AMPK activator well tolerated, safe for NASH
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Poxel SA announced positive results for the phase 2a trial of PXL770 for the treatment of nonalcoholic steatohepatitis, according to a press release.
PXL770 is an oral direct adenosine monophosphate-activated protein kinase (AMPK) activator.
“The underlying pathophysiological drivers of nonalcoholic fatty liver disease (NAFLD) and NASH are highly complex and support the need for development of novel therapies acting on different targets that can address a variety of key disease drivers,” Vlad Ratziu, MD, PhD, professor of hepatology at Sorbonne University and Pitié-Salpêtrière Hospital, said in the release. “AMPK activation is a differentiated approach for NASH and these results demonstrate that it could have a beneficial role in controlling key pathways that lead to liver injury. By also directly targeting inflammation and fibrogenesis, as demonstrated in preclinical models including human cells, PXL770 has the potential to independently impact multiple disease components. As an oral agent, PXL770 also has the potential to be used in combination with other agents, which could provide for broad treatment of this disease.”
According to the release, STAMP-NAFLD was a 12-week, randomized, parallel group study comprising 120 patients with NASH with or without diabetes in which researchers assessed three doses of PXL770 compared with placebo. Investigators randomly assigned patients into four groups; PXL770 at 250 mg once-daily, 250 mg twice-daily, 500 mg once-daily, compared with patients who received placebo.
PXL770 produced a mean relative decrease of 18% in liver fat mass from baseline at 12 weeks in the 500 mg once daily group as measured by MRI-PDFF (P = .0036), meeting the trial’s primary efficacy endpoint. There was a greater response observed in patients with type 2 diabetes. Also, more patients who received PXL770 achieved more than a 30% relative reduction in liver fat content vs. placebo. Greater liver fat content reduction was also seen in more responsive patients, according to the release.
Investigators reported that PXL770 was generally safe and well tolerated, according to the release.
“Along with previous data from our PK/PD trial where AMPK target engagement (suppression of de novo lipogenesis) and insulin sensitization were observed, the phase 2a results are encouraging and further characterize this novel molecule and mechanism. Looking at the aggregate picture of preclinical and clinical results obtained to date as well as published literature in the field, we believe that PXL770 has the potential to improve the underlying root causes of the disease, such as insulin resistance, dysregulation of lipid and glucose metabolism and inflammation,” Pascale Fouqueray, MD, PhD, executive vice president, Clinical Development and Regulatory Affairs at Poxel, said in the release. “These results support continued advancement of PXL770, which could include longer-term assessment of important histological endpoints such as inflammation and fibrosis and exploring subpopulations for further differentiation.”
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