Skeletal Muscle Metabolic Flux Engine
Simulating 12S rRNA peptide export, folate cycle feedback, AICAR buildup & AMPK Thr172 phosphorylation
Endogenous: ~5-12 nM | High Supp: >50 nM
Mitochondrial Origin: 16-aa MOTS-c (mtDNA 12S rRNA)
Inhibition: 10-formyl-THF Folate Cycle & Purine synthesis
Activation: AICAR accumulation & AMPK phosphorylation
Clinical Workspace & Regulatory Evidence
NCT07505745 human Phase 2a parameters, Matsuda Index projections, & PCAC vote context
Hudson Biotech / PKU Shenzhen Hospital (Phase 2a)
Recruiting Since Apr 1, 2026
Study Identifier
NCT07505745 (Double-blind RCT)
Dosing Architecture
Once-daily Subcutaneous (12 Wks)
Masking Level
Quadruple (Participant, Care, Inv, Assessor)
Primary Readout
Matsuda Index (OGTT, Feb 2027)
Simulated 12-Week Matsuda Index Shift (Baseline vs Modeled End-of-Study)
+42% Projected
Analog Historical Control: CB4211, an engineered synthetic analogue developed by CohBar, underwent Phase 1a/1b testing in non-alcoholic fatty liver disease (NAFLD) in 2021 before termination. MOTS-MET represents the first registered trial of native, sequence-identical mitochondrial MOTS-c.
July 23, 2026 PCAC Advisory Determination
Section 503A Bulk List
The Pharmacy Compounding Advisory Committee evaluated MOTS-c for inclusion on the 503A list allowing compounding pharmacies to reconstitute bulk active pharmaceutical ingredients without standard NDA approval.
7
Recommend
Recommend
5
Oppose
Oppose
2
Abstain
Abstain
Majority Position (7 Votes): Emphasized high homology of endogenous human peptide, favorable toxicology profile in preclinical non-human primates, and critical physiological role in exercise mimetics.
Minority / Dissent (5 Votes): Cited lack of completed human Phase 2/3 efficacy endpoints, absence of standardized United States Pharmacopeia (USP) monographs, and concerns over potential off-target purine pool depletion.
Statutory Distinction: A PCAC advisory recommendation is not FDA drug approval. Section 503A compounding does not establish therapeutic equivalence, safety verification, or on-label marketing rights.
| Biological Claim | Evidentiary Model | Validation Status |
|---|---|---|
| Folate Inhibition & AICAR Increase | In vitro myoblasts (Lee et al. 2015) | Replicated |
| Prevention of Diet-Induced Obesity | C57BL/6J High-Fat Diet Mice | Proven Preclinical |
| Post-Exercise Endogenous Plasma Surge | Human Athletes & Rodents (Reynolds 2021) | Corroborated |
| Sustained Human Insulin Sensitization | NCT07505745 (MOTS-MET Phase 2a) | Under Evaluation (2027) |
| Statutory 503A Compounding Clearance | FDA Advisory Committee July 2026 | Advisory Rec (7-5) |