Evaluation of PXL065–deuterium-stabilized (R)-pioglitazone in patients with NASH: a phase II randomized placebo-controlled trial (DESTINY-1)

Abstract

BACKGROUND & AIMS Pioglitazone (Pio) is efficacious in NASH but encumbered by PPARγ-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARγ activity but retains non-genomic pathways. We tested the hypothesis that PXL065 would retain the efficacy of Pio with reduced adverse events in patients with NASH. METHODS Patients (≥8% liver fat, NAS ≥ 4, F1-F3) received daily doses of PXL065 (7.5, 15, 22.5 mg) or placebo 1:1:1:1 for 36 weeks. The primary endpoint was relative % change in liver fat (LFC; MRI-PDFF); histology from liver biopsies, non-invasive tests, safety-tolerability, and pharmacokinetics (PK) were assessed. RESULTS 117 patients were evaluated. All PXL065 groups met the primary endpoint (-21 to -25% LFC, p=0.008-0.02 vs. placebo); 40% (22.5 mg) achieved ≥30% LFC reduction. Favorable trends in ALT, ELF, FIB-4 and reductions in PIIINP (p=0.02, 22.5 mg) and NFS (p=0.04, 22.5 mg) were observed. On histology (n=92), ≥1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p=0.06), 35% (22.5 mg) vs. 17% placebo; up to 50% achieved ≥2 point NAS improvement without fibrosis worsening vs. 30% placebo. Metabolic improvements included: HbA1c (-0.41% p=0.003) and insulin sensitivity (HOMA-IR, p=0.04; Adipo-IR, p=0.002). Adiponectin increased (+114%, 22.5 mg, p<0.0001) vs. placebo. There was no dose dependent effect on body weight or PXL065-related peripheral oedema signal. Overall, PXL065 was safe and well tolerated. PK confirmed dose-proportional and higher steady-state R-vs. S-Pio exposure. CONCLUSIONS PXL065 is a novel molecule which retains an efficacy profile in NASH similar to Pio with reduced potential for PPARγ-driven side effects. Confirmation of histologic benefits by testing in a pivotal clinical trial is warranted.