Selonsertib

Not content with navigating Rezdiffra’s trajectory to blockbuster territory, Madrigal Pharmaceuticals has spent 2026 shopping for a range of drugs that the company hopes could work alongside its metabolic dysfunction-associated steatohepatitis (MASH) trailblazer. Madrigal kicked off the year paying $50 million to Pfizer for the rights to a DGAT2i inhibitor, before spending $60 million the following month on six preclinical siRNA programs from China’s Ribo Life Science and its Swedish subsidiary Ribocure Pharmaceuticals that Madrigal wants to use to silence genes implicated in MASH. The company explained at the time that both deals were aimed at securing therapies that could be combined with Rezdiffra. The biopharma was back at the dealmaking table in May, paying $25 million upfront to Arrowhead Pharmaceuticals for a phase 1-stage RNA interference therapeutic that had previously been rejected by Johnson & Johnson. Early clinical data had suggested the asset could reduce liver fat in a mutation found in 30% of MASH patients, including high prevalence in Hispanic populations. Combined with a preclinical GLP-1 agonist licensed from China’s CSPC Pharmaceutical for $120 million upfront last year, Madrigal now has a diverse array of MASH assets coming up behind Rezdiffra. So what’s the strategy behind this rapid pipeline expansion? “The question early on was what mechanisms we wanted,” Madrigal CEO Bill Sibold told Fierce in an interview at the company’s office in Waltham, Massachusetts. “My answer was: we want all of them,” Sibold continued. “We want anything that makes sense mechanistically or has proven already to have an effect on MASH.” It’s a sign of just how much Rezdiffra has changed the game since being approved as the first-ever treatment for MASH in 2024. Before that point, Sibold said he had counted 23 drugs across the industry that had failed to treat the fatty liver disease previously known as nonalcoholic steatohepatitis (NASH). This rollcall of failure meant MASH had become “the graveyard of drug development,” lumped in with other difficult-to-treat conditions like sepsis and lupus, he remembered. The disease occurs when fat builds up in the liver, causing inflammation and eventually cell death. It is the leading cause of liver transplants for women and the second biggest cause for men in the U.S. “Industry had been really interested in this area for a long time, but nobody could crack the nut,” Sibold said. Many companies tried and failed to find a breakthrough. Gilead’s ASK1 inhibitor selonsertib and its LOXL2 enzyme-targeting simtuzumab both flopped in the clinic, as did Genfit’s dual PPAR alpha/delta agonist elafibranor and Conatus Pharmaceuticals' pan-caspase inhibitor emricasan. Rezdiffra’s origins go back to Roche. Madrigal founder Rebecca Taub, Ph.D., left the Swiss pharma’s metabolic unit to work for VIA Pharmaceuticals, which licensed the thyroid hormone receptor (THR)-β agonist. Madrigal assumed the rights to that agreement when it was founded in 2011 and continued to develop the therapy. Sibold remembers getting a call from a recruiter about the Madrigal CEO position in 2023 while he was president for North America at Sanofi, having helped launch immunology blockbuster Dupixent. “There's no way I'm going to leave this to go to that,” he remembers of his initial reaction to the offer. But as Sibold dug into the company, educating himself on the trials and the science behind its lead asset, he became convinced that this was a unique opportunity to make a special impact. The year after Sibold joined up, Madrigal had secured Rezdiffra’s historic FDA approval. As well as the company's headquarters in West Conshohocken, Pennsylvania, the company now also has an office in Massachusetts—which Fierce visited—as well as an international outpost in Switzerland. “There were so many Big Pharma companies trying to solve [MASH], and this little Pennsylvania company of very few people had the tenacity, the guts and the grit to get there,” Sibold said. Madrigal reported $958.4 million in annual net sales for the drug in 2025. By the second quarter of this year, Rezdiffra was bringing in $364.3 million, equivalent to year-over-year growth of 71%. Sibold told Fierce that it wasn’t always this way. Early on, a MASH advocate told him: “We didn't know whether to believe you at first because it seemed like such a huge hill to climb that you guys didn't even have an approved product. But you are doing exactly what you said you would do.” After establishing itself as the market leader in MASH, what’s next? Does the company stay in its lane, expand into immunology targets or look at new indications? For Sibold, the answer lies in Madrigal’s five-word purpose: leading the fight against MASH. The biopharma wants to continue working with the MASH community it has come to know so well to build out its pipeline with more effective and comprehensive treatments for different subpopulations. Rather than generate data and hope to get bought by a bigger fish, Sibold said he is planning for an independent and sustainable company 10 to 20 years down the line. His vision is for MASH treatments to grow like other specialty markets, such as rheumatoid arthritis, psoriasis or inflammatory bowel disease, with dozens of products that generate tens of billions of dollars in annual sales. “We feel like MASH will emerge like that, and as a result, we want to have the portfolio of products that can best help all or subpopulations of patients,” Sibold said. Unlike a Big Pharma, where MASH may be one of a myriad of indications being focused on, Sibold suggested Madrigal's strength comes from the fact it is committed to the disease. This approach is reflected in trial enrollment and feedback, he said. “The community values expertise, and I think we've made a conscious decision to be experts in MASH,” he said. “Through expertise comes insight into what might be the next best mechanism, or the next best mechanism to combine with your current mechanism, or the best way to design the next trial.” Because reducing liver fat is so important to preventing or treating MASH, GLP-1s are moving into the space and posing a potential threat. Last year, Novo Nordisk’s Wegovy was approved to treat MASH, and some people have warned Sibold that Madrigal could be crushed by GLP-1s in the future. Instead, the CEO insisted more activity in the space is a good thing for Madrigal. “It's great to have another company who's putting resources into diagnosis, awareness and treatment,” he said. “There are some patients that are getting Wegovy, but it is helping to grow the market. It's not to our detriment.” But other Big Pharmas are circling. Last year saw GSK acquire the FGF21 analog efimosfermin from Boston Pharmaceuticals for $1.2 billion upfront, while Roche picked up a similar drug called pegozafermin as part of its $3.5 billion buyout of 89bio . Madrigal may be looking to become the MASH version of what Vertex Pharmaceuticals has achieved in cystic fibrosis, but that doesn’t mean Sibold and his team couldn’t eventually broaden their focus. “Would we look at other diseases? Yes. We would in time, or if the biology takes us there,” he told Fierce. But for now, the company is leaning into MASH specialization, developing relationships with patient groups, clinicians and researchers while raising Rezdiffra’s profile and growing a specialized portfolio of complementary therapies. “It's been fun. It's making a difference. It's helping patients,” Sibold said. “This is as good as it gets.