French biotech Genfit is on its way out of fatty liver R&D after a phase 3 flop, but compatriot Poxel is on its way up. The latter’s nonalcoholic steatohepatitis (NASH) treatment beat placebo at reducing liver fat in a phase 2 study, offering hope that Poxel’s approach could succeed where others have failed.
Poxel tested three dose regimens of the drug, PXL770 against placebo in 120 patients who had presumed NASH—that is, diagnosed through noninvasive tests but not confirmed by liver biopsy—with or without diabetes. To join the study, patients had to score 300 dB/m or higher on a measure of liver fat; that score translates to fatty buildup in about two-thirds or more of the liver.
The top dose, 500 mg once daily, cut liver fat 18% from baseline levels, as measured by MRI-PDFF, an imaging-based measure of liver fat. Another dose regimen, 250 mg twice daily, reduced liver fat by 14% from baseline. Both figures were statistically significant, the company said in a press release. The full data will be presented at an upcoming medical meeting.
More patients on PXL770 saw a relative reduction in liver fat of at least 30% compared to those on placebo, with 28% of patients on the 500 mg dose hitting this goal, compared to 7% of those on placebo. And the top dose also made a dent in levels of a liver enzyme called ALT.
In patients with Type 2 diabetes, the 500 mg dose cut liver fat by 27%, compared to 6% for patients taking placebo. Poxel plans to dig deeper into the results across all dose groups for patients with diabetes.
“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,” said Pascale Fouqueray, M.D., Ph.D., executive vice president of clinical development and regulatory affairs at Poxel, in a statement. “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.”
PXL770 activates AMPK, which regulates several metabolic pathways, including lipid metabolism, glucose control and inflammation. It is a new target for NASH, an area rife with failed approaches, including PPAR agonists like Genfit’s elafibranor, Gilead’s ASK1 inhibitor, selonsertib, and Novartis and Conatus’ pan caspase inhibitor, emricasan.
Because AMPK plays a role in so many pathways, PXL770 could address multiple facets of NASH, rather than say, fibrosis alone or inflammation alone. And the oral drug has a promising safety profile, too: Patients on PXL770 experienced side effects at similar rates to placebo, and they were mostly mild to moderate, the company said.
“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,” said Vlad Ratziu, M.D., Ph.D., Professor of Hepatology, Sorbonne University and Pitié-Salpêtrière Hospital, in the statement.
And it could come in handy beyond NASH, too.
“In addition to the potential to further pursue PXL770 in NASH, clinical evidence of target engagement—including effects on glycemia—suggest that PXL770 and AMPK activation could provide utility to treat a broader range of other metabolic diseases, such as diabetic nephropathy and certain rare diseases,” Poxel Chief Scientific Officer David Moller, M.D., said.
The company is digging through its library of compounds that target AMPK for candidates to take forward in other chronic and rare metabolic diseases, Moller said.