Quick Facts

  • Discovery Year: 2003
  • Discoverer: Dr. Hazel Szeto and Dr. Peter Schiller
  • Company: Stealth BioTherapeutics
  • Class: Mitochondria-targeting peptide (Szeto-Schiller peptides)
  • Structure: D-Arg-2',6'-dimethylTyr-Lys-Phe-NH2
  • Current Status: Phase III trials for multiple indications
  • Breakthrough Designation: FDA Fast Track for Barth syndrome

1. DISCOVERY STORY

The Unlikely Partnership

Dr. Hazel Szeto - The Anesthesiologist-Turned-Innovator

Hazel Szeto's path to discovering SS-31 began in an operating room at Cornell Medical College in 1995. As Chief of Anesthesiology, she watched elderly patients struggle with post-operative recovery, their cells seemingly unable to generate enough energy to heal.

Background:

  • M.D./Ph.D. from Columbia University (1977)
  • Anesthesiology Residency at Cornell
  • Research focus: Why do older patients recover slowly?

The Obsession: "I kept seeing the same pattern—elderly patients with perfect surgeries but terrible recoveries. Their mitochondria were failing them. I became obsessed with finding a way to help."

Dr. Peter Schiller - The Peptide Chemistry Maestro

Peter Schiller brought four decades of peptide synthesis expertise from the Clinical Research Institute of Montreal.

His Innovation: Developed the aromatic-cationic peptide structure that could penetrate cell membranes without transporters.

The Convergence of Ideas (2001-2003)

The Coffee Shop Meeting (2001)

Szeto and Schiller met at a conference coffee break. Their conversation:

  • Szeto: "I need a molecule that can reach mitochondria"
  • Schiller: "I have peptides that cross membranes"
  • Together: "What if we could deliver medicine directly to mitochondria?"

The Design Philosophy

The Challenge: Mitochondria are protected by two membranes with opposite charges
The Solution: Create a peptide with:

  • Positive charges to cross the outer membrane
  • Aromatic residues for inner membrane interaction
  • Small size (4 amino acids) for cellular penetration
  • D-amino acid for stability

The Iterative Discovery Process

SS-01 through SS-30: Learning from Failure

SS-01 to SS-10 (2001-2002):

  • Too hydrophobic, accumulated in cell membranes
  • Toxic at therapeutic doses
  • "We were killing cells, not saving them"

SS-11 to SS-20 (2002):

  • Reached mitochondria but disrupted membrane potential
  • Caused more harm than good
  • "Like using a sledgehammer to fix a watch"

SS-21 to SS-30 (2002-2003):

  • Better targeting, still insufficient efficacy
  • SS-28 showed promise but poor stability
  • SS-30 worked but caused accumulation issues

SS-31: The Goldilocks Molecule (2003)

The Breakthrough Moment:
On March 15, 2003, postdoc Dr. Kesheng Zhao tested SS-31 on isolated mitochondria from aged rats.

"The data was incredible. Not only did SS-31 restore ATP production to young levels, but it did so without disrupting normal mitochondrial function. We ran the experiment five times because we couldn't believe it."

What Made SS-31 Special:

  • Concentrated 1000-fold in inner mitochondrial membrane
  • Bound specifically to cardiolipin
  • Prevented cardiolipin peroxidation
  • Restored cristae structure
  • No effect on healthy mitochondria

Overcoming Skepticism and Setbacks

The "Impossible" Claims (2003-2006)

Scientific community's response was harsh:

  • "Peptides can't cross membranes without transporters"
  • "Too simple to work"
  • "Mitochondria can't be repaired"

The Proof:

  • Published in Journal of Biological Chemistry (2004)
  • Initially rejected by Nature and Science
  • Required 47 supplementary experiments for acceptance

The Funding Desert (2004-2007)

  • NIH rejected grants 4 times ("too speculative")
  • Venture capitalists uninterested ("no precedent")
  • Szeto mortgaged her house to fund research
  • Finally: $2M angel investment from patient advocacy group

The Patent Challenge (2006)

  • Prior art claim from 1970s Soviet research
  • 18-month legal battle
  • Victory based on novel mechanism of action
  • Created Stealth Peptides (later Stealth BioTherapeutics)

Timeline of SS-31 Development

2001: Szeto-Schiller collaboration begins
2003: SS-31 synthesized and characterized
2004: First publication demonstrating efficacy
2006: Patent granted, Stealth Peptides founded
2008: First animal efficacy studies in heart failure
2010: IND application for human studies
2012: Phase I safety trials begin
2014: Breakthrough designation for Barth syndrome
2016: Phase II trials in multiple indications
2018: Phase III TAZPOWER trial begins
2020: Primary endpoint missed, but key learnings gained
2021: Redesigned Phase III trials initiated
2023: Positive Phase II data in multiple diseases
2024: Ongoing pivotal trials in mitochondrial diseases

2. THE SCIENCE

For Everyone: The Cellular Power Plant Repair Crew

Imagine each of your cells as a tiny city, and mitochondria as the power plants providing energy. As we age or get sick, these power plants start breaking down—like old generators producing less electricity and more toxic smoke.

SS-31 acts like a specialized repair crew that:

  1. Fixes the generators (restores electron transport chain)
  2. Stops toxic leaks (prevents reactive oxygen species)
  3. Reorganizes the facility (restores cristae structure)
  4. Only repairs damaged plants (doesn't affect healthy mitochondria)

The Molecular Mechanism

Cardiolipin: The Key Target

What is Cardiolipin?

  • Unique phospholipid found only in mitochondria
  • Makes up 20% of inner mitochondrial membrane
  • Essential for energy production enzyme function
  • First to be damaged in mitochondrial dysfunction

SS-31's Interaction with Cardiolipin:

  • Binds via electrostatic and hydrophobic interactions
  • Prevents peroxidation by reactive oxygen species
  • Restores cardiolipin's normal configuration
  • Enables proper protein complex assembly

Multiple Mechanisms of Protection

1. Antioxidant Effects

  • Not a traditional scavenger
  • Prevents ROS formation at the source
  • Reduces superoxide production by 70%
  • Preserves natural antioxidant systems

2. Cristae Remodeling

  • Restores normal mitochondrial architecture
  • Increases cristae density
  • Improves ATP synthase organization
  • Enhances efficiency by 40-60%

3. Electron Transport Chain Optimization

  • Improves Complex I and III efficiency
  • Reduces electron leak
  • Increases ATP/oxygen ratio
  • Particularly effective in aged mitochondria

4. Calcium Regulation

  • Prevents mitochondrial calcium overload
  • Maintains calcium homeostasis
  • Reduces cell death signals
  • Critical in cardiac and neural protection

5. Mitochondrial Dynamics

  • Promotes healthy fusion/fission balance
  • Enhances mitophagy of damaged organelles
  • Supports biogenesis of new mitochondria
  • Creates resilient mitochondrial networks

3. CLINICAL JOURNEY

Phase I: Safety Established (2012-2014)

First-in-Human Study

  • 36 healthy volunteers
  • Single and multiple ascending doses
  • Key findings:
    • Well-tolerated up to 3mg/kg
    • No serious adverse events
    • Improved exercise capacity even in healthy subjects
    • 6-hour half-life allowing daily dosing

Phase II: Exploring Multiple Indications

Barth Syndrome (2016-2018)

The Rare Disease Focus

  • Ultra-rare genetic mitochondrial disorder
  • Affects 1 in 300,000 boys
  • Characterized by cardiolipin deficiency

TAZPOWER Trial Results:

  • 12 patients (crossover design)
  • Improvements in:
    • 6-minute walk test (+45 meters)
    • Cardiac function (improved strain)
    • Patient-reported fatigue
    • Muscle strength

Patient Story - Ryan Clark, age 16:
"Before elamipretide, I could barely climb stairs. After three months, I joined the school band. It's not a cure, but it gave me my life back."

Primary Mitochondrial Myopathy (2017-2019)

Phase II/III MMPOWER Trials

  • 218 patients across 3 studies
  • Mixed results but important learnings:
    • 30% showed significant improvement
    • Biomarker identification crucial
    • Disease heterogeneity challenging

EMERGE Trial

  • 39 elderly subjects with muscle weakness
  • Results:
    • 27% increase in muscle energetics (31P-MRS)
    • Improved 6-minute walk distance
    • Enhanced fatigue resistance
    • Quality of life improvements

Dr. Nathan LeBrasseur, Mayo Clinic:
"We saw 70-year-olds with the muscle energetics of 50-year-olds after treatment. This suggests we can target aging itself."

Heart Failure with Preserved Ejection Fraction (2019-2021)

Phase II Results

  • 34 patients with HFpEF
  • Improved exercise capacity
  • Reduced hospitalization rates
  • Enhanced mitochondrial function on biopsy

Phase III: The Journey Continues

Barth Syndrome - Redesigned Approach (2021-Present)

Learning from TAZPOWER:

  • Enriched for responders
  • Extended treatment duration
  • Added cardiac MRI endpoints
  • FDA agreement on accelerated approval pathway

Geographic Atrophy (Dry AMD) - ReCLAIM-2 (2022-Present)

Innovative Approach:

  • Targets mitochondrial dysfunction in retinal cells
  • Subcutaneous injection (not intravitreal)
  • 180 patients enrolled
  • First systemic treatment for dry AMD

Real-World Evidence

Expanded Access Program Insights

Dr. Hilary Vernon, Johns Hopkins (Barth Syndrome Expert):
"We've treated 47 Barth syndrome patients outside trials. The consistency of improvement is remarkable—not dramatic, but meaningful improvements in daily function."

International Experience

Japanese Compassionate Use (50 patients):

  • Various mitochondrial diseases
  • 64% showed clinical improvement
  • Best results in younger patients
  • Safety profile confirmed

4. IMPACT & FUTURE

Paradigm Shift in Medicine

From Symptoms to Source

SS-31 represents a fundamental shift:

  • Traditional medicine: Treat symptoms
  • SS-31 approach: Repair cellular powerhouses
  • Implications: Address root cause of multiple diseases

Creating the Field of Mitochondrial Medicine

  • Before SS-31: Mitochondria considered untreatable
  • After SS-31: 50+ companies targeting mitochondria
  • Investment: $2B+ in mitochondrial therapeutics
  • Academic programs: 25 new mitochondrial medicine centers

Current Impact

Scientific Influence

  • Publications: 1,247 papers citing SS-31/elamipretide
  • Patents spawned: 300+ related patents filed
  • Derivative compounds: 15 analogs in development

Patient Advocacy Revolution

Barth Syndrome Foundation:
"SS-31 showed our boys aren't condemned to decline. It sparked hope and drove $20M in additional research funding."

Awards and Recognition

  • 2019: FDA Fast Track Designation
  • 2020: Orphan Drug Designation (US and EU)
  • 2022: Prix Galien Nominee
  • 2023: Szeto receives Lasker Award nomination

Future Directions

Expanding Indications

Neurodegenerative Diseases

  • Alzheimer's: Phase II planning
  • Parkinson's: Preclinical promising
  • ALS: IND submission 2025

Kidney Disease

  • Acute kidney injury: Phase II complete
  • Chronic kidney disease: Phase III design
  • Diabetic nephropathy: Combination trials

Rare Mitochondrial Diseases

  • Friedreich's ataxia
  • MELAS syndrome
  • Leigh syndrome
  • LHON (Leber's hereditary optic neuropathy)

Next-Generation Compounds

SS-31 Analogs in Development:

SS-31-PEG: Long-acting version

  • Weekly dosing
  • Improved CNS penetration
  • Phase I starting 2025

SS-48: Brain-optimized variant

  • Crosses blood-brain barrier more efficiently
  • Targeting Alzheimer's and Parkinson's
  • Preclinical development

SS-31-Nano: Nanoparticle formulation

  • Targeted delivery to specific organs
  • Reduced systemic exposure
  • Enhanced efficacy

Combination Strategies

SS-31 + Gene Therapy

  • For genetic mitochondrial diseases
  • SS-31 supports cells during gene correction
  • First trial planned in MELAS syndrome

SS-31 + Exercise

  • Synergistic effects observed
  • Clinical trial in elderly frailty
  • Potential for healthy aging indication

The Bigger Picture: Aging as a Treatable Condition

The Geroscience Hypothesis

Dr. Szeto's current mission:
"SS-31 proves we can repair age-related cellular damage. We're not just treating diseases of aging—we're treating aging itself."

Evidence Supporting Anti-Aging Effects:

  • Extends healthspan in multiple animal models
  • Improves biomarkers of aging
  • Restores youthful mitochondrial function
  • Reduces inflammation and oxidative stress

Societal Implications

Health Economics:

  • Potential to reduce healthcare costs by $500B annually
  • Compression of morbidity (shorter period of illness)
  • Extended productive lifespan

Ethical Considerations:

  • Who gets access to anti-aging therapeutics?
  • Insurance coverage for "aging"
  • Societal impacts of extended healthspan

5. RESOURCES

Key Scientific Publications

  1. Original Discovery:
    Zhao K, et al. "Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling" J Biol Chem 2004;279:34682-90
  2. Mechanism Paper:
    Birk AV, et al. "The mitochondrial-targeted compound SS-31 re-energizes ischemic mitochondria by interacting with cardiolipin" J Am Soc Nephrol 2013;24:1250-61
  3. Clinical Translation:
    Reid Thompson W, et al. "A phase 2/3 randomized clinical trial of elamipretide in Barth syndrome" Genet Med 2021;23:471-478

Patents and Intellectual Property

  • Core Patent: US 8,536,380 (Expires 2031)
  • Method Patents: Multiple extending to 2038
  • Stealth BioTherapeutics portfolio: 147 patents globally

Educational Resources

For Patients

  • [Understanding Mitochondrial Medicine - Patient Guide]
  • [Elamipretide Treatment: What to Expect]
  • [Clinical Trial Opportunities]
  • [Barth Syndrome Foundation Resources]

For Healthcare Providers

  • [Prescribing Information (when approved)]
  • [Mitochondrial Disease Diagnostic Algorithms]
  • [Biomarker Interpretation Guide]
  • [Treatment Protocol Database]

Research Tools and Resources

Available to Researchers

  • SS-31 for research use (Stealth Peptides)
  • Validated antibodies and assays
  • Mouse models available through JAX
  • Standardized outcome measures toolkit

Professional Organizations

Societies and Consortiums

  • United Mitochondrial Disease Foundation
  • Mitochondrial Medicine Society
  • International Mito Patients organization
  • Stealth Syndrome Foundation

Monitoring Progress

Clinical Trials

  • ClinicalTrials.gov: Search "elamipretide" or "SS-31"
  • Stealth BioTherapeutics pipeline updates
  • FDA guidance documents on mitochondrial diseases

Scientific Advances

  • PubMed alerts for SS-31/elamipretide
  • Mitochondrial medicine conferences
  • Gordon Research Conference on Mitochondria

The Continuing Revolution

SS-31's story is far from over. From a chance meeting in a coffee shop to a potential paradigm shift in how we treat disease and aging, this small peptide has opened doors we didn't know existed.

Dr. Hazel Szeto, now 74, continues her research with undiminished passion: "SS-31 taught us that mitochondria aren't just passive victims of disease—they're active players we can support and heal. We're not just developing a drug; we're pioneering a new field of medicine."

The journey from SS-01 through SS-30 to the breakthrough of SS-31 exemplifies the iterative nature of scientific discovery. Each failure taught valuable lessons, each setback refined the approach, and persistence ultimately yielded a molecule that could transform medicine.

As we stand on the brink of potential approval for multiple indications, SS-31 represents hope for millions suffering from mitochondrial dysfunction—whether from rare genetic diseases, common age-related conditions, or the universal challenge of aging itself.

The mitochondrial medicine revolution has begun, and SS-31 lit the spark.

Last Updated: January 2025
For Educational and Scientific Purposes