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

Background & Aims: Pioglitazone (Pio) is efficacious in NASH, but its utility is limited by PPARy-driven side effects. Pio is a mixture of two enantiomers (R, S). PXL065, deuterium-stabilized R-Pio, lacks PPARy activity but retains non-genomic activity. We tested the hypothesis that PXL065 would have similar efficacy but a better safety profile than Pio in patients with NASH.Methods: Patients (>-8% liver fat, NAFLD activity score [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 content (LFC) on MRI-proton density fat fraction; liver histology, non-invasive tests, safety-tolerability, and pharmacokinetics were also assessed.Results: One hundred and seventeen 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 a >-30% LFC reduction. Favorable trends in non-invasive tests including re-ductions in PIIINP (p = 0.02, 22.5 mg) and NAFLD fibrosis score (p = 0.04, 22.5 mg) were observed. On histology (n = 92), a >-1 stage fibrosis improvement occurred in 40% (7.5 mg), 50% (15 mg, p = 0.06), and 35% (22.5 mg) vs. 17% for placebo; up to 50% of PXL065-treated patients achieved a >-2 point NAS improvement without fibrosis worsening vs. 30% with 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. Pharmacokinetics 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 PPARy-driven side effects. A pivotal clinical trial is warranted to confirm the histological benefits reported herein. (c) 2023 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Automated summary

The study aimed to evaluate the efficacy and safety of PXL065 in NASH patients. The results showed that PXL065 had similar efficacy as Pio in reducing liver fat content and improving liver histology, but with reduced potential for side effects. These findings suggest that PXL065 may be a safer treatment option for NASH.