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

STAMP-NAFLD, a randomized, double-blind, placebo-controlled phase 2a study was conducted at 15 clinical sites in the United States. Patients aged 18 to 75 years with a hepatic fat content of at least 10% at baseline during the proton fat fraction density MRI assessment (MRI-PDFF) were eligible. Patients were randomized (1: 1: 1: 1), via an interactive web response system, to receive 250 mg of PXL770 orally once daily, 250 mg twice daily, or 500 mg once daily , or a matched placebo. Patients were stratified according to their type 2 diabetes status and study site. The primary endpoint was the relative change in liver fat content from baseline versus placebo at week 12, assessed by MRI-PDFF. The primary endpoint was analyzed in an ANCOVA model with treatment and stratification criteria as factors and baseline liver fat content as a covariate in the modified intention-to-treat population, defined as all randomized patients who received at least one dose of study treatment. . Safety was analyzed in the safety population, defined as all untreated patients receiving at least one dose of study treatment. The test is complete and the final results are communicated. The trial is registered with ClinicalTrials.gov, NCT03763877.

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.

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