VM-PAD-096Concept Validation

Chrono-MUPS

IR Nicotinamide Riboside → ER Metformin for PAD

Peripheral Artery Disease (Intermittent Claudication)Fixed-Dose Combination

First chrono-bioenergetic therapy

Overview

PAD patients exhibit skeletal-muscle bioenergetic failure from chronic ischemia-reperfusion: oxidative phosphorylation impairment, mitochondrial damage, and delayed PCr recovery. Current drugs have modest effect; exercise is the main standard.

Unmet Medical Need

Limited pharmacologic options to improve walking performance beyond supervised exercise therapy and modest-effect vasodilators (cilostazol). No therapy targets skeletal-muscle bioenergetics directly.

Therapeutic Hypothesis

Chrono-sequenced combo in MUPS: IR nicotinamide riboside (NR) pulse to raise NAD⁺ ('redox priming'), followed by ER metformin to activate AMPK. Exploits NAD⁺–SIRT1–AMPK–PGC-1α coupling to amplify mitochondrial remodeling more than simultaneous dosing.

Computational Work Performed

PK window mapping using published human PK/PD data
NR: rapid NAD⁺ signal by DF-¹H-MRS; metformin ER t_max ≈ 7-8h
MUPS formulation feasibility screening (ethylcellulose/HPMC)
Chemical compatibility check: NR base-catalyzed hydrolysis risk with basic metformin
Supports physical segregation and/or acidic micro-environment for NR pellets

Next Milestones (Success Criteria)

1
In-vitro: NR-preload → metformin improves Spare Respiratory Capacity ≥25% vs simultaneous
2
Preclinical PAD model (hindlimb ischemia): superior treadmill endurance vs co-admin
3
On-target PD: muscle NAD⁺↑, p-AMPK↑, p-ACC↑
4
Human PK/PD: blood NAD⁺ metabolomics, ³¹P-MRS PCr-τ shortening

Competitive Landscape

Guideline-backed: supervised exercise therapy, revascularization. Drug options (cilostazol) offer modest functional gains. NICE RCT showed NR improved 6MWD (+17.6m overall; +31m with ≥75% adherence).

Key Differentiation

First-in-class chrono-bioenergetic therapy
Programs upstream NAD⁺ rise before AMPK activation
Mechanism-linked endpoints (³¹P-MRS PCr-τ, NIRS) anchor claims to muscle bioenergetics

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