Elamipretide

What is the molecular mechanism of action for elamipretide?

Elamipretide is a mitochondrial-targeted peptide compound that penetrates cell membranes and specifically targets the inner mitochondrial membrane where it binds reversibly to cardiolipin . This interaction helps normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function .

Through preclinical and clinical investigations, elamipretide has demonstrated several key effects:

• Increases mitochondrial respiration

• Improves electron transport chain function

• Enhances ATP production

• Reduces formation of pathogenic reactive oxygen species (ROS)

The functional benefit appears to be achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress . This mechanism makes it particularly relevant for disorders characterized by mitochondrial dysfunction.

For which medical conditions is elamipretide currently being investigated?

Elamipretide is being investigated in late-stage clinical studies across several disease categories that involve mitochondrial dysfunction:

• Ophthalmic diseases:

  • Dry age-related macular degeneration (AMD)

  • Intermediate AMD with high-risk drusen

• Rare neuromuscular disorders:

  • Primary mitochondrial myopathy (PMM)

• Rare cardiomyopathies:

  • Barth syndrome (BTHS)

Additionally, Stealth BioTherapeutics is evaluating their second-generation clinical-stage candidate, Bevemipretide (SBT-272), for rare neurological disease indications such as amyotrophic lateral sclerosis .

What are the standard outcome measures used in elamipretide clinical trials?

Clinical trials evaluating elamipretide have employed several standardized outcome measures depending on the condition being studied:

For primary mitochondrial myopathy:

• 6-minute walk test (6MWT) - measures distance walked in meters over 6 minutes

• Primary Mitochondrial Myopathy Symptom Assessment (PMMSA) Total Fatigue Score (TFS)

• NeuroQoL Fatigue Short-Form

• Patient and Clinician Global Impression scales

For Barth syndrome:

• 6-minute walk test (6MWT)

• Barth Syndrome Symptom Assessment (BTHS-SA) scale

• Knee extensor strength

• Patient global impression of symptoms

• Cardiac parameters

For age-related macular degeneration:

• Normal-luminance best-corrected visual acuity (BCVA)

• Low-luminance best-corrected visual acuity (LLVA)

• Normal-luminance binocular reading acuity (NLRA)

• Low-luminance binocular reading acuity (LLRA)

• Retinal pigment epithelium-drusen complex volume by OCT

• Fundus autofluorescence (FAF)

• Mesopic microperimetry

• Dark adaptation

• Low-luminance questionnaire (LLQ)

How should researchers design clinical trials to assess elamipretide efficacy in mitochondrial disorders?

Based on the analysis of current clinical trials, researchers should consider the following methodological approaches:

Study Design Considerations:

• Implement randomized, double-blind, placebo-controlled designs with adequate power

• Consider crossover designs with washout periods for rare diseases (used in Barth syndrome trial)

• Include open-label extension phases to assess long-term safety and efficacy

• Determine appropriate treatment duration (current trials range from 12-24 weeks for primary endpoints, with extensions up to 144 weeks)

Sample Size Calculation:
For MMPOWER-3, sample size calculation determined that 202 participants (101 per treatment arm) would provide:

• 90% power to detect a 30-meter difference between treatment groups in the 6MWT

• 90% power to detect a 1-unit difference in the PMMSA TFS

• Assuming standard deviations of 60 meters for 6MWT and 2 units for PMMSA TFS

• At an alpha level of 0.025

Dosing Protocol:

• Standard dosing across trials has been 40 mg/day of elamipretide administered subcutaneously

• Consider pharmacokinetic analysis to evaluate factors such as age, genotype, weight, height, lean body mass, BMI, liver function, serum creatinine, and renal function

Statistical Analysis Approach:

• Employ mixed-model repeated measures approach with fixed effects for treatment, visit, treatment-by-visit interaction, and participant as random effect

• Include baseline values and baseline-by-visit interaction as covariates

• Implement appropriate multiplicity adjustments (e.g., Hochberg procedure) when using multiple primary endpoints

What explains the differential efficacy of elamipretide across different mitochondrial disorders?

The varying efficacy of elamipretide across different mitochondrial disorders warrants careful consideration by researchers:

Confirmed Efficacy in Barth Syndrome:

• In Barth syndrome, elamipretide demonstrated significant improvements at 36 weeks in:

  • 6MWT (+95.9 m, p = 0.024)

  • BTHS-SA (-2.1 points, p = 0.031)

  • Additional improvements in knee extensor strength, patient global impression, and cardiac parameters

Lack of Efficacy in Primary Mitochondrial Myopathy:

• MMPOWER-3 trial showed elamipretide did not improve outcomes in 6MWT or PMMSA TFS compared to placebo, despite being well-tolerated

Possible Explanations for Differential Efficacy:

• Disease-specific pathophysiology: Barth syndrome has a specific defect in cardiolipin remodeling due to TAZ mutations, which directly aligns with elamipretide's mechanism of binding to cardiolipin

• Genetic heterogeneity: Primary mitochondrial myopathy encompasses a broader spectrum of genetic defects, potentially limiting uniform response to treatment

• Time-dependent effects: Significant benefits in Barth syndrome were observed at 36 weeks rather than 24 weeks, suggesting longer treatment duration may be necessary in some conditions

• Endpoint sensitivity: Different conditions may require different outcome measures to detect meaningful clinical changes

Researchers should carefully consider these factors when designing future trials, potentially focusing on more homogeneous patient populations or employing more sensitive outcome measures specific to each disorder.

What are the optimal pharmacokinetic considerations for elamipretide administration in clinical research?

When conducting elamipretide studies, researchers should account for these pharmacokinetic considerations:

Administration Route:

• Subcutaneous administration has been the standard in clinical trials

• Injection site reactions are the most common adverse events, which should be monitored and managed accordingly

Pharmacokinetic Analysis:

• MMPOWER-3 employed PK modeling for elamipretide and its metabolites (M1 and M2) using NONMEM computer software

• Consider analyzing the following covariates:

  • Age

  • Genotype

  • Weight and height

  • Lean body mass

  • Body mass index

  • Liver function tests

  • Serum creatinine

  • Renal function (eGFR)

Exposure-Response Analysis:

• Consider examining response based on the 6MWT as a function of steady-state exposure to elamipretide and its metabolites

• Evaluate whether specific patient subgroups show differential exposure-response relationships

Dosing Optimization:

• Current trials have standardized on 40 mg/day dosing

• Future research might explore dose optimization studies to determine if higher or lower doses might be more effective for specific conditions

How should researchers interpret the conflicting results between MMPOWER-3 and the Barth syndrome trial?

The contrasting outcomes between these two major elamipretide trials require careful analysis:

Key Differences Between Trials:

Interpretation Considerations:

• Timing of assessments: The Barth syndrome trial found significant benefits at 36 weeks but not at earlier timepoints, suggesting that mitochondrial improvements may require longer treatment periods to manifest clinically

• Genetic homogeneity: Barth syndrome has a single genetic cause (TAZ mutations) directly affecting cardiolipin, while PMM encompasses diverse genetic causes of mitochondrial dysfunction

• Statistical power: The sample size calculations and assumptions may have differed between trials, potentially affecting the ability to detect significant changes

• Disease severity and progression rate: Different mitochondrial disorders progress at different rates, potentially affecting treatment response windows

Researchers should consider these factors when designing future trials, potentially incorporating longer treatment durations and more homogeneous patient populations.

What approaches can be used to optimize visual function assessment in elamipretide AMD trials?

Based on the AMD clinical trials , researchers should consider these approaches for assessing visual function:

Comprehensive Visual Assessment Battery:

• Normal-luminance best-corrected visual acuity (BCVA)

• Low-luminance best-corrected visual acuity (LLVA)

• Normal-luminance binocular reading acuity (NLRA)

• Low-luminance binocular reading acuity (LLRA)

Functional Testing:

• Mesopic microperimetry to assess light sensitivity across the visual field

• Dark adaptation testing to evaluate rod and cone recovery function

• Low-luminance questionnaire (LLQ) to capture patient-reported visual function

Anatomical Assessments:

• Spectral-domain OCT to measure retinal pigment epithelium-drusen complex (RPE-DC) volume

• Fundus autofluorescence (FAF) to assess RPE health

Analysis Recommendations:

• Report both mean changes and proportion of patients meeting clinically significant thresholds

• Consider analyzing correlations between functional and anatomical measures

• Evaluate low-luminance measures as potentially more sensitive to early intervention effects

The AMD trials showed promising results in visual function measures, with mean change in BCVA from baseline to 24 weeks of +3.6 letters (p = 0.014) and LLVA of +5.6 letters (p = 0.004) . This suggests that low-luminance testing may be particularly sensitive to elamipretide's effects on mitochondrial function in the retina.

What are the optimal endpoints for assessing elamipretide efficacy in rare mitochondrial diseases?

Based on the current clinical trials, researchers should consider the following when selecting endpoints for rare mitochondrial disease studies:

Primary Endpoints with Demonstrated Sensitivity:

• 6-minute walk test (6MWT) - showed significant improvement in Barth syndrome

• Disease-specific symptom scales (e.g., BTHS-SA for Barth syndrome)

Secondary Endpoints to Consider:

• Objective strength measures (e.g., knee extensor strength)

• Patient and clinician global impression scales

• Disease-specific quality of life measures

• Biomarkers of mitochondrial function:

  • ATP production

  • Oxygen consumption

  • Reactive oxygen species levels

  • Cardiolipin remodeling (particularly in Barth syndrome)

Endpoint Selection Considerations:

• Match endpoints to specific disease manifestations

• Include both objective and subjective measures

• Consider testing sensitivity through small pilot studies

• Incorporate both functional and molecular endpoints when feasible

• Set realistic timeframes for improvement based on disease pathophysiology

Statistical Approaches:

• Consider responder analyses in addition to mean changes

• Employ appropriate multiplicity adjustments when using multiple primary endpoints

• Evaluate subgroup analyses based on genetic variants or baseline severity

What are the most common adverse events associated with elamipretide and how should they be monitored?

Based on the clinical trials reviewed, elamipretide demonstrates a consistent safety profile:

Most Common Adverse Events:

• Injection site reactions (most frequent adverse event)

• Mild to moderate adverse events (majority of adverse events were classified as mild (57-73.7%) or moderate (26.3-43%))

Monitoring Recommendations:

• Regular assessment of injection sites for:

  • Redness

  • Swelling

  • Pain

  • Pruritis

  • Induration

• Laboratory monitoring:

  • Liver function tests

  • Renal function (serum creatinine, eGFR)

  • Complete blood count

• Standardized adverse event reporting:

  • Use consistent grading systems for severity (mild, moderate, severe)

  • Document relationship to study drug

  • Track time course and resolution

• Discontinuation assessment:

  • Across trials, discontinuation due to adverse events was relatively uncommon

  • In the AMD trial, one participant discontinued due to injection site reaction

  • In the MMPOWER-3 trial, the most common reason for discontinuation was participant decision rather than adverse events

Special Considerations:

• Monitor for disease-specific adverse events (e.g., visual changes in AMD patients)

• Consider potential drug interactions, particularly with other medications targeting mitochondrial function

How should researchers design long-term safety studies for elamipretide?

For long-term safety evaluation of elamipretide, researchers should consider these methodological approaches:

Study Design Elements:

• Open-label extension studies following randomized controlled trials:

  • The Barth syndrome trial included an open-label extension where significant benefits were observed at 36 weeks

  • MMPOWER-3 planned a 144-week open-label extension to assess long-term safety and tolerability

• Safety monitoring schedule:

  • Early frequent monitoring (e.g., weeks 1, 2, 4)

  • Progressive spacing of visits (e.g., weeks 12, 24, 36, 48)

  • Annual comprehensive assessments for multi-year studies

• Comprehensive safety assessments:

  • Standardized adverse event collection

  • Regular laboratory assessments

  • Disease-specific monitoring (e.g., ophthalmologic exams for AMD)

  • Quality of life measures to capture subjective experiences

• Independent safety monitoring:

  • Data Safety Monitoring Board oversight

  • Predefined stopping rules for serious adverse events

Long-term Safety Endpoints:

• Cumulative incidence of treatment-emergent adverse events

• Changes in laboratory parameters over time

• Development of anti-drug antibodies

• Assessment of injection site reactions over extended use

• Disease-specific safety concerns (e.g., progression to neovascular AMD)

Statistical Considerations:

• Appropriate methods for handling missing data in long-term studies

• Time-to-event analyses for adverse events

• Modeling of laboratory parameter changes over time

How might elamipretide's effects on cardiolipin explain its differential efficacy across mitochondrial disorders?

Elamipretide's mechanism of binding to cardiolipin suggests a potential explanation for its varying efficacy:

Cardiolipin and Mitochondrial Function:

• Cardiolipin is a unique phospholipid located in the inner mitochondrial membrane (IMM)

• It plays crucial roles in:

  • Stabilizing respiratory chain supercomplexes

  • Maintaining cristae structure

  • Supporting efficient electron transport

  • Facilitating ATP production

Disease-Specific Cardiolipin Abnormalities:

• Barth Syndrome:

  • Caused by mutations in TAZ gene, which encodes the transacylase involved in the final remodeling step of cardiolipin

  • Results in abnormal cardiolipin species and reduced total cardiolipin

  • Elamipretide's direct binding to cardiolipin may compensate for these specific defects

  • May explain the positive clinical trial results in this population

• Primary Mitochondrial Myopathy:

  • Encompasses heterogeneous genetic defects affecting various components of mitochondrial function

  • May involve multiple pathways beyond cardiolipin abnormalities

  • The lack of efficacy in MMPOWER-3 may reflect that cardiolipin binding alone is insufficient to address the complex pathophysiology

• Age-Related Macular Degeneration:

  • Associated with mitochondrial dysfunction in retinal pigment epithelium

  • May involve age-related changes in cardiolipin composition and oxidative damage

  • The early phase trials showed promising results in visual function measures

Research Implications:

• Future studies might benefit from stratifying patients based on the degree of cardiolipin abnormalities

• Consider measuring cardiolipin species and content as potential biomarkers of treatment response

• Investigate combination therapies addressing multiple aspects of mitochondrial dysfunction

What biomarkers should be incorporated into elamipretide clinical trials to better assess mitochondrial function?

To enhance the assessment of elamipretide's effects on mitochondrial function, researchers should consider incorporating these biomarkers:

Tissue-Specific Functional Biomarkers:

• Muscle bioenergetics:

  • 31P-Magnetic Resonance Spectroscopy to measure ATP synthesis rates

  • Oxygen consumption in muscle biopsy samples

  • Lactate production during standardized exercise

• Cardiac function:

  • Strain rate imaging for subtle changes in myocardial contractility

  • Phosphocreatine/ATP ratio by cardiac magnetic resonance spectroscopy

• Ocular biomarkers:

  • Rod-mediated dark adaptation rates

  • Electroretinography responses

  • Mitochondrial function in circulating leukocytes from patients

Molecular Biomarkers:

• Cardiolipin analysis:

  • Cardiolipin content and species distribution in accessible tissues

  • Oxidized cardiolipin levels

• Mitochondrial dynamics markers:

  • Mitochondrial DNA copy number

  • Mitochondrial morphology in accessible tissues

  • Expression of fusion/fission proteins

• Oxidative stress markers:

  • F2-isoprostanes

  • Protein carbonyl content

  • Glutathione redox status

• Mitochondrial proteomics:

  • Assembly of respiratory chain complexes

  • Post-translational modifications of mitochondrial proteins

Implementation Considerations:

• Select biomarkers most relevant to the specific mitochondrial disorder under study

• Establish baseline values and expected ranges for each biomarker

• Consider the timing of biomarker assessment relative to treatment duration

• Correlate biomarker changes with clinical outcomes

How should researchers approach combination therapy studies involving elamipretide?

As mitochondrial disorders often involve multiple pathways, combination therapy approaches may be beneficial:

Potential Combination Strategies:

• Complementary mechanisms:

  • Combine elamipretide (targeting cardiolipin) with agents addressing other aspects of mitochondrial dysfunction

  • Examples: antioxidants, NAD+ precursors, mitochondrial biogenesis activators

• Tissue-specific combinations:

  • For multi-system disorders, combine elamipretide with tissue-targeted therapies

  • Example: elamipretide plus retina-specific therapies for AMD

• Sequential therapy approaches:

  • Priming therapy followed by elamipretide

  • Example: mitochondrial biogenesis induction followed by elamipretide to optimize newly formed mitochondria

Study Design Considerations:

• Factorial design:

  • 2×2 factorial design to assess individual and combined effects

  • Example groups: placebo, elamipretide alone, combination agent alone, elamipretide plus combination agent

• Adaptive design:

  • Interim analyses to identify promising combinations

  • Dropping ineffective combinations early

• Crossover elements:

  • Within-subject comparisons of monotherapy versus combination

  • Particularly useful in rare disorders with limited patient numbers

Endpoints and Analysis:

• Include biomarkers specific to each therapy's mechanism

• Assess for synergistic versus additive effects

• Monitor for potential drug interactions

• Consider pharmacokinetic studies to rule out drug-drug interactions

Safety Considerations:

• Carefully monitor for additive toxicities

• Start with lower doses of each agent when combining

• Establish clear stopping rules for combination-specific adverse events