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A Phase 1 Randomized, Placebo-Controlled, Parallel Study of the Novel Peroxisome Proliferator-Activated Receptor δ Agonist REN001 in Healthy Volunteers during and After Limb Immobilization

Madhu Davies*, Alejandro Dorenbaum, Shulin Wang, Bettina Mittendorfer

Objective: Assess the safety, tolerability and effects of the Peroxisome Proliferator-Activated Receptor δ (PPARδ) agonist REN001 on muscle recovery after limb immobilization.

Methods: Eligible healthy adults were randomly assigned 1:1 to REN001 100 mg twice daily or placebo for 28 days. Participants were leg-immobilized with a knee brace and used crutches from 1 to 14 days. Changes in muscle strength, gene expression from muscle biopsies and muscle Cross-Sectional Area (CSA) in the immobilized leg were evaluated. After 14 days of dosing the brace was removed and the subjects took study drug for another 14 days, gradually resuming regular physical activity. The primary pharmacodynamics endpoint was the change from baseline to day 21 in muscle strength as measured by knee extension.

Results: Twenty-four male participants were enrolled and treated, 12 in each treatment group. Four participants (16.7%, 2 in each group) prematurely discontinued. In the primary endpoint, REN001-treated subjects had greater mean increases from baseline to Day 21 in single knee extension strength vs. placebo (mixed models repeated measures and mixed model baseline covariate analysis P-values both <0.05). REN001-treated individuals had up to 3.5-fold increases from baseline from Day 14 in pyruvate dehydrogenase lipoamide kinase isozyme 4, angiopoietin-like 4, and solute carrier family 25 member 34, important PPARδ-regulated genes involved in mitochondrial function and biogenesis. No treatment group differences in the mean change from baseline in muscle CSA or muscle volume were observed. Adverse events were reported by 58.3% taking REN001 vs. 33.3% placebo; none were severe or serious and all resolved without sequelae.

Conclusion: REN001 was safe and well tolerated in this study. Data from this study in humans support the safety and purported action of PPARδ agonists by preventing muscle atrophy and increasing muscle strength, providing a rationale to evaluate REN001 in patients with mitochondrial myopathies.