NASH, non-alcoholic steatohepatitis

NASH, nonalcoholic steatohepatitis

The lack of therapies for non-alcoholic steatohepatitis, or NASH, has attracted many companies in the search for a cure for this fatty liver disease. Madrigal Pharmaceuticals pushes to the front of the pack with basic data from clinical trials showing improvements in the liver, results that pave the way for an FDA submission the company plans to file in 2023.

Data reported Monday by Conshohocken, Pennsylvania-based Madrigal validates the biotech’s approach to treating NASH, a disease in which fatty buildup in the liver leads to worsening inflammation and fibrosis that can reach the point of requiring a liver transplant . The company’s drug, resmetirom, is a small molecule designed to bind to the thyroid hormone beta receptor, one of several receptors that mediate that hormone’s activity. By selectively targeting this receptor and activating it, the Madrigal pill aims to have an effect on multiple pathways that play a role in liver health, such as cholesterol metabolism and anti-inflammation.

The preliminary results, which come from an analysis of liver biopsies, are from a nearly 1,000-patient, placebo-controlled phase 3 trial that tested two doses of resmetirom once daily. The first primary objective of the study was to demonstrate resolution of NASH. This score was achieved by 26% of patients in the low-dose group and 30% of those in the high-dose group. By comparison, only 10% of those in the placebo group achieved this goal.

Fibrosis or liver scarring is classified according to four stages, with the last and most severe stage being cirrhosis of the liver. The second main aim of the study was to measure at least one stage of improvement in fibrosis without worsening of the disease. According to the results, 24% of patients in the low-dose group and 26% of those in the high-dose group achieved this goal, compared with 14% in the placebo arm. As measured by a secondary goal of lowering cholesterol at week 24, 12% of patients in the low-dose group and 16% of patients in the high-dose group achieved this measure, compared with 1% in the placebo group.

Both doses of resmetirom were well tolerated by patients and the most common adverse reactions were transient diarrhea and mild nausea, both reported at the start of treatment. Stephen Harrison, chairman of Pinnacle Clinical Research and Summit Clinical Research and lead principal investigator of the resmetirom clinical trials, said the overall results so far are welcome news for the estimated 20 million to 25 million Americans who suffer from NASH.

“When we started this trial clinically in 2015, I think this is exactly what we dreamed of for a therapy for this disease,” Harrison said, speaking Monday on a Madrigal conference call. “It’s taken orally, it’s well tolerated, and it’s potentially groundbreaking.” It targets the drivers of NASH, particularly toxic fatty acids. The results demonstrate a positive impact on both endpoints as well as multiple non-invasive assessments.”

Harrison’s optimism for resmetirom follows several high-profile clinical trial failures of other NASH drugs. In 2020, Genfit reported that its drug candidate for NASH had failed a pivotal study. Soon after, the FDA rejected Intercept Pharmaceuticals’ application for its NASH drug, Ocaliva. The New York-based company announced last summer additional phase 3 data, which he said met both goals of reducing fibrosis and showing resolution of NASH without worsening fibrosis. The Intercept said it plans to resubmit its NASH drug by the end of this year. But one drawback of Ocaliva is pruritus, a severe itch that was reported as a side effect by more than half of the patients who received the high dose of the drug.

After drug failures for NASH two years ago, the FDA said new drug applications for this indication must be supported by liver biopsy analyses, the results of which are read separately by two independent pathologists. Becky Taub, Madrigal’s chief medical officer and president of research and development, said resmetirom meets that standard.

“If you just took each pathologist independently, they each saw a statistically significant endpoint at each dose,” she said.

Data from the ongoing resmetirom clinical trial remain withheld to preserve the integrity of the study. Taub said Madrigal plans to submit the initial results for publication in a peer-reviewed journal and to present them at a future scientific meeting. Meanwhile, the company will use the data it has now to prepare a new drug application seeking accelerated FDA approval for both doses; the presentation could be ready in the first half of 2023. Investors welcomed these plans. Madrigal shares opened Monday at $202.99, up more than 213% from Friday’s closing price.

Andy Hsieh, an analyst at William Blair, wrote in a research note that the Madrigal data are “transformational and paradigm-shifting, and we believe resmetirom is likely to be the first highly effective therapeutic for the management of NASH.” He added that the resmetirom results lend validity to Viking Therapeutics, which is developing a NASH drug that works in the same way as Madrigal’s drug. However, the liver-targeted design of Viking’s drug, VK2809, may improve the safety and efficacy of this approach. Phase 2b data for the Viking drug is expected in the first half of 2023.

Others in the search for NASH therapy include Akero Therapeutics, which is developing a drug called efruxifermin. In September, the South San Francisco-based biotech reported positive Phase 2 data for the synthesized protein.

Public domain image by Flickr user NIH Image Gallery

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