Poxel's PXL770 Shows Promise in Patients With NASH, T2D

Results from a phase 2 trial show PXL770, an oral first-in-class adenosine monophosphate–activated protein kinase (AMPK) activator, yielded consistently greater responses in high-risk patients with comorbid nonalcoholic steatohepatitis (NASH) and type 2 diabetes (T2D) compared with placebo. The trial was conducted by Poxel, a French biopharmaceutical company.

There are currently no approved pharmacological treatments for NASH. Recommendations for managing the disease include diet modification, exercise, and weight loss.

However, “AMPK is a master regulator of several important metabolic pathways, including lipid metabolism, glucose control, and inflammation, and is a novel target for NASH and additional chronic and rare metabolic diseases,” a company statement reads.

Approximately 50% of patients with NASH also suffer from T2D. Poxel’s phase 2a STAMP-NAFLD trial was a 12-week, randomized study conducted in 120 presumed patients with NASH, with or without T2D. Specifically, the trial evaluated 3 dosing mechanisms of PXL770 vs placebo: 250 mg once daily, 250 mg twice daily, or 500 mg once daily.

To be enrolled in the trial, patients needed to exhibit hepatic steatosis, or nonalcoholic fatty liver disease, determined via a controlled attenuation parameter score of > 300 db/m measured by MRI-derived proton density fat fraction (MRI-PDFF). The trial’s primary end point was assessment of the change in the percentage of liver fat mass assessed by MRI-PDFF. Secondary end points included changes in metabolic parameters (lipids), changes in nonmetabolic parameters (inflammation), and assessment of safety and tolerability.

Between 41% and 47% of each dosing cohort and placebo groups had T2D. Overall, “treatment with PXL770 resulted in a –27% mean relative reduction in liver fat content at 500 mg QD (P = .004) versus baseline.”

Among those with comorbid NASH and T2D, the researchers found:

• A significant increase in the proportion of responders (>30% reduction in liver fat)
• Dose-responsive and significant mean decreases in alanine transaminase (ALT) and aspartate transaminase levels were achieved, despite only slightly elevated mean baseline ALT levels (36-47 IU/L; normal range < 41 IU/L)
• Baseline fasting glucose (121-144 mg/dL) and glycated hemoglobin (6.6%-7.1%) levels were well controlled
• Significant placebo-adjusted decreases were observed in both glycemic parameters along with improvements in commonly used fasting indexes of insulin sensitivity (HOMA-IR and QUICKI scores)
• PXL770 was generally safe and well tolerated and was similar to the whole trial population

Complete phase 2a trial results are to be submitted for presentation at an upcoming scientific meeting.

Furthermore, “In recent in vitro experiments with human macrophages, incubation with PXL770 resulted in significant suppression of cytokine (IL-6 [interleukin-6], TNFα [tumor necrosis factor alpha], MCP-1 [monocyte chemoattractant protein-1]) release,” the company stated; findings which are consistent with the potential for PXL770 to have direct effects leading to reduced inflammation and fibrosis in NASH.

In the upcoming phase 2b trial, set to begin during the second half of 2021, histology measures will be included to confirm theses preclinical findings. The 52-week trial in noncirrhotic biopsy-proven NASH with coexisting prediabetes or T2D will evaluate up to 2 oral doses of PXL770 compared with placebo. A group of 120 patients will be included per study arm, while the primary endpoint will be NASH resolution with no worsening of fibrosis assessed on histology.

“PXL770 is one of the only therapies in development that has demonstrated the potential to treat NASH with specific use in patients with coexisting type 2 diabetes that are at higher risk for faster disease progression and for comorbidities, including cardiovascular complications,” said Pascale Fouqueray, MD, PhD, executive vice president of clinical development and regulatory affairs at Poxel. “We believe PXL770 has the potential to be a much-needed and differentiated therapeutic option for NASH and could be particularly important for the high-risk population with type 2 diabetes.”