the Phase I/II MMPOWER trial, intravenous Elamipretide demonstrated a dose-dependent increase in the distance walked in the 6MWT after just 5 days of treatment, providing Class I evidence of improved exercise performance.[5]

These encouraging results led to the pivotal MMPOWER-3 trial, a large, 218-participant, Phase 3 study evaluating 24 weeks of daily subcutaneous Elamipretide.[5] This trial, however, failed to meet its co-primary endpoints: change in 6MWT distance and change in the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) total fatigue score.[5] Despite the negative top-line result, the study confirmed that the drug was well-tolerated.[5]

A critical finding emerged from a pre-specified post-hoc analysis of the MMPOWER-3 data. While the overall population showed no benefit, the subgroup of patients whose PMM was caused by nuclear DNA (nDNA) mutations exhibited a statistically significant and clinically meaningful improvement in the 6MWT compared to placebo.[5] This discovery was transformative for the program. It led directly to the design and initiation of the NuPOWER trial, a new Phase 3 study specifically enrolling this nPMD patient population, particularly those with mutations affecting the mitochondrial replisome.[27]

Ophthalmic Indications

Mitochondrial dysfunction is a key driver of pathology in several ophthalmic diseases, prompting investigation of Elamipretide in this area.

• Leber's Hereditary Optic Neuropathy (LHON): A Phase 2 trial evaluated a topical ophthalmic solution of Elamipretide in patients with genetically confirmed LHON.[24] The study did not meet its primary efficacy endpoint, which was the change in best-corrected visual acuity (BCVA). However, the treatment was well-tolerated, and a post-hoc analysis revealed encouraging and statistically significant improvements in the mean deviation of the central visual field as measured by Humphrey automated perimetry. These secondary findings were deemed to warrant further exploration.[24]
• Dry Age-Related Macular Degeneration (AMD): The Phase 1/2 ReCLAIM studies assessed subcutaneous Elamipretide in patients with intermediate AMD and high-risk drusen.[1] The trials confirmed the drug was safe and well-tolerated. While primary endpoints related to disease progression markers like drusen volume were not met, exploratory analyses showed a positive effect on visual function, particularly under low-luminance conditions, and a potential slowing of photoreceptor degradation.[1] These promising signals supported the advancement of the program into two large, global Phase 3 trials, ReNEW and ReGAIN, which are currently underway to evaluate Elamipretide in a larger population of patients with dry AMD.[27]

Cardiovascular Indications

Given the high energy demands of the heart, cardiovascular diseases were an early and logical target for Elamipretide.

• Heart Failure with Reduced Ejection Fraction (HFrEF): The Phase 2 PROGRESS-HF trial evaluated a single intravenous infusion of Elamipretide in patients with stable HFrEF.[23] The study demonstrated that the infusion was safe and well-tolerated. While it did not meet its primary endpoint of reducing left ventricular end-systolic volume (LVESV), it did show favorable, dose-dependent reductions in both LV end-diastolic and end-systolic volumes at the highest dose, suggesting a beneficial effect on cardiac remodeling.[23]
• Ischemia-Reperfusion Injury: The EMBRACE-STEMI trial was a Phase 2a study in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI).[1] The trial did not show a reduction in myocardial infarct size, its primary endpoint. However, a secondary analysis found that Elamipretide treatment was associated with a significantly reduced incidence of new-onset heart failure within the first 24 hours post-PCI.[2]

The clinical development history of Elamipretide reveals a consistent and telling pattern: the failure to meet primary endpoints in broadly defined patient populations, followed by the discovery of promising signals in post-hoc analyses of specific subgroups or alternative endpoints. This occurred in PMM (leading to the NuPOWER trial), in LHON (central visual field improvement), in STEMI (early heart failure benefit), and in Barth syndrome (pivot to muscle strength as a surrogate endpoint). This trajectory suggests that the drug possesses genuine biological activity, but its clinical benefit is challenging to capture using traditional, one-size-fits-all clinical trial designs. It underscores a crucial lesson for the development of drugs targeting fundamental cellular processes in complex, heterogeneous diseases: initial "failures" may harbor the data necessary to define a more precise path to success through rigorous patient stratification and endpoint selection.

Trial Name/Program	Indication	Phase	Status	Primary Endpoint(s)	Key Outcomes
TAZPOWER	Barth Syndrome (BTHS)	2, 3	Completed	6-Minute Walk Test (6MWT)	Did not meet primary endpoint in crossover. Open-label extension showed significant improvement in knee extensor strength (>45%) and cardiac stroke volume (27%), forming the basis for NDA. 31
MMPOWER-3	Primary Mitochondrial Myopathy (PMM)	3	Terminated	Change in 6MWT; PMMSA Total Fatigue Score	Failed to meet co-primary endpoints. Well-tolerated. Post-hoc analysis showed significant 6MWT improvement in the nuclear DNA (nDNA) mutation subgroup. 5
NuPOWER	PMM (nDNA mutations)	3	Active, Not Recruiting	Change in 6MWT	Ongoing trial specifically designed for the responsive nPMD subgroup identified in MMPOWER-3. 27
ReNEW / ReGAIN	Dry Age-Related Macular Degeneration (AMD)	3	Recruiting	Rate of change in photoreceptor loss	Pivotal trials initiated based on positive safety and visual function signals from earlier phase studies. 27
LHON Phase 2	Leber's Hereditary Optic Neuropathy (LHON)	2	Completed	Change in Best-Corrected Visual Acuity (BCVA)	Failed to meet primary BCVA endpoint. Well-tolerated. Post-hoc analysis showed encouraging improvement in central visual field. 24
PROGRESS-HF	Heart Failure with Reduced Ejection Fraction (HFrEF)	2	Completed	Change in LV End-Systolic Volume (LVESV)	Did not meet primary endpoint. Showed favorable, dose-dependent changes in LV volumes. Safe and well-tolerated. 23
EMBRACE-STEMI	ST-Segment Elevation Myocardial Infarction (STEMI)	2	Completed	Myocardial Infarct Size	Failed to meet primary endpoint. Associated with reduced incidence of early-onset heart failure post-PCI. 1
Table 2: Summary of Major Clinical Trials of Elamipretide. This table provides a consolidated overview of the extensive and varied clinical development program for Elamipretide across its key indications.

Integrated Safety and Tolerability Assessment

Across its extensive clinical development program, which has involved diverse patient populations, various routes of administration, and long-term treatment periods, Elamipretide has consistently demonstrated a favorable safety and tolerability profile. This robust safety record is a cornerstone of its therapeutic proposition, particularly for the ultra-rare and life-threatening conditions it aims to treat.

Consolidated Safety Profile

Multiple clinical trials have concluded that Elamipretide is generally safe and well-tolerated.[5] The majority of adverse events (AEs) reported have been mild to moderate in severity and often transient.[5] In studies involving long-term administration, such as the open-label extension of the TAZPOWER trial, the safety profile has remained consistent without the emergence of new safety signals.[1]

Common Adverse Events (AEs)

The most frequently reported treatment-emergent AEs are related to the subcutaneous route of administration. These are typically mild-to-moderate injection site reactions, including erythema (redness), pruritus (itching), pain, swelling, induration (hardening), and bruising.[5] These reactions are generally self-limited or manageable with local care. Other commonly reported non-serious side effects across trials include headaches, dizziness, and gastrointestinal symptoms such as abdominal pain and flatulence.[19]

Serious Adverse Events (SAEs) and Discontinuations

The incidence of serious adverse events has been low across all clinical trials and, when they have occurred, they have generally been assessed by investigators as not being related to the study drug.[5] The rate of discontinuation due to adverse events has also been low. In the large MMPOWER-3 trial, 7.3% of participants in the Elamipretide group discontinued due to an AE, compared to 1.8% in the placebo group, with injection site reactions being a primary driver.[5] In the ReCLAIM study for dry AMD, only one participant discontinued due to an injection site reaction.[25] No treatment-related deaths have been reported in the clinical trial program.

Contraindications and Drug Interactions

As Elamipretide is an investigational drug that has not yet received marketing approval from any regulatory agency, there are no formally established contraindications or drug interactions listed in an approved product label.[19] Clinical pharmacology studies to formally assess drug-drug interaction potential have not been detailed in the available literature, and trial protocols have typically excluded participants based on clinically significant comorbidities or concomitant medications that could interfere with trial assessments.[36] This represents a data gap that would need to be addressed through post-marketing surveillance and further studies should the drug be approved.

The consistently favorable safety profile is a major strategic asset for Elamipretide. In the context of devastating ultra-rare diseases like Barth syndrome, where there is a high unmet medical need and no approved therapies, a drug with a low-risk profile and plausible evidence of benefit presents a compelling risk-benefit proposition. This strong safety record likely influenced the positive recommendation from the FDA Advisory Committee, providing a counterbalance to the agency's reservations about the non-traditional efficacy data. The safety profile thus lowers the perceived risk of approval and strengthens the case for regulatory flexibility.

Regulatory Trajectory: A Case Study in Ultra-Rare Disease Drug Approval

The regulatory history of Elamipretide for Barth syndrome in the United States is a landmark case study that encapsulates the profound challenges and evolving dynamics of drug approval for ultra-rare diseases. The multi-year saga illustrates the tension between the FDA's statutory requirement for "substantial evidence of effectiveness," traditionally derived from adequate and well-controlled trials, and the practical impossibility of conducting such trials in patient populations numbering only a few hundred worldwide.

U.S. Food and Drug Administration (FDA) Journey for Barth Syndrome

The regulatory pathway for Elamipretide has been complex and non-linear, involving multiple submissions, setbacks, and strategic pivots.

• Initial Submissions and Setbacks: Following initial discussions with the FDA starting in 2019, Stealth BioTherapeutics first submitted an NDA for Elamipretide. In 2021, the agency issued a "refusal to file" letter, citing the lack of a single, adequate, and well-controlled trial to support the application.[42] The company resubmitted the NDA in January 2024, this time including data from a natural history control study to bolster the evidence from the TAZPOWER open-label extension.[43]
• The Pivotal Advisory Committee Meeting: On October 10, 2024, the FDA convened the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) to review the application.[45] The briefing documents prepared by the FDA ahead of the meeting expressed significant skepticism regarding the efficacy data, highlighting the limitations of the open-label and externally controlled study designs.[44] However, the meeting became a powerful forum for patient and physician testimony, which detailed the devastating impact of Barth syndrome and the life-changing benefits observed with Elamipretide.[45] In a surprising outcome that underscored the power of the patient voice, the committee voted 10 to 6 to recommend approval, concluding that the totality of the evidence supported the drug's effectiveness.[42]
• Complete Response Letter and a New Path Forward: Despite the positive AdCom vote, the FDA's review period was extended, and in May 2025, the agency issued a Complete Response Letter (CRL), declining to approve the application in its current form.[31] The CRL cited the need for a post-marketing confirmatory study and also noted observations from a recent inspection of a third-party manufacturing facility.[31] Critically, however, the FDA's response also outlined a potential path forward: for the first time, the agency agreed to consider accelerated approval based on the improvement in knee extensor muscle strength as a reasonably likely surrogate endpoint. This represented a significant compromise, acknowledging the infeasibility of another pre-approval randomized trial while maintaining its evidentiary standards by requiring a post-marketing study to confirm clinical benefit.[31]
• Current Status: Acting on this new guidance, Stealth BioTherapeutics resubmitted its NDA for the third time in August 2025. The application was accepted for review by the FDA, which classified it as a Class 2 response with a planned PDUFA goal date in late 2025 or early 2026.[31] The review of this application is currently ongoing.

European Medicines Agency (EMA) Status

Elamipretide has also received regulatory designations in Europe that support its development for rare diseases.

• It holds an Orphan Drug Designation from the EMA for the treatment of Barth syndrome.[31]
• On May 16, 2022, the EMA also granted Elamipretide an Orphan Drug Designation for the treatment of myopathic mitochondrial DNA depletion syndrome, another rare mitochondrial disease.[34]

These designations provide the developer with benefits such as scientific advice and protocol assistance from the EMA, but they do not constitute marketing authorization. A formal Marketing Authorisation Application has not yet been submitted to the EMA.

Date	Event	Significance/Outcome
2021	First NDA Submission	The FDA issued a "Refusal to File" letter, citing the lack of a single adequate and well-controlled trial. 42
Jan 29, 2024	Second NDA Submission	Stealth resubmitted the NDA, supported by data from the TAZPOWER trial and a natural history control study. 43
May 6, 2024	Priority Review Granted	The FDA granted Priority Review, shortening the initial review timeline. 43
Oct 10, 2024	FDA Advisory Committee Meeting	The CRDAC voted 10-6 to recommend approval, concluding the drug was effective despite FDA skepticism about the trial design. 44
Jan 14, 2025	PDUFA Date Extension	The FDA extended the target action date from January to April 29, 2025, to review new analyses. 43
Apr 29, 2025	PDUFA Date Missed	The FDA announced it would not meet the extended action date, delaying the decision further. 43
May 29, 2025	Complete Response Letter (CRL) Issued	The FDA declined to approve the NDA but proposed a path forward for accelerated approval based on knee extensor muscle strength as a surrogate endpoint, contingent on a post-marketing study. 31
Aug 15, 2025	Third NDA Resubmission	Stealth resubmitted the NDA seeking accelerated approval based on the FDA's new guidance. 31
Aug 21, 2025	NDA Resubmission Accepted	The FDA accepted the resubmitted NDA for review, with a planned PDUFA goal date of September 26, 2025. 52
Table 3: Timeline of Key Regulatory Milestones for Elamipretide in Barth Syndrome (U.S. FDA). This timeline details the complex and protracted regulatory review process, highlighting the multiple setbacks and pivotal shifts in strategy.

Future Directions and Strategic Outlook

The future of Elamipretide and its developer, Stealth BioTherapeutics, is at a critical juncture. The outcome of the ongoing regulatory review for Barth syndrome will have profound implications, not only for that patient community but also for the company's broader strategic platform and the future of its clinical programs in larger indications.

Probability of Success and Market Potential

The commercial outlook for Elamipretide varies significantly by indication, reflecting a high-risk, high-reward development strategy.

• Barth Syndrome: Following the FDA's explicit guidance on an accelerated approval pathway, the probability of eventual approval for Barth syndrome is now reasonably high. However, the commercial market is exceptionally small, with an estimated prevalence of only around 150 individuals in the United States.[31] Success will depend on securing favorable pricing and reimbursement for this ultra-orphan indication.
• Primary Mitochondrial Myopathy: The NuPOWER trial, which specifically targets the nPMD subgroup that showed a response signal in the failed MMPOWER-3 study, represents a more focused and scientifically justified approach. This targeted strategy likely carries a higher probability of success than the previous trial in the broader PMM population.[27] The overall market for mitochondrial myopathies, while small, is projected to grow, reaching an estimated USD 36.5 million by 2035, offering a modest commercial opportunity.[57]
• Dry Age-Related Macular Degeneration (AMD): This indication represents the largest potential commercial opportunity by a significant margin. The market size for dry AMD in the seven major markets was estimated at approximately USD 1.3 billion in 2023.[39] However, this is also the highest-risk program. Given the mixed results from the earlier Phase 1/2 ophthalmic studies, achieving success in the large, long-duration Phase 3 ReNEW and ReGAIN trials is a formidable challenge.[38] A positive outcome would be transformative for the company, while a failure would be a major setback.

Corporate Strategy of Stealth BioTherapeutics

Stealth BioTherapeutics, founded in 2006 as Stealth Peptides, has maintained a singular focus on the discovery and development of therapies for diseases involving mitochondrial dysfunction.[12] The company is executing a classic biotechnology platform strategy. Elamipretide serves as the lead asset to validate the novel biological mechanism of cardiolipin modulation and the principle of mitochondrial targeting. The intense and costly multi-year effort to secure approval for Barth syndrome, an indication with limited standalone commercial potential, is strategically sound when viewed through this lens. An approval in Barth syndrome would provide critical validation for the entire platform, de-risking the mechanism of action for larger indications and future pipeline assets.

The company's pipeline demonstrates this long-term strategy. Beyond Elamipretide, Stealth is developing a second-generation clinical-stage molecule, Bevemipretide (SBT-272), as well as follow-on compounds like SBT-255 and the SBT-580 series for various neurological and cardiac indications.[27] Furthermore, the development of a Mitochondrial Carrier Technology (MCT) platform aims to leverage their proprietary targeting chemistry to deliver other biologically active cargo (such as peptides, proteins, and oligonucleotides) to mitochondria. This indicates a vision that extends far beyond a single molecule, positioning the company as a leader in the field of mitochondrial medicine.[27]

The Broader Landscape for Mitochondrial Therapies

The development journey of Elamipretide offers crucial lessons for the burgeoning field of mitochondrial therapeutics. It has highlighted the immense difficulty in selecting appropriate clinical endpoints for diseases with systemic and heterogeneous manifestations. The experience with MMPOWER-3 and the subsequent pivot to the NuPOWER trial underscores the critical importance of patient stratification based on underlying genetics or biomarkers. Finally, its regulatory saga in Barth syndrome has helped to define the boundaries of regulatory flexibility for ultra-rare diseases and has established a precedent for the use of surrogate endpoints to support accelerated approval in this context. The successes and failures of Elamipretide will continue to inform the clinical and regulatory strategies for the next generation of mitochondrial drugs.

Expert Conclusion and Synthesis

Elamipretide is a pioneering therapeutic agent, representing a scientifically elegant and highly targeted approach to correcting the fundamental bioenergetic deficits that drive a multitude of human diseases. Its mechanism of action, centered on the stabilization of mitochondrial cardiolipin, is a novel concept in pharmacology that has been well-supported by a robust body of preclinical and mechanistic evidence. The drug's ability to restore function preferentially in diseased mitochondria while sparing healthy ones has endowed it with an exceptionally favorable safety profile, a significant asset that has been consistently demonstrated across a broad and diverse clinical program.

However, the translation of this elegant mechanism into unequivocal clinical benefit has been a formidable challenge. The clinical development of Elamipretide has been a story of persistence in the face of repeated setbacks, with multiple trials in broad patient populations failing to meet their primary endpoints. Yet, within these datasets, rigorous post-hoc analyses have consistently unearthed signals of activity in specific patient subgroups or through alternative measures of efficacy. This has allowed for a more refined, iterative approach to its development, as exemplified by the pivot from the broad MMPOWER-3 trial to the genetically-defined NuPOWER study in primary mitochondrial myopathy.

The regulatory journey of Elamipretide for Barth syndrome has become a seminal case study in modern drug development. It has pushed the boundaries of regulatory science, forcing a confrontation between the need for rigorous, controlled evidence and the stark reality of studying ultra-rare diseases where such evidence is often impossible to obtain. The eventual path toward a potential accelerated approval, forged through scientific debate, intense patient advocacy, and regulatory compromise, may serve as a critical precedent for future therapies targeting similar patient populations.

In conclusion, while its path to market has been arduous and its ultimate place in the therapeutic armamentarium is still being defined, Elamipretide has already made an indelible mark. It has validated a novel therapeutic target, advanced our understanding of mitochondrial medicine, and illuminated a new regulatory path for ultra-rare disease drug development. Its future now rests on the outcomes of its highly targeted late-stage clinical trials and the final verdict from regulatory agencies—decisions that will have far-reaching implications for patients, for its developer, and for the entire field of mitochondrial-targeted therapeutics.

Works cited

1. Elamipretide: A Review of Its Structure, Mechanism of Action, and ..., accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11816484/
2. Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential, accessed September 3, 2025, https://www.mdpi.com/1422-0067/26/3/944
3. What is Elamipretide Hydrochloride used for? - Patsnap Synapse, accessed September 3, 2025, https://synapse.patsnap.com/article/what-is-elamipretide-hydrochloride-used-for
4. Elamipretide for Barth syndrome cardiomyopathy: gradual rebuilding of a failed power grid, accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9388406/
5. Efficacy and Safety of Elamipretide in Individuals With Primary Mitochondrial Myopathy: The MMPOWER-3 Randomized Clinical Trial - Neurology.org, accessed September 3, 2025, https://www.neurology.org/doi/10.1212/WNL.0000000000207402
6. Elamipretide Improves Mitochondrial Function in the Failing Human Heart - Stealth BioTherapeutics, accessed September 3, 2025, https://stealthbt.com/wp-content/uploads/Elamipretide-Improves-Mitochondrial-Function-in-the-Failing-Human-Heart.pdf
7. Elamipretide – Knowledge and References - Taylor & Francis, accessed September 3, 2025, https://taylorandfrancis.com/knowledge/Medicine_and_healthcare/Pharmaceutical_medicine/Elamipretide/
8. elamipretide (Pending FDA Approval) - Medscape Reference, accessed September 3, 2025, https://reference.medscape.com/drug/elamipretide-1000077
9. Elamipretide: A Review of Its Structure, Mechanism of Action, and Therapeutic Potential, accessed September 3, 2025, https://www.researchgate.net/publication/388194911_Elamipretide_A_Review_of_its_Structure_Mechanism_of_Action_and_Therapeutic_Potential
10. Mitochondrial protein interaction landscape of SS-31 - PNAS, accessed September 3, 2025, https://www.pnas.org/doi/10.1073/pnas.2002250117
11. Elamipretide - Friedreich's Ataxia Research Alliance, accessed September 3, 2025, https://www.curefa.org/drug-development/elamipretide/
12. Elamipretide - Wikipedia, accessed September 3, 2025, https://en.wikipedia.org/wiki/Elamipretide
13. Elamipretide: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed September 3, 2025, https://go.drugbank.com/drugs/DB11981
14. Elamipretide Completed Phase 2 Trials for Primary Mitochondrial Diseases Treatment, accessed September 3, 2025, https://go.drugbank.com/drugs/DB11981/clinical_trials?conditions=DBCOND0132407&phase=2&purpose=treatment&status=completed
15. ELAMIPRETIDE - gsrs, accessed September 3, 2025, https://gsrs.ncats.nih.gov/ginas/app/ui/substances/3a8a2740-697d-4ad3-9e42-89727f036fee
16. Elamipretide (MTP-131) | Antioxidant Peptide - MedchemExpress.com, accessed September 3, 2025, https://www.medchemexpress.com/Elamipretide.html
17. Elamipretide (MTP-131, SS-31) | 99.37%(HPLC) | Peroxidases inhibitor - Selleck Chemicals, accessed September 3, 2025, https://www.selleckchem.com/products/elamipretide-mtp-131.html
18. Elamipretide | CAS#736992-21-5 | cardiolipin peroxidase inhibitor - MedKoo Biosciences, accessed September 3, 2025, https://www.medkoo.com/products/6723
19. Elamipretide Clinical Studies and Trials - Stealth BioTherapeutics, accessed September 3, 2025, https://stealthbt.com/programs-pipeline-copy/
20. SS-31 (also known as Elamipretide®, Bendavia®, and MTP-131) - Alzheimer's Drug Discovery Foundation, accessed September 3, 2025, https://www.alzdiscovery.org/uploads/cognitive_vitality_media/SS-31-Cognitive-Vitality-For-Researchers.pdf
21. Compound: ELAMIPRETIDE (CHEMBL3833370) - ChEMBL - EMBL-EBI, accessed September 3, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL3833370
22. Elamipretide Completed Phase 1 Trials for Normal and Impaired Renal Function Basic Science - DrugBank, accessed September 3, 2025, https://go.drugbank.com/drugs/DB11981/clinical_trials?conditions=DBCOND0076451&phase=1&purpose=basic_science&status=completed
23. Novel Mitochondria-Targeting Peptide in Heart Failure Treatment: A Randomized, Placebo-Controlled Trial of Elamipretide, accessed September 3, 2025, https://www.ahajournals.org/doi/10.1161/circheartfailure.117.004389
24. Elamipretide Topical Ophthalmic Solution for the Treatment of ..., accessed September 3, 2025, https://pubmed.ncbi.nlm.nih.gov/37923251/
25. Phase 1 Clinical Trial of Elamipretide in Intermediate Age-Related ..., accessed September 3, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9560633/
26. Elamipretide Improves Mitochondrial Function in the Failing Human Heart - JACC Journals, accessed September 3, 2025, https://www.jacc.org/doi/10.1016/j.jacbts.2018.12.005
27. Elamipretide Clinical Studies and Trials - Stealth BioTherapeutics, accessed September 3, 2025, https://stealthbt.com/programs-pipeline/
28. Elamipretide for the Treatment of Barth Syndrome - FDA, accessed September 3, 2025, https://www.fda.gov/media/182608/download
29. The heart of the matter: Elamipretide in the treatment of Barth syndrome, accessed September 3, 2025, https://researchoutreach.org/articles/heart-matter-elamipretide-treatment-barth-syndrome/
30. Neuroprotective Effects of a Small Mitochondrially ... - Frontiers, accessed September 3, 2025, https://www.frontiersin.org/journals/integrative-neuroscience/articles/10.3389/fnint.2021.747901/full
31. STEALTH BIOTHERAPEUTICS RESUBMITS NEW DRUG APPLICATION FOR ELAMIPRETIDE FOR THE TREATMENT OF BARTH SYNDROME, accessed September 3, 2025, https://stealthbt.com/stealth-biotherapeutics-resubmits-new-drug-application-for-elamipretide-for-the-treatment-of-barth-syndrome/
32. tazpower - Barth Syndrome Foundation, accessed September 3, 2025, https://www.barthsyndrome.org/research/clinicaltrials/tazpower.html
33. Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy - Neurology.org, accessed September 3, 2025, https://www.neurology.org/doi/10.1212/WNL.0000000000005255
34. Primary mitochondrial myopathies: elamipretide is well tolerated but does not improve the 6-minute walk test or fatigue, accessed September 3, 2025, https://www.institut-myologie.org/en/2023/08/31/primary-mitochondrial-myopathies-elamipretide-is-well-tolerated-but-does-not-improve-the-6-minute-walk-test-or-fatigue/
35. Elamipretide for Adult Patients with Primary Mitochondrial Disease, accessed September 3, 2025, https://www.research.chop.edu/elamipretide-for-adult-patients-with-primary-mitochondrial-disease
36. UCSD Myopathy Trial → Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD), accessed September 3, 2025, https://clinicaltrials.ucsd.edu/trial/NCT05162768
37. Elamipretide Topical Ophthalmic Solution for the Treatment of Subjects With Leber's Hereditary Optic Neuropathy: A Randomized Trial, accessed September 3, 2025, https://www.opticnervenetwork.com/2571/elamipretide-topical-ophthalmic-solution-for-the-treatment-of-subjects-with-lebers-hereditary-optic-neuropathy-a-randomized-trial/
38. First Patient Enrolled in Global Phase 3 Clinical Program | Stealth Biotheraputics, accessed September 3, 2025, https://stealthbt.com/stealth-biotherapeutics-announces-first-patient-enrolled-in-global-phase-3-clinical-program-for-elamipretide-in-patients-with-dry-age-related-macular-degeneration/
39. Dry AMD Market Size In The 7MM Was ~ USD 1,300 Million In 2023, Estimated DelveInsight, accessed September 3, 2025, https://www.barchart.com/story/news/29760674/dry-amd-market-size-in-the-7mm-was-usd-1300-million-in-2023-estimated-delveinsight
40. Elamipretide: Side Effects, Uses, Dosage, Interactions, Warnings - RxList, accessed September 3, 2025, https://www.rxlist.com/elamipretide/generic-drug.htm
41. Elamipretide: Uses, Side Effects, Dosage - MedicineNet, accessed September 3, 2025, https://www.medicinenet.com/elamipretide/article.htm
42. After lengthy review, FDA snubs Stealth's Barth syndrome therapy, accessed September 3, 2025, https://firstwordpharma.com/story/5967205
43. Stealth BioTherapeutics Announces Delay in FDA Action Date for Barth Syndrome Application, accessed September 3, 2025, https://stealthbt.com/stealth-biotherapeutics-announces-delay-in-fda-action-date-for-barth-syndrome-application/
44. 'Impossible' FDA adcomm ends in favor of Stealth's ultra-rare disease med - Fierce Biotech, accessed September 3, 2025, https://www.fiercebiotech.com/biotech/impossible-fda-adcomm-ends-favor-stealths-ultra-rare-disease-med
45. elamipretide - Barth Syndrome Foundation, accessed September 3, 2025, https://www.barthsyndrome.org/advocacy/elamipretide.html
46. FDA Advisory Committee Review of Elamipretide - Barth Syndrome Foundation, accessed September 3, 2025, https://www.barthsyndrome.org/advocacy/fdaadcomm.html
47. FDA Advisory Committee Supports Approval of Elamipretide for Barth Syndrome, accessed September 3, 2025, https://synapse.patsnap.com/article/fda-advisory-committee-supports-approval-of-elamipretide-for-barth-syndrome
48. Barth Syndrome Foundation Responds to FDA's Proposed 'Path Forward' for Elamipretide, accessed September 3, 2025, https://www.barthsyndrome.org/article/2025/05/29/barth-syndrome-foundation-responds-to-fda-s-proposed-path-forward-for-elamipretide
49. FDA Denies Approval for Elamipretide, Forcing Stealth BioTherapeutics to Halt Production of Rare Disease Treatment - MedPath, accessed September 3, 2025, https://trial.medpath.com/news/411e9121a0c4dc63/fda-denies-approval-for-elamipretide-forcing-stealth-biotherapeutics-to-halt-production-of-rare-disease-treatment
50. Stalled Hope: Families Urge FDA to Clear Elamipretide for Barth ..., accessed September 3, 2025, https://patientworthy.com/2025/08/24/stalled-hope-families-urge-fda-to-clear-elamipretide-for-barth-syndrome/
51. Stealth BioTherapeutics Announces "Path Forward" Despite Disappointing Delay for Ultra-rare Barth Syndrome, accessed September 3, 2025, https://stealthbt.com/stealth-biotherapeutics-announces-path-forward-despite-disappointing-delay-for-ultra-rare-barth-syndrome/
52. STEALTH BIOTHERAPEUTICS ANNOUNCES FDA ACCEPTANCE ..., accessed September 3, 2025, https://www.biospace.com/press-releases/stealth-biotherapeutics-announces-fda-acceptance-of-elamipretide-nda-resubmission
53. Stealth Biotherapeutics Announces FDA Acceptance of Elamipretide NDA Resubmission, accessed September 3, 2025, https://www.drugs.com/nda/elamipretide_250821.html
54. Union Register of medicinal products - Public health - European Commission, accessed September 3, 2025, https://ec.europa.eu/health/documents/community-register/html/o2614.htm
55. EU/3/22/2614 - orphan designation for treatment of myopathic ..., accessed September 3, 2025, https://www.ema.europa.eu/en/medicines/human/orphan-designations/eu-3-22-2614
56. Stealth BioTherapeutics Announces PDUFA Action Date Extension for Elamipretide to Treat Patients with Barth Syndrome - PR Newswire, accessed September 3, 2025, https://www.prnewswire.com/news-releases/stealth-biotherapeutics-announces-pdufa-action-date-extension-for-elamipretide-to-treat-patients-with-barth-syndrome-302358052.html
57. Mitochondrial Myopathies Market to Reach USD 36.5 Million by 2035, Impelled by Advancements in Targeted Drug Therapies - BioSpace, accessed September 3, 2025, https://www.biospace.com/press-releases/mitochondrial-myopathies-market-to-reach-usd-36-5-million-by-2035-impelled-by-advancements-in-targeted-drug-therapies
58. www.investing.com, accessed September 3, 2025, https://www.investing.com/equities/stealth-biotherapeutics-inc-company-profile#:~:text=Stealth%20BioTherapeutics%20Corp%20was%20formerly,in%20Camana%20Bay%2C%20Cayman%20Islands.
59. Stealth BioTherapeutics is an innovative, clinical stage biopharmaceutical company committed to bringing patients mitochondria-t, accessed September 3, 2025, https://stealthbt.com/wp-content/uploads/Sr-Director-Discovery-Job-Description-FINAL-06-29-21.pdf
60. Our Company | StealthBiotherapeutics, accessed September 3, 2025, https://stealthbt.com/our-company/
61. About Stealth BioTherapeutics Corp (MITO) - Investing.com, accessed September 3, 2025, https://www.investing.com/equities/stealth-biotherapeutics-inc-company-profile
62. Stealth BioTherapeutics 2025 Company Profile: Valuation, Funding & Investors | PitchBook, accessed September 3, 2025, https://pitchbook.com/profiles/company/64697-14