Akero Metabolic Disorders Biotech Wins Key Clinical Trial in NASH Liver Disease

The history of drug research in nonalcoholic steatohepatitis (NASH), a liver disease, is littered with clinical trial failures, but Akero Therapeutics is now announcing a Phase 2 Victory. Basically, the success of the clinical trial was determined using a new methodology that the FDA requires NASH drug developers to meet before seeking drug approval.

According to preliminary results released Tuesday, the Akero drug efruxifermin led to at least one step improvement in a measure of fibrosis, or liver scarring, that develops from fatty liver disease. This result, as well as no worsening of the disease at week 24 of the study, was achieved by 41% of people in the high dose group and 39% of those who received the low dose. By comparison, 20% of people in the placebo group achieved the study endpoint.

South San Francisco-based Akero also reported success against a secondary goal of resolving NASH without worsening fibrosis. At the high dose, 76% of patients achieved this score; 47% of those who received the low dose achieved this goal. Only 5% of people in the placebo group met this secondary endpoint. Shares of Akero opened Tuesday at $28.04 apiece, up more than 128% from Monday’s closing price.

NASH is an advanced form of liver disease characterized by an accumulation of fat in the organ which leads to inflammation and fibrosis. Risk factors associated with the development of NASH include obesity and high cholesterol. There are no FDA-approved medications for NASH, which is primarily treated through dietary adjustments and other lifestyle changes. At the most advanced stage of the disease, the only treatment is a liver transplant.

Efruxifermin is a fusion protein designed to act as an analogue of fibroblast growth factor 21 (FGF21), a hormone that protects against cellular stress and regulates the metabolism of fats, carbohydrates and proteins. Akero licensed the drug from Amgen in 2018. Preliminary data released on Tuesday comes from a phase 2b trial involving 128 adults whose biopsy-confirmed NASH reached fibrosis stage 2 or 3 (there are four stages , stage 4 – cirrhosis – being the most severe). These participants were randomly assigned to receive either a high or low dose of the injectable drug Akero once a week, or a placebo, for 24 weeks.

The effectiveness of Akero’s drug was assessed by liver biopsies that were scored independently by two pathologists, with a third pathologist available to step in if the first two failed to reach consensus. The FDA now requires this consensus liver biopsy analysis for NASH drugs. When the FDA rejected Intercept Pharmaceuticals’ NASH competitor, obeticholic acid, in 2020, the agency requested a data analysis performed under this “consensus reading methodology.” Intercept reported the results of such an analysis in July, which the company says should support the resubmission of its new drug application. The Phase 3 failure of Genfit’s NASH drug led the Paris-based company to abandon the search for a treatment for this disease in favor of a rarer liver disorder. Last year, Genfit sold the rights to this drug, elafibranor, to Ipsen.

To pass Phase 3, the FDA requires that a NASH drug achieve one of two goals: improvement of fibrosis by one or more stages without worsening of disease symptoms, or resolution of NASH without worsening of fibrosis. The European Medicines Agency requires both of these objectives to be met to support the marketing authorization of a NASH drug.

While preliminary results for Akero’s NASH drug show better results for the high dose compared to the low dose, this benefit does not hold when measuring improvement in fibrosis by two or more stages. Biotechnology reports in a investor presentation that 16% of patients given the low dose showed such improvement, a benchmark achieved by 15% of patients in the high dose group. In comparison, 5% of patients in the placebo group showed an improvement in fibrosis of two or more stages.

The drug Akero was well tolerated by patients. The most commonly reported adverse events in the study included diarrhea, nausea, increased appetite, and frequent bowel movements. One serious drug-related adverse event, inflammation of the esophagus, was reported in one patient in the high dose group. Akero said this patient had a history of gastroesophageal reflux disease.

“We think the data is very compelling and shows [efruxifermin’s] potential to address the critical, global unmet need of patients by intervening at all stages of disease progression, potentially addressing both early-stage metabolic drivers and inflammation and fibrosis at a later stage,” Andrew Cheng, Chairman and CEO of Akero, said in a prepared statement. .

A separate Phase 2b trial of the drug Akero is underway in NASH patients who have achieved compensated cirrhosis, Child-Pugh Class A, which is the least severe classification of the most advanced stage of NASH. Akero said it expects to report the results of this mid-term study in the second half of next year. This study also expanded to include treating patients on the drug Akero with a type of diabetes medicine called a GLP-1 agonist. Results for this group are expected in the first half of 2023.

Public domain image by Flickr user NIH Image Gallery

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