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Poxel reports positive histology results from DESTINY-1 phase 2 trial of PXL065 for treatment of NASH

Lyon, France
Thursday, September 22, 2022, 18:00 Hrs  [IST]

Poxel SA, clinical stage biopharmaceutical company, announced positive histology results for DESTINY-1 (Deuterium-stabilized R-pioglitazone [PXL065] Efficacy and Safety Trial In NASH), the dose-ranging phase 2 trial of PXL065 for the treatment of NASH. PXL065 is a novel, proprietary deuterium-stabilized R-stereoisomer of pioglitazone which has reduced PPAR? activity, but retains non-genomic thiazolidinedione (TZD) actions.

“Pioglitazone’s positive effects in 6 independent prior trials where NASH patients were assessed via liver biopsy propelled the study of PXL065 in patients with NASH and fibrosis. PXL065 is differentiated from pioglitazone based on its distinct pharmacology and lower potential for PPAR?-mediated side effects,” said Stephen Harrison, MD, president, Summit Clinical Research, and principal investigator of this study. “The primary endpoint findings observed on liver fat content reduction along with the other positive findings observed in secondary analysis of key histopathologic features of NASH and fibrosis are promising. When coupled with the benefits seen in glycaemic control and a very good safety and tolerability profile, larger studies in NASH are warranted.”

“In addition to our previously reported finding of clinically meaningful improvements in liver fat content and circulating biomarkers related to NASH and metabolic health, these results address the high unmet need for fibrosis improvement that remains, particularly for oral products, which we believe will be the cornerstone to treatment,” said Thomas Kuhn, CEO of Poxel. “Based on pioglitazone’s proven efficacy in NASH, PXL065 could become a key product for the treatment of NASH, alone and in combination with other treatment modalities. We will initiate discussions to pursue a potential pivotal program in NASH – leveraging the FDA 505(b)(2) regulatory path and the extensive safety database of pioglitazone as an approved medicine for Type 2 diabetes – which would represent a potentially accelerated and de-risked development with a high probability of success.”

DESTINY-1 is a phase 2, 36-week, randomized, dose-ranging, double-blind, placebo-controlled, parallel group study designed to assess the efficacy and safety of PXL065 in patients with noncirrhotic biopsy-proven NASH across multiple clinical sites in the US. The primary endpoint of the study measured the relative change in the percentage of liver fat content based on magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF). The study also assessed the effects of PXL065 on liver histology and other metabolic and non-metabolic biomarkers.

117 subjects were randomized to one of 4 daily (QD) treatment arms (7.5 mg, 15 mg, 22.5 mg, placebo). Analysis of histologic changes was based on paired liver biopsies in PXL065 vs. placebo-treated NASH patients before and after the 36-week treatment period. This trial was not powered to detect statistically significant changes in histology endpoints.

PXL065 is a novel, proprietary deuterium-stabilized R-pioglitazone. Although pioglitazone is not approved by the FDA for the treatment of NASH, it is the most extensively studied drug for NASH; in multiple prior trials, improvements in liver histology, including reductions in fibrosis, were demonstrated. Pioglitazone is the only drug recommended for biopsy-proven NASH patients by the Practice Guidelines published by the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL). Pioglitazone’s off-label use for NASH, however, has been limited due to the PPAR?-related side effects, which include weight gain, bone fractures and fluid retention.

Pioglitazone is a 1:1 mixture of two mirror-image compounds (R- and S-stereoisomers) that interconvert in vivo. Using deuterium, Poxel stabilized each stereoisomer and characterized their different pharmacological properties. In in vitro studies, PXL065 has been shown to target non-genomic pathways including mitochondrial pyruvate carrier (MPC) and acyl-CoA synthetase 4 (ACSL4). In preclinical animal models, PXL065 exhibits the NASH efficacy associated with pioglitazone with no significant weight gain or fluid retention, side effects which are associated with the S-stereoisomer. NASH phase 2 (DESTINY 1 trial) results available to-date show statistically significant effects of PXL065 on liver fat content, biomarkers related to liver fibrogenesis-fibrosis risk, as well as positive effects on fibrosis and other key parameters based on histology analysis. Relative to published data for pioglitazone, reduced potential for weight gain and edema was also evident. Based upon preclinical, phase 1 and phase 2 results, Poxel believes that PXL065 may have a better therapeutic profile than pioglitazone for NASH and may also have suitable properties for further development in other indications including adrenoleukodystrophy (ALD).

Non-alcoholic steatohepatitis (NASH) is a metabolic disease with no clear disease origin that is quickly becoming a worldwide epidemic. It is characterized by the accumulation of fat in the liver causing inflammation and fibrosis. The disease can be silent for a long period of time, but once it accelerates, severe damage and liver cirrhosis can occur, which can significantly impact liver function or can even result in liver failure or liver cancer. Typical risk factors for NASH include obesity, elevated levels of blood lipids (such as cholesterol and triglycerides) and type 2 diabetes. Currently no curative or specific therapies are available.

Poxel is a clinical stage biopharmaceutical company developing innovative treatments for chronic serious diseases with metabolic pathophysiology, including non-alcoholic steatohepatitis (NASH) and rare disorders.

 

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