A chronic metabolic disease in which fat buildup leads to worsening liver function that can ultimately require an organ transplant now has its first FDA-approved therapy, a once-daily pill developed by Madrigal Pharmaceuticals.
The FDA decision Thursday is for adults with noncirrhotic non-alcoholic steatohepatitis, or NASH. The approval specifically covers those who have reached the point of moderate-to-advanced liver scarring, which is also called fibrosis. The Conshohocken, Pennsylvania-based company’s drug, known in development as resmetirom, will be marketed under the brand name Rezdiffra.
“We’ve had patients waiting and waiting for something that could impact underlying fibrosis in the setting of NASH, and this truly represents a milestone achievement that frankly I, and many others, have been working on since the turn of the century,” Stephen Harrison, medical director of Pinnacle Clinical Research and the lead investigator for Rezdiffra’s pivotal clinical trial, said during a Madrigal conference call Thursday evening.
NASH is sometimes called a “silent disease” because it rarely presents with any symptoms. But the disorder, which much of the liver field is starting to call metabolic dysfunction-associated steatohepatitis, or MASH, develops over time as the fatty buildup leads to inflammation and fibrosis. Fibrosis is classified according to four stages with stage 4 being liver cirrhosis. Because MASH has no symptoms, its exact prevalence is not known. But the FDA cites an estimate of about 6 to 8 million people in the U.S. who have this disease with moderate to advanced liver scarring. In this range, patients have stage 2 or stage 3 fibrosis.
Rezdiffra is a small molecule designed to target and activate a receptor in the liver called thyroid hormone receptor beta (THR-beta). This receptor mediates metabolic activity in the organ, including the lowering of fat levels. The Madrigal molecule selectively activates THR-beta without also activating THR-alpha and sparking safety problems associated with hitting that receptor. Resmetirom was discovered in the labs of Roche; Madrigal licensed global rights to the molecule in 2011 and commenced clinical development.
The Phase 3 study’s two main goals were to measure resolution of MASH and to show an improvement in fibrosis by at least one stage with no worsening in score according to a scale used to measure the severity of the liver disorder. In the trial, biopsy-confirmed results showed MASH resolution with no worsening of fibrosis was achieved by 25.9% of those given a low dose of the Madrigal drug and 29.9% of those treated with the high dose. In the placebo arm, 9.7% of patients achieved this goal. Fibrosis improvement by at least one stage was achieved by 24.2% of patients in the low-dose group and 25.9% of patients given the high dose. Just 14.2% of patients who received a placebo met this goal. The side effects reported for Rezdiffra include diarrhea and nausea. Results were published last month in the New England Journal of Medicine.
The FDA approval covers three doses of Rezdiffra, which is dosed according to patient weight and is intended to be used alongside diet and exercise. Though the clinical trial enrolled patients whose disease was confirmed by liver biopsy, a biopsy is not a requirement in the drug’s label. Patients will be diagnosed with non-invasive tests, Madrigal CEO Bill Sibold said.
In an interview ahead of the Rezdiffra approval announcement, Dr. Lisa Ganjhu, a gastroenterologist and hepatologist at NYU Langone Health, said MASH can be diagnosed as part of routine metabolic tests that are part of a patient’s annual exam. When the tests flag a potential problem with liver or kidney function, the next step could be an ultrasound that spots the fat buildup on the liver. Ganjhu, who was not involved in Rezdiffra’s clinical trials, said not all fatty liver disease turns into fibrosis. But she added that the Madrigal drug is promising for patients because it is the first medication to show it can reverse that scarring.
“We really have nothing but diet and exercise for patients right now,” Ganjhu said. “This is something that could get them better from stage 3 [fibrosis] to 2, or stage 2 to 1. Any reduction in fibrosis reduces the risk of developing cirrhosis or other complications down the road.”
Leerink Partners analyst Thomas Smith wrote in an investor note that Rezdiffra’s label represents a near best-care scenario for Madrigal. In addition to no liver biopsy requirement, there are no unexpected safety concerns or restrictive warnings. Smith said it remains to be seen whether payers will impose biopsy or monitoring requirements. But he added that Rezdiffra’s approval as the first NASH/MASH therapy reduces risk for entire field, which has seen a long list of companies encounter clinical trial failures and regulatory setbacks.
“We consider the approval of the first therapeutic specifically for NASH to significantly derisk the regulatory pathway and establish a precedent for other companies developing therapeutic candidates for the indication,” Smith said. “Moreover, we expect the necessary launch activities of increasing patient awareness, educating physicians, and developing payor agreements that are key to establishing a new commercial market will lay a positive foundation for follow-on companies.”
Companies still in the field of NASH/MASH drug development include Viking Therapeutics, whose THR-beta-targeting small molecule is in Phase 2b testing. Those with different approaches to the metabolic disorder include 89bio, Akero Therapeutics, and Sagimet Biosciences. Diabetes and obesity drugs that target the GLP-1 receptor are also showing the potential to treat MASH. Recently, Boehringer Ingelheim and Eli Lilly posted encouraging mid-stage data for their respective drugs. NYU Langone’s Ganjhu acknowledged the potential of GLP-1 drugs to treat MASH. But she said that those drugs work by reducing fat overall, while Rezdiffra specifically reduces fat in the liver.
Madrigal set an annual wholesale price of $47,400 for Rezdiffra. That’s within the $39,600 to $50,100 price range that drug price group ICER said would be cost-effective. Sibold said Rezdiffra is a high-value medicine addressing a disease that poses a high burden to patients and the healthcare system. In setting the drug’s price, Madrigal aimed to balance value and patient access. The company expects to launch the drug in April, distributing it through a limited specialty pharmacy network.
The FDA decision for Rezdiffra is an accelerated approval that requires Madrigal to produce additional data from confirmatory studies. An ongoing outcomes study will serve as that confirmatory study to potentially support full FDA approval of the drug.
