Madrigal Pharma’s NASH Drug Has Positive Results in Phase II

Madrigal Pharmaceuticals, located in Conshohocken, Pennsylvania, announced positive topline data from its Phase II clinical trial of MGL-3196 in patients with biopsy-proven non-alcoholic steatohepatitis (NASH).

MGL-3196 is a first-in-class, oral, once-daily, liver-directed thyroid hormone receptor beta-selective agonist. In the trial, it showed statistically significant reduction of liver fat on magnetic resonance imaging-estimated proton density fat fraction (MRI-PDFF) at 12 weeks in an earlier announcement in December, and now at Week 36, statistically significant results in the primary endpoint as well as key secondary endpoints, reduction and resolution of NASH.

NASH is similar to cirrhosis of the liver, but it is seen in patients who drink little or no alcohol. It is generally associated with obesity and the obesity epidemic, which is linked to diabetes and cardiovascular diseases. There are no current treatments except diet and exercise.

The endpoints observed at Week 36 include a reduction in liver fat compared to placebo, decreases in low-density lipoprotein cholesterol (LDL-C), triglycerides, ApB and lipoprotein, and a cut in liver enzymes. Other endpoints include a statistically significant decrease in fibrosis biomarkers compared to patients receiving placebo. The drug was reasonably tolerated, with mostly mild and moderate adverse effects, including an increase in incidence of transient mild diarrhea at the beginning of the trial.

“NASH is a common liver disease in the United States, with a growing prevalence, for which no FDA approved treatment is yet available,” said Stephen Harrison, principal investigator of the trial and medical director for Pinnacle Clinical Research in San Antonio, Texas, in a statement. “Compared with Week 12, at Week 36 MGLL-3196 showed sustained effects to reduce liver fat on MRI-PDFF, and more reduction in liver enzymes than placebo. MGL-3196 demonstrates improvement relative to placebo on measurements of NASH on liver biopsy, including resolution of NASH. Importantly, this study is the first to demonstrate a correlation between efficacy in a non-invasive imaging test, MRI-PDFF at 12 weeks, and improvement in NASH on liver biopsy at 36 weeks.”

Company shares jumped 66 percent in premarket trading at the news. NASH is considered an open and large market and many companies are working to be the first with a new therapeutic. The market is projected to range from $20 billion to $35 billion.

Other companies working in this area include Terns Pharmaceuticals, partnerships between Regeneron and Alnylam Pharmaceuticals, Allergan, Ionis Pharmaceuticals and AstraZeneca. In 2016, Allergan acquired several NASH development companies, and the same year,Bristol-Myers Squibb spent $100 million to buy the rights to a NASH program from Nitto Denko Corporation Corporation, based in Osaka, Japan.

NASH has several modalities, including fatty liver, chronic inflammation, progressive fibrosis, cirrhosis and eventually end-stage liver diseases. Most researchers in the field expect a cocktail of drugs to tackle each aspect of the disease will be required.

BioPharma Dive recently pointed out there are 195 treatments in the pipeline for NASH by a wide range of companies. Most are in early- or mid-stage development.

In April, MediciNova, headquartered in La Jolla, California, halted a Phase II trial in NASH after interim data analysis showed that its tipelukaast (MN-001) had significant positive data in treating NASH and non-alcoholic fatty liver disease (NAFLD) with hypertriglyceridemia.

Physicians have a tendency to not give a diagnosis of NASH, but to tackle the disease on a modality-by-modality basis (except for endocrinologists, who tend to diagnose it as NASH), such as high cholesterol, high triglycerides, high liver enzymes, diabetes, cardiovascular problems.

“The commercial strategy for these drugs will need to provide a clear case for why to treat those patients now, especially with all of their other co-morbidities like diabetes and heart disease—those are the things clinicians are trained to worry about first,” Greg Rotz, principal in PwC’s Advisory business, told BioPharma Dive.

But that’s an after-approval problem. Now, companies like Madrigal are making headway in getting their NASH drugs that much closer to approval.