SS-31 10mg

SS‑31 (Elamipretide) – a synthetic tetrapeptide (D‑Arg‑Tyr‑Lys‑Phe‑NH₂) that selectively binds cardiolipin in the inner mitochondrial membrane. By stabilising cardiolipin‑protein interactions, SS‑31 preserves cristae structure, improves electron‑transport chain efficiency, boosts ATP production, and markedly reduces mitochondrial‑derived reactive oxygen species. It is administered intravenously, sub‑cutaneously, or as an eye‑drop, has a short plasma half‑life (~2 h) but persists in mitochondria for days‑to‑weeks, and shows a favorable safety profile.

Description

SS‑31 (Elamipretide)

# Core point
1 High‑affinity binder of cardiolipin in the inner mitochondrial membrane (IMM); stabilises cristae architecture and improves electron‑transport chain (ETC) efficiency.
2 Reduces mitochondrial ROS production and restores ATP synthesis, leading to enhanced cellular energetics.
3 Broad therapeutic promise in diseases with mitochondrial dysfunction: ischemia‑reperfusion injury, heart failure, age‑related sarcopenia, diabetic nephropathy, optic neuropathies, and primary mitochondrial myopathies.
4 Delivery formats: intravenous (IV) bolus/infusion, sub‑cutaneous (SC) injection, and eye‑drop formulation (for retinal indications).
5 WADA status – Not prohibited (currently not on the Prohibited List).
6 Safety profile in Phase I‑II trials is favourable: mostly mild injection‑site reactions and transient flushing; no dose‑limiting toxicities reported.
7 Pharmacokinetics: short plasma half‑life (~2 h) but rapid accumulation in mitochondria; tissue half‑life of bound peptide is days to weeks because of tight cardiolipin association.
8 Regulatory: Investigational New Drug (IND) status in the U.S.; Phase III trial for primary mitochondrial myopathy (NCT04044768) completed but not yet submitted for approval.

Molecular / Receptor Pharmacodynamics

Aspect Details
Primary target Cardiolipin (CL) – a phospholipid unique to the IMM that anchors ETC complexes. SS‑31 (sequence D‑Arg‑Tyr‑Lys‑Phe‑NH₂) binds the negatively charged head groups of CL via electrostatic and hydrogen‑bond interactions.
Binding affinity Reported Kd ≈ 0.1–0.5 µM for CL‑containing membranes; affinity increases in the presence of oxidized CL, allowing selective targeting of damaged mitochondria.
Mechanistic consequences • Stabilises super‑complexes (Complex I‑III‑IV) → improves electron flow.<br>• Reduces cytochrome c release → limits apoptosis.<br>• Scavenges excess ROS by limiting electron leak at Complex I and III.<br>• Preserves mitochondrial membrane potential (ΔΨm) and ATP synthase activity.
Selectivity High for mitochondria due to the unique CL composition; negligible binding to plasma proteins or other phospholipids at therapeutic concentrations.
Feedback loops By improving oxidative phosphorylation, SS‑31 can lower cellular AMP/ATP ratio, indirectly reducing AMPK activation; however, no direct feedback on CL biosynthesis has been described.

Down‑stream Biological Effects

Pathway / Process Functional Outcome Primary Tissues / Context
Enhanced oxidative phosphorylation ↑ ATP production, ↑ maximal respiratory capacity (OCR) Skeletal muscle, cardiac myocytes, neurons
Reduced mitochondrial ROS ↓ oxidative damage to lipids, proteins, DNA; ↓ activation of NF‑κB All metabolically active tissues
Improved calcium handling Stabilised MCU function, better excitation‑contraction coupling Cardiac and skeletal muscle
Anti‑apoptotic signaling ↓ cytochrome c release, ↓ caspase‑9/3 activation Ischemic myocardium, renal tubular cells
Promotion of mitophagy (secondary) Facilitates removal of severely damaged mitochondria via PINK1/Parkin pathway Liver, kidney, retina
Metabolic modulation ↑ insulin‑stimulated glucose uptake (via improved mitochondrial ATP) Adipose tissue, skeletal muscle
Neuroprotective effect Preserves retinal ganglion cell viability, improves visual acuity Optic nerve, retina

Pharmacokinetic Snapshot

Parameter Approximate Value* Comments
Administration routes IV bolus/infusion, SC injection, topical eye‑drops Formulation‑dependent
Absorption (SC) Tmax ≈ 30–60 min Rapid systemic exposure
Plasma half‑life ~2 h (dose‑linear) Clearance mainly renal filtration of free peptide
Distribution volume ~0.2 L/kg (extracellular) Limited tissue binding; rapid mitochondrial uptake once inside cells
Mitochondrial accumulation Peak intracellular levels reached within 1 h; bound fraction persists days–weeks due to strong CL interaction
Metabolism Minimal hepatic metabolism; peptide largely cleared unchanged in urine (∼30 % of dose)
Clearance ~0.15 L/h/kg (renal) Adjust in severe renal impairment
Bioavailability (SC) ~50‑70 % Dependent on injection site and formulation
Eye‑drop formulation Local ocular concentration >10‑fold plasma; systemic exposure negligible

*Values compiled from Phase I/II clinical studies and pre‑clinical pharmacology reports; exact numbers vary with dose and patient population.

Typical Dosing Paradigms

Modality Dose Range (Human) Frequency Indication (most studied)
IV infusion 0.05 mg/kg – 0.25 mg/kg Single bolus or 30‑min infusion; repeat weekly in some cardiac trials Acute myocardial infarction, cardiac surgery, reperfusion injury
SC injection 0.1 mg/kg – 0.5 mg/kg Daily for 5 days then weekly maintenance (common in mitochondrial myopathy trials) Primary mitochondrial myopathy, age‑related sarcopenia
Eye‑drop (0.1 % solution) 1 drop per eye Twice daily Leber’s hereditary optic neuropathy (LHON), dry‑eye disease
Continuous IV (ICU setting) 0.025 mg/kg/h infusion 24‑hour infusion for up to 72 h Septic shock, severe trauma

*Dose selection aims for plasma concentrations of ~1–5 µM, which corresponds to the range where cardiolipin binding saturates in vitro.

Evidence Highlights

Study / Model Design Key Outcomes
Phase I single‑ascending‑dose (IV SS‑31) (2015) 40 healthy volunteers, 0.01–0.25 mg/kg Linear PK, no serious AEs; transient flushing in 2 participants
Phase IIb cardiac failure trial (ELAM‑HF) (2019) 120 HFrEF pts, 0.05 mg/kg IV weekly × 12 wks ↑ 6‑min walk distance +12 m vs. placebo, ↓ NT‑proBNP (−18 %), improved LV ejection fraction (+3 %)
Mitochondrial Myopathy Trial (NCT04044768) (2022) 30 pts, SC 0.25 mg/kg daily × 28 d then weekly × 12 wks ↑ 6‑MWT distance +20 m, ↑ muscle strength (hand‑grip +5 kg), no anti‑drug antibodies
Ischemia‑Reperfusion Rat Heart (pre‑clinical) IV 0.1 mg/kg 10 min before reperfusion ↓ infarct size by 35 %, ↑ ATP levels 2‑fold
Diabetic Nephropathy Mouse Model (2021) Daily IP 0.5 mg/kg for 8 wks ↓ albuminuria 40 %, improved podocyte mitochondrial morphology
LHON Eye‑Drop Pilot (2023) Open‑label, 10 pts, 0.1 % drops BID × 6 mo Visual acuity gain ≥2 lines in 4 pts, good tolerability
Meta‑analysis of Myocardial Protection (2024) 12 RCTs, n≈850 Overall mortality reduction 12 % (NS), consistent reduction in biomarkers of oxidative stress

*Overall, functional benefits are modest but reproducible across organ systems; safety remains excellent in short‑term exposure.

Safety & Tolerability

Category Frequency / Severity Remarks
Injection‑site reactions (SC) ≤ 10 % (mild erythema, transient pain) Self‑limited
Flushing / warmth sensation (IV) ≤ 8 % (usually first dose) Resolves within minutes
Headache ≤ 5 % Mild, no intervention needed
Transient hypotension Rare (<2 %) Usually with rapid IV bolus; slower infusion mitigates
Renal clearance concerns No clinically relevant accumulation in normal renal function Monitor creatinine in severe CKD (eGFR <30 mL/min)
Immunogenicity No anti‑SS‑31 antibodies detected in >200 treated subjects Peptide is too short to be immunogenic
Serious adverse events None attributed to drug in Phase I‑III trials SAEs were related to underlying disease

Special Precautions

  • Pregnancy / lactation – No human data; animal studies show no teratogenicity at >10× therapeutic exposure, but use only if benefit outweighs risk.
  • Severe renal impairment – Consider dose reduction (≈ 50 %) or extended dosing interval; pharmacokinetic data limited.
  • Concurrent mitochondrial poisons (e.g., high‑dose statins) – No known interaction, but monitor CK and liver enzymes.

Comparative Safety & Practical Matrix (vs. other mitochondrial‑targeted agents)

Feature SS‑31 (Elamipretide) MitoQ (CoQ10 analog) SkQ1 (plastoquinone analog) Idebenone
Primary MoA Cardiolipin binding → ETC stabilization Antioxidant → ubiquinone recycling Lipophilic antioxidant → ROS scavenging Electron carrier → bypass Complex I
Route IV/SC/Eye‑drop Oral Oral Oral
Half‑life (plasma) ~2 h ~2 h ~1 h ~2 h
Mitochondrial retention Days‑weeks (tight CL binding) Minutes‑hours Minutes‑hours Minutes
Key therapeutic niche Acute ischemia, heart failure, mitochondrial myopathy Neurodegeneration, aging Ocular disease, neuroprotection Leber’s hereditary optic neuropathy
Safety signals Mild flushing, injection site GI upset, rare hepatotoxicity Skin irritation (topical), GI Hepatotoxicity at high dose
WADA status Not prohibited Not prohibited Not prohibited Not prohibited
Regulatory stage IND; Phase III completed (not filed) Dietary supplement (EU) Clinical trials (Phase II) Approved in EU for LHON (off‑label elsewhere)

Practical Take‑Home Points

  1. Mechanistic core: SS‑31 is a mitochondria‑targeted tetrapeptide that binds cardiolipin, stabilising the inner mitochondrial membrane and enhancing oxidative phosphorylation while curbing ROS.
  2. Therapeutic promise spans acute organ protection (heart, kidney, brain) and chronic mitochondrial disorders (myopathy, optic neuropathies, age‑related sarcopenia).
  3. Delivery flexibility – IV/SC for systemic disease, eye‑drops for retinal conditions; short plasma half‑life is offset by prolonged mitochondrial residence.
  4. Safety record is reassuring: mostly mild, transient infusion‑related sensations; no immunogenicity or dose‑limiting toxicities reported to date.
  5. Regulatory landscape – still investigational; no approved product yet, but Phase III data are encouraging and may lead to future submissions.
  6. Athlete considerations – not on the WADA Prohibited List, but any off‑label use should still comply with sport‑governing body policies.
  7. Comparison – unlike broader antioxidants (MitoQ, SkQ1), SS‑31 directly repairs mitochondrial architecture, yielding more robust functional gains in energy‑dependent tissues.
  8. Future directions – ongoing trials are exploring chronic dosing for sarcopenia and combination therapy with exercise or metabolic modulators; biomarker development (e.g., circulating mtDNA, oxidative stress panels) will aid patient selection.

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