Efficacy and safety of PXL770, a direct activator of AMP kinase, for the treatment of non-alcoholic fatty liver disease (STAMP-NAFLD): randomized, double-blind, placebo-controlled phase 2a study

Background

AMP kinase (AMPK) is an energy sensor involved in the regulation of lipid metabolism, inflammation and insulin sensitivity. Our objective was to assess the efficacy and safety of PXL770, a new direct activator of AMPK, in patients with non-alcoholic fatty liver disease (NAFLD).

Methods

Results

Between March 29, 2019 and March 13, 2020, 387 patients were screened, of which 120 were included in the modified intention-to-treat and tolerance analyzes (30 in the 250 mg once daily group, 30 in the 250 mg once daily group 29 mg twice daily in the 500 mg once daily group and 31 in the placebo group). The mean relative change from baseline in liver fat content at week 12 was -1.1% in the placebo group, -1.0% in the 250 mg once daily group (difference mean versus placebo of 0.1% [95% CI −15·4 to 15·7], p = 0.99), -14.3% in the 250 mg twice daily group (-13.1% [–28·1 to 1·8], p = 0.084) and -14.7% in the 500 mg once daily group (-13.5% [–28·5 to 1·4], p = 0.076). At least one treatment-related adverse event occurred in 23 (77%) of 30 patients in the 250 mg once daily group, 20 (67%) of 30 patients in the 250 mg twice daily group, 21 (72%) of 29 patients in the 500 mg once daily group, and 21 (68%) of 31 patients in the placebo group. The most common treatment-related adverse event was diarrhea (five [17%] of patients in the 250 mg once daily group, seven [23%] in the 250 mg twice daily group, six [21%] in the 500 mg once daily group and none in the placebo group). No life-threatening events or deaths related to treatment have occurred.

Interpretation

Treatment with PXL770 did not meet the primary endpoint of improvement in liver fat compared to placebo. The treatment was well tolerated. Given the indications that metabolic characteristics improved with treatment with PXL770, activation of AMPK could be a promising pharmacological target for patients with type 2 diabetes and NAFLD, and could also be considered for further evaluation in patients with non-alcoholic steatohepatitis.

Funding

Poxel.