The lack of therapies for nonalcoholic steatohepatitis, or NASH, is drawing many companies into the pursuit of a treatment for this fatty liver disease. Madrigal Pharmaceuticals is pushing to the front of the pack with pivotal clinical trial data showing improvements in the liver, results that pave the way for an FDA submission that the company plans to file in 2023.
The data reported Monday from Conshohocken, Pennsylvania-based Madrigal lend validation to the biotech’s approach for treating NASH, a disease in which the buildup of fat 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 thyroid hormone receptor beta, one of several receptors that mediates the activity of this hormone. By selectively targeting this receptor and activating it, Madrigal’s pill is intended to have an effect on multiple pathways that play a role in liver health, such as cholesterol metabolism and counteracting inflammation.
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The preliminary trial results, which come from analysis of liver biopsies, are from a nearly 1,000-patient, placebo-controlled Phase 3 study that tested two once-daily doses of resmetirom. The first main goal of the study was to show a resolution of NASH after 52 weeks according to a scale used to assess the disease’s severity. That mark was achieved by 26% of patients in the low dose group and 30% of those in the high dose group. By comparison, just 10% of those in the placebo group achieved that goal.
Fibrosis, or liver scarring, is classified according to four stages with the last and most severe stage representing liver cirrhosis. The study’s second main goal was to measure for at least one stage of improvement in fibrosis with no 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. On a secondary goal of measuring for reductions in cholesterol at 24 weeks, results showed 12% of patients in the low dose group and 16% of patients in the high dose group met that mark compared with 1% in the placebo group.
Both doses of resmetirom were well tolerated by patients and the most common side effects were transient diarrhea and mild nausea, both reported at the beginning of treatment. Stephen Harrison, chairman for Pinnacle Clinical Research and Summit Clinical Research and the 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 embarked on this process clinically back in 2015, I think this is exactly what we dreamed of for a therapy for this disease,” Harrison said, speaking Monday during a Madrigal conference call. “It’s oral, it’s well tolerated, it is potentially foundational. It targets the drivers of NASH, particularly toxic fatty acids. The results demonstrate a positive impact on both endpoints as well as numerous non-invasive assessments.”
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Harrison’s optimism for resmetirom follows several high-profile clinical trial failures of other NASH drugs. In 2020, Genfit reported its NASH drug candidate failed a pivotal study. Soon after, the FDA rejected Intercept Pharmaceuticals’ application for its NASH drug, Ocaliva. This past summer, the New York-based company reported additional Phase 3 data that it said met one trial goal of achieving one stage of fibrosis improvement with no worsening of the disease at 18 months. However, on the trial goal of showing a resolution of NASH with no worsening of fibrosis, the numeric improvement seen in the results was not enough to reach statistical significance. The FDA had told the company that meeting just one of the two main goals would be enough sufficient. Intercept has said it plans to resubmit an application for its NASH drug by the end of this year. But one drawback of Ocaliva is pruritus, severe itching that was reported as a side effect by more than half of patients who received the high dose of the drug.
Following the NASH drug setbacks of two years ago, the FDA has said new drug applications in this indication must be supported by liver biopsy analyses whose results are read separately by two independent pathologists. Becky Taub, Madrigal’s chief medical officer and president of research & development, said resmetirom met that standard.
“If you just took each pathologist independently, they each saw a statistically significant endpoint at each dose,” she said.
Data for the ongoing resmetirom clinical trial remain blinded to maintain the study’s integrity. Taub said Madrigal plans to submit the initial results for publication in a peer-reviewed journal and present them at a future scientific meeting. In the meantime, the company will use the data it now has to prepare a new drug application seeking accelerated FDA approval for both doses; the submission could be ready in the first half of 2023. Investors welcomed those plans. Shares of Madrigal 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-changing, and we believe resmetirom will likely be the first highly effective therapeutic modality for the management of NASH.” He added that resmetirom’s results lend validation to Viking Therapeutics, which is developing a NASH drug that works the same way as Madrigal’s drug. However, the liver-targeted design of Viking’s drug, VK2809, could improve on the safety and efficacy of this approach. Phase 2b data for the Viking drug are expected in the first half of 2023.
Others in the hunt for a 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 fusion protein.
Public domain image by Flickr user NIH Image Gallery
