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The bulk of the metabolic dysfunction-associated steatohepatitis companies have traded steadily along the same lines over the past month. Madrigal Pharmaceuticals’ FDA approval could change that. Madrigal Pharmaceuticals’ metabolic dysfunction-associated steatohepatitis (MASH) drug has been approved, to be sold as Rezdiffra. For the other companies with up-and-coming treatments trailing in the clinic, the question is: What now? Terns Pharmaceuticals already signaled a retreat from the space in January, shelving the oral thyroid hormone receptor-beta (THR-β) agonist TERN-501 in MASH, previously known as nonalcoholic steatohepatitis (NASH). But the therapy was expected to go on, potentially finding a foothold in another competitive indication: obesity. In an earnings release that coincidentally was released the same day as Madrigal’s triumph, the company indicated that the hunt for a future indication is still ongoing for TERN-501. While the journey may be over for Terns, analysts at William Blair and Global Data saw a brighter side to the Rezdiffra label. The FDA will not require a liver biopsy before treatment, which means patient selection should be easier and access more streamlined. Could there still be hope for the companies to come after Madrigal? “The absence of liver biopsy requirement in Rezdiffra’s label should buoy biotech stocks with exposure to MASH,” William Blair wrote in a Friday morning note. “Accordingly, we expect biotech companies with MASH exposure to broadly rally today, given that one of the commercial overhangs has been removed.” That’s exactly what happened Friday morning when the markets opened—at least for Madrigal, which jumped more than 16% to $283.55. Other companies in the space had more modest bumps, such as 89bio, which climbed 4.5% to $13.18; Aligos Therapeutics saw barely a blip, with a 1% gain to 88 cents; Terns stepped up just over 6% to $7.15. The closer trailing competitors fell: Viking Therapeutics went down 2% to $63.47, while Akero Therapeutics fell just under 5% to $26.07.  https://public.flourish.studio/visualisation/17172049/ While the bulk of the MASH companies have traded steadily along the same lines over the past month, Viking is an outlier, thanks to data published Feb. 26 linking the company’s obesity drug VK2735 to weight loss of up to 14.7% after 13 weeks of treatment. The dual agonist of GLP-1 and GIP has emerged as the star of Viking’s pipeline, but VK2809 has put up strong data in MASH. The therapy was linked to mean relative changes in liver fat of up to 51.7% without causing widespread gastrointestinal side effects in a phase 2b study that read out in May 2023. Viking used the weight loss data to raise $550 million in an underwritten public offering after the obesity data, with the proceeds going toward both VK2809 and VK2735 as well as VK0214 for the rare genetic disorder X-linked adrenoleukodystrophy. William Blair believes VK2809 could “outshine” Madrigal’s clinical profile. Rezdiffra was specifically approved for the treatment of MASH with moderate or severe liver scarring, or fibrosis, consistent with stage F2 and F3 disease. The therapy met both goals of MASH resolution and fibrosis improvement in a phase 3 trial. The FDA nod was based on an analysis of about 900 patients with biopsy-confirmed MASH and liver fibrosis who enrolled in the MAESTRO-NASH trial. In the study, Rezdiffra, given at either 80 mg or 100 mg once daily, cleared MASH with no worsening of fibrosis in 25.9% and 29.9% of patients, respectively, versus 9.7% for those who received placebo, according to data published in The New England Journal of Medicine. In addition, 24.2% and 25.9% of patients on the two Rezdiffra doses showed fibrosis improvement of at least one stage, with no worsening on a fatty liver disease activity score. The rates were significantly more than the 14.2% seen in the placebo group. These data will now be the bar that companies like Viking will have to clear, Global Data Senior Pharma Analyst Sravani Meka said in a Friday morning note. “In an indication where there were previously no approved therapies and multiple development failures, the approval of Rezdiffra will now set the standard for all other treatments in development,” Meka said. “Future therapies will now have to meet or outperform efficacy and safety data generated from resmetirom’s Phase III MAESTRO studies.” GlobalData estimates that the total MASH market is expected to reach $25.7 billion in 2032 across the U.S., France, Germany, Italy, Spain, the U.K. and Japan. Competitors such as Viking and the GLP-1 heavyweights Novo Nordisk and Eli Lilly should arrive in 2024 through 2032. Madrigal has a major head start, but the GLP-1 challengers like Novo’s Wegovy and Lilly’s Zepbound pose a huge challenge to the small biotech’s potential market share. Novo has also looked outside its GLP-1 stable to lock in future prospects in the market. The company signed a deal with venture creation firm Flagship Pioneering in January to gain access to two cardiometabolic disease partnerships, each worth up to $532 million. Flagship biotech Cellarity is working on a small molecule to treat MASH.  Elsewhere, Boehringer Ingelheim recently announced that a Zealand Pharma-partnered candidate called survodutide improved disease activity and liver scarring in a phase 2 trial. Up to 83% of adults treated with survodutide achieved a statistically significant improvement of MASH, with the trial also meeting all secondary endpoints, including a statistically significant improvement in liver fibrosis. Boehringer was not specific on the phase 3 plans in MASH but did say the therapy has already moved into late-stage studies across subpopulations of people living overweight and with obesity, including cardiovascular and chronic kidney disease patients. Meanwhile, small biotechs in the race will need to differentiate. 89bio just this week initiated a phase 3 program for pegozafermin with hopes of securing an accelerated approval for non-cirrhotic MASH, or fibrosis stages F2-F3—the same as Madrigal. That could be a tough climb, as patients in that category now have a treatment option with Rezdiffra. The biotech will likely have to show MASH improvements way outside of what Madrigal has achieved to convince the FDA that an accelerated nod is warranted.  89bio CEO Rohan Palekar acknowledged the huge achievement that the approval of Rezdiffra is for patients, in a statement provided to Fierce Biotech Friday afternoon. But his company is charging ahead with its plans.  "This is just the beginning and we at 89bio look forward to building further on this success as we progress development of pegozafermin," Palekar said. "Because of the large and growing patient population in MASH, many therapeutic options will be both needed and successful." He specifically cited patients with advanced fibrosis and suggested the community needs options that improve tolerability and dosing convenience to ensure compliance.  Palekar is confident the FDA will be open to an accelerated approval.  "We worked closely with the FDA prior to the initiation and aligned on key elements of our MASH development strategy. Based on these discussions, if our phase 3 trials are successful, we do expect the FDA will grant pegozafermin accelerated approval for both F2-F3 and cirrhotic MASH using histology endpoints," the CEO said.  Over at Aligos, CEO Lawrence Blatt, Ph.D., similarly made the case for his own drug, issuing a statement suggesting there’s room for more. “Despite this approval, there still remains a large patient population that may need additional or different therapy than what resmetirom can offer,” Blatt said in a statement. “Aligos is not only supportive of the progress this approval represents but happy to see this class validated as we begin the phase 2a trial of our own highly potent and selective THR-β agonist, ALG-055009.” Editor's note: This story was updated at 5 p.m. ET on Friday, March 15, to add comment from 89bio. 

Pictured: Illustration of alphabetical letters rising, with MASH highlighted in yellow/Modified from iStock, carloscastilla Thursday afternoon marked a major regulatory milestone. In one of the year's most highly anticipated FDA decisions, the regulator approved Madrigal Pharmaceuticals’ Rezdiffra (resmetirom) as the first-ever therapy for the treatment of adults with noncirrhotic non-alcoholic steatohepatitis (NASH). Or was the approval for metabolic dysfunction-associated steatohepatitis (MASH)? If you’re confused by the NASH versus MASH indication, you’re not alone. After all, the FDA’s announcement on Thursday invoked the NASH nomenclature. “NASH is a result of the progression of nonalcoholic fatty liver disease where liver inflammation, over time, can lead to liver scarring and liver dysfunction,” according to the agency. And yet, BioSpace and some other media outlets—though not all—reported Rezdiffra’s approval as being in MASH. Why the difference, you ask? Months before Thursday’s FDA approval under the accelerated approval pathway, NASH was being referred to as MASH—and not just by some members of the trade press. As Madrigal explained in its announcement: NASH is also known as MASH. “In 2023, global liver disease medical societies and patient groups came together to rename the disease, with the goal of establishing an affirmative, non-stigmatizing name and diagnosis,” the company stated. And so, the NASH moniker became MASH. Still, it didn’t stop Madrigal from using NASH in the headline of its press release on the FDA approval and throughout the biopharma’s announcement. I guess old habits die hard, even for a company “pursuing novel therapeutics” for NASH (they mean MASH!). Likewise, the nonprofit Global Liver Institute (GLI) couldn’t resist using the old name for the disease. “NASH is most common among people with obesity and/or type 2 diabetes. As these conditions have become more prevalent, the risk for NASH also increased,” Jeff McIntyre, vice president of Liver Health Programs at GLI, said in a statement. “This approval gives patients and healthcare providers a long-awaited tool to change the trajectory of their chronic liver disease.” No matter what you call it, Rezdiffra’s approval is a big deal for the estimated 6 million to 8 million people in the U.S. who have the condition with moderate to advanced liver scarring—a number that is expected to grow significantly. According to GLI, researchers anticipate 27 million cases in this country by 2030. The FDA’s accelerated pathway for earlier approval of drugs that treat serious conditions and address an unmet medical need was sorely needed for this growing patient population, as once NASH/MASH progresses to significant liver fibrosis the risk of adverse liver outcomes increases dramatically. Speaking with BioSpace ahead of the FDA’s decision on Thursday, experts said the approval could signal a sea-change in the diagnosis and treatment of MASH. “There are no effective approved therapies, and so Madrigal’s resmetirom, even though it has limited efficacy, would be an important first,” Rajarshi Banerjee, CEO of Perspectum, which supported Madrigal’s clinical trials, said. For me, MASH—a leading cause of liver-related mortality—is personal. I lost my father to the disease, a complication of his diabetes. Though the approval of Rezdiffra comes too late for him, this medication is a breakthrough treatment, to be used along with diet and exercise, for a long-neglected patient population. As with any groundbreaking drug, it must be affordable and be made widely available to truly benefit the patients who need it most. That should be the next item on Madrigal’s agenda. Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

The first drug for metabolic dysfunction-associated steatohepatitis will cost $47,400 per year, its developer, Madrigal Pharmaceuticals, said Thursday.Madrigal revealed the price and launch plan for Rezdiffra on a conference call discussing the decision by the Food and Drug Administration to approve the medicine.Rezdiffra is the first available therapy for MASH, a disease caused by a buildup of fat in the liver that leads to progressive organ damage. Its availability is a milestone in the fight against the condition, which has bedeviled drugmakers for about a decade.MASH is projected to affect millions of people globally and as a result has been seen by Wall Street analysts as a significant and untapped market opportunity. In its statement Thursday,the FDA noted that about 6 to 8 million people in the U.S. are estimated to have MASH with moderate to severe liver scarring, making them eligible for treatment with Rezdiffra.Yet the sales outlook for Rezdiffra has long been uncertain. MASH often goes undiagnosed for years and is typically confirmed through a liver biopsy, a painful and expensive procedure. Some of its symptoms can also be addressed through diet and exercise. And more recently, a popular group of weight loss medicines have shown promise treating the condition, with early results that compare favorably with Rezdiffra and other MASH drugs in development.Notably, Rezdiffras prescribing information doesnt require patients to receive a liver biopsy before treatment, something Wall Street analysts pointed to Thursday as boosting both Madrigal and the broader MASH field. It also didnt include any unexpected or onerous monitoring requirement, wrote Leerink Partners analyst Thomas Smith. The label appears clean. Those factors made for a near-best case scenario, according to Smith, and Madrigals shares climbed more than 20% following the news.Still, Madrigal now faces the challenge of identifying patients for treatment and convincing insurers that Rezdiffra is worth the cost. Analysts forecasted a list price of at least $30,000 per year. At $47,400, the cost is above our expectations, but still within the threshold of cost-effectiveness set by the Institute for Clinical and Economic Review, a prominent drug pricing watchdog, Smith wrote.Madrigal was also given an accelerated approval based on Rezdiffras ability to affect markers associated with the disease, and some outside experts have described the drugs effects as modest. An ongoing trial meant to prove whether treatment can improve health outcomes is ongoing, with results expected in 2026 or 2027.Madrigal executives said the company will initially focus on the 315,000 MASH patients in the U.S.with moderate to advanced fibrosis and are seen by a group of 14,000 physician specialists its specifically targeted. The companys data show that, in clinical testing, Rezdiffra halted or reversed liver scarring in about 80% of patients fitting that descriptionThis is a high value medicine for a disease that has a significant burden on patients and the healthcare system, said CEO Bill Sibold, on Thursdays call. Now it's about wiring the system over the next 12 months to develop the market the right way.To do so, Madrigal has to ensure Rezdiffra is added to electronic medical record systems in doctors offices, align physicians on what noninvasive tests could be used to diagnose patients and get the support of insurers.Based on discussions with insurers, Madrigal doesnt expect them to mandate liver biopsies to receive treatment, Sibold said. But the company does anticipate that theyll require prior authorization and to establish testing requirements for diagnosis as part of the reimbursement process. Additionally, filling prescriptions could initially take 60 days, and Madrigal expects physicians to prescribe Rezdiffraonly when patients come in for their annual or bi-annual visits.Taken together, those factors could make for a slow initial launch trajectory, according to executives. But Sibold said coverage will steadily ramp up in 2024, with about 80% of people on commercial insurance covered by the end of the year, and Medicare following in 2025.Over the next 12 months, we are taking the important first steps required to build a blockbuster and establish ourselves as the leading [MASH] company, Sibold said.Smith, of Leerink, forecasts $76 million in revenue this year and peak sales of about $3.5 billion worldwide by 2030. '