The history of drug research in the liver disease nonalcoholic steatohepatitis (NASH) is littered with failed clinical trials, but Akero Therapeutics is now trumpeting Victory in Phase 2. Most importantly, the success of the clinical trial was determined using a new methodology that the FDA is requiring NASH drug developers to meet before seeking drug approval.
Akero’s drug efruxifermin led to at least a one-stage improvement in a measure of fibrosis, or liver scarring, that develops from fatty liver disease, according to preliminary results published Tuesday. This result, along with no disease worsening by week 24 of the study, was achieved by 41% of those in the high-dose group and 39% of those in the low-dose group. In comparison, 20% of those in the placebo group met the study’s goal.
South San Francisco-based Akero also reported success against a secondary objective of achieving resolution of NASH without worsening fibrosis. At the high dose, 76% of patients achieved this score; 47% of those given the low dose achieved this goal. Only 5% of those in the placebo group met this secondary endpoint. Akero shares opened Tuesday at $28.04 a share, up more than 128% from Monday’s closing price.
NASH is an advanced form of liver disease characterized by the accumulation of fat in the organ, leading to inflammation and fibrosis. Risk factors associated with the development of NASH include obesity and high cholesterol. There are no FDA-approved drugs for NASH, which is treated primarily with dietary adjustments and other lifestyle changes. In the most advanced stage of the disease, the only treatment is a liver transplant.
Efruxifermin is a fusion protein designed to act as an analog of fibroblast growth factor 21 (FGF21), a hormone that protects against cellular stress and regulates fat, carbohydrate, and protein metabolism. Preliminary data released Tuesday are from a phase 2b trial involving 128 adults whose biopsy-confirmed NASH had reached fibrosis stage 2 or 3 (there are four stages, with stage 4 — cirrhosis — being the most severe). These participants were randomly assigned to receive a high or low dose of the injectable drug Akero once a week or a placebo for 24 weeks.
The efficacy of Akero’s drug was assessed by liver biopsies that were independently evaluated by two pathologists, with a third pathologist available to judge if the first two did not reach consensus. The FDA now requires this consensus liver biopsy analysis for NASH drugs. When the FDA rejected Intercept Pharmaceuticals’ NASH contender, obeticholic acid, in 2020, the agency requested a data analysis performed according to this “consensus reading methodology.” The Intercept reported the results of such an analysis in July, which the company said should help resubmit its new drug application. The phase 3 failure of Genfit’s NASH drug led the Paris-based company to abandon seeking treatment for this disease in favor of a less common liver disease. Last year, Genfit sold the rights to this drug, elafibranor, to Ipsen.
To succeed in Phase 3, the FDA requires a NASH drug to achieve one of two goals: improve fibrosis by one or more stages without worsening disease symptoms, or resolve NASH without worsening fibrosis. The European Medicines Agency requires both targets to be met to support the marketing authorization of a drug for NASH.
Although preliminary results for Akero’s NASH drug showed better results for the high dose than the low dose, this advantage did not hold when measuring improvement in fibrosis at two or more stages. Biotechnology reported in an investor presentation that 16% of patients who received the low dose showed such an improvement, a figure 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 is well tolerated by patients. The most common side effects reported by the study included diarrhea, nausea, increased appetite, and frequent bowel movements. A drug-related serious adverse event of esophagitis was reported in one patient in the high-dose group. Akero said this patient had a history of gastroesophageal reflux disease.
“We believe the data is very compelling and shows [efruxifermin’s] potential to address critical, global unmet patient need by intervening across stages of disease progression, potentially addressing both early-stage metabolic drivers and later-stage inflammation and fibrosis,” said Andrew Cheng, President and Chief CEO of Akero, in a prepared statement.
A separate phase 2b trial of Akero is being conducted in patients with NASH who have reached Child-Pugh Class A compensated cirrhosis, the mildest classification of the most advanced stage of NASH. Akero said it expects to report the results of this interim study in the second half of next year. This study has also been expanded to include treating patients with the drug Akero along with a type of diabetes drug called a GLP-1 agonist. Results for this group are expected in the first half of 2023.
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