GLP-1R x FGF21

Pictured: A fatty liver over a cell/Taylor Tieden for BioSpace You would be forgiven if, with all the cancer news from ASCO24 in Chicago this week, you missed the hepatology data dump at the 2024 Congress of the European Association for the Study of the Liver in Milan, Italy. However, there’s a battle brewing between Eli Lilly and the partnered companies Boehringer Ingelheim and Zealand Pharma in metabolic dysfunction-associated steatohepatitis (MASH), previously referred to as nonalcoholic steatohepatitis (NASH). The drugs being tested in MASH belong to the now-blockbuster class of therapies known as glucagon-like peptide-1 receptor agonists (GLP-1s). Lilly’s tirzepatide is already approved for type 2 diabetes (marketed as Mounjaro) and weight loss (marketed as Zepbound), spaces it shares with Novo Nordisk’s semaglutide products Ozempic and Wegovy—a duopoly that has led to skyrocketing revenue for both companies, which continue to seek additional indications. Meanwhile, Boehringer and Zealand are looking to leap into the space with its own GLP-1 agonist, survodutide, which is under investigation for obesity and other indications. What was interesting this week at EASL24 was the GLP-1 clash between Lilly and Boehringer/Zealand in the MASH space, with both sides providing readouts on their latest Phase II data and each declaring victory. MASH is a potentially deadly fatty liver disease that affects more than 115 million people globally and is expected to increase to 357 million by 2030. In March, the FDA approved Madrigal Pharmaceuticals’ Rezdiffra, a liver-directed thyroid hormone receptor (THR)-β agonist, as the first-ever treatment for the disease. On Wednesday, Lilly’s Phase II data was presented at the European Association for the Study of the Liver (EASL24), showing that 54.9% of MASH patients treated with a 5-mg dose of tirzepatide saw at least a one-stage improvement in fibrosis. In the study of MASH patients with F2 and F3 fibrosis, tirzepatide treatment was found to be more effective than placebo in achieving MASH resolution without worsening of fibrosis. Just two days later, following a data leak snafu at EASL24 on Thursday, Boehringer and Zealand announced that survodutide demonstrated “breakthrough improvement” in liver fibrosis with no worsening of MASH in 64.5% of patients with F2 and F3 fibrosis. The companies said the new data also revealed up to 52.3% of adults with fibrosis stages F1, F2 and F3 had improvement in fibrosis without worsening of MASH. Survodutide, which is licensed to Boehringer from Zealand, is moving into a Phase III study. While GLP-1 drugs may have beneficial effects on MASH by improving insulin sensitivity, reducing liver fat accumulation and reversing fibrosis, Jefferies analysts said in a note to investors this week that they “don’t think GLP-1s will eliminate the market opportunity” for Madrigal in MASH. Likewise, Evercore ISI analysts opined, “there is room for different treatment options for patients with different needs, including daily oral pills and injectable products.” Evercore estimated a potential U.S. market opportunity for Madrigal’s Rezdiffra of $4 billion, while Jefferies’ estimate was considerably lower, pegging peak U.S. sales for Rezdiffra at $2.3 billion. Of course, there are a host of other promising MASH candidates, including Akero Therapeutics. Also at EASL24 this week, Viking Therapeutics announced its candidate VK2809—a thyroid hormone beta receptor agonist—significantly improved secondary histologic endpoints at 52 weeks with no worsening of fibrosis, as assessed by hepatic biopsy. And tomorrow, 89bio will be presenting Phase IIb data for pegozafermin, a specifically engineered glycoPEGylated analog of fibroblast growth factor 21. Meanwhile, new data from Altimmune and a preclinical poster presentation from Aligos Therapeutics also hint at promise in the treatment of MASH. Still, MASH is a complex and confounding disease that has caused many once-promising programs to be discontinued. However, with a projected $25.7 billion total market by 2032 in the U.S., France, Germany, Italy, Spain, the U.K. and Japan, competitors will continue to be in hot pursuit of Madrigal, which has set the standard. Let the clash of the MASH titans begin! Greg Slabodkin is the news editor at BioSpace. You can reach him at greg.slabodkin@biospace.com. Follow him on LinkedIn.

Pictured: A collage containing a fatty liver over blood vessels/Taylor Tieden for BioSpace When Madrigal Pharmaceuticals’ Rezdiffra was approved last month as the first-ever treatment for metabolic dysfunction-associated steatohepatitis, experts hailed the drug as an “important first.” However, the consensus among experts is that Rezdiffra is just the beginning for a disease that has been notoriously difficult to treat. Metabolic dysfunction-associated steatohepatitis (MASH) is inflammation of the liver caused by excess fat cells, which can lead to progressive fibrosis and cirrhosis of the liver. “[Rezdiffra] is the first oral drug that’s been demonstrated to show reversal of fibrosis in Phase III clinical studies,” said Lawrence Blatt, CEO of Aligos Therapeutics, which is also developing a candidate for MASH. “If you look at the magnitude of the impact of Madrigal’s drug, it’s good for patients,” he told BioSpace. “I don’t want to downplay what they’ve achieved . . . but there’s a lot of room for improvement.” About a quarter of patients treated with Rezdiffra have an improvement in fibrosis, he noted. “That leaves 75% of patients with the need for better therapies.” A day before Rezdiffra’s approval, Ionis Pharmaceuticals announced that its own metabolic dysfunction-associated steatohepatitis (MASH) candidate hit the primary endpoint in a Phase II trial, showing significant improvement in steatohepatitis without worsening fibrosis, according to the company. And this is only the tip of the iceberg. Here, BioSpace looks at five mid- to late-stage investigational MASH drugs. Ionis’s ION224 The FDA asks MASH drug developers to show in Phase III clinical trials a one-stage improvement in fibrosis (ranked on a scale from F0, or the absence of fibrosis, to F4, full-blown cirrhosis) with no worsening of MASH, or the resolution of MASH with no worsening of fibrosis. Ionis appears to be well on its way to this metric, as 32% of people in the high dose arm of its Phase II trial of ION224 had at least a one-stage improvement in fibrosis without worsening of steatohepatitis as measured by biopsy, compared to 12.5% of patients in the placebo cohort. The drug was safe and well-tolerated in the trial, Ionis stated, and there was a lower rate of early termination in the ION224 study arms compared to placebo. ION224 is designed to cut production of DGAT2, an enzyme that studies have linked to fatty liver disease. The Phase II trial “is the first to demonstrate clinical evidence that the reduction of hepatic fat after DGAT2 inhibition correlates with improvements in MASH histological endpoints,” Rohit Loomba, a professor of medicine and chief of the division of gastroenterology and hepatology at the University of California San Diego, said in a company statement. Altimmune’s Pemvidutide Pemvidutide, developed by Altimmune and currently entering Phase IIb trials, is a peptide-based GLP-1/glucagon dual receptor agonist. While activation of the GLP-1 receptors leads to appetite suppression, activation of glucagon increases energy expenditure, both of which are important for weight loss. Glucagon is also believed to have direct effects on hepatic fat metabolism, leading to rapid reductions in levels of liver fat and serum lipids, according to Altimmune. Mayank Mamtani, head of healthcare research at B. Riley Securities, is bullish on therapies targeting the glucagon receptor to treat MASH. In addition to pemvidutide, he cited Eli Lilly’s retatrutide and Boehringer Ingelheim’s survodutide. “If you look at [these programs], they’re telling you that this is the drug class that’s going to win in MASH.” On top of a “profound” lowering of liver fat, he said there are other benefits with this drug class, including lowering of liver enzymes and cholesterol, “that you’re not getting from Madrigal.” Boehringer Ingelheim reported positive data from its own Phase II trial in February. So far in clinical trials, once weekly pemvidutide has shown “compelling weight loss, robust reductions in triglycerides, LDL cholesterol, liver fat content and blood pressure,” and a clean safety profile, according to Altimmune. Topline 24-week data from the Phase II IMPACT trial is due in the first quarter of 2025. 89bio’s Pegozafermin San Francisco–based 89bio is one of a handful of companies developing an analog of FGF21, a hormone that may address underlying metabolic issues that drive liver and cardiometabolic diseases, including MASH. The primary unmet need in MASH is in more advanced disease, Mamtani said. “Something that works in F4 is obviously the holy grail,” he said, adding that analogs of fibroblast growth factor 21 (FGF21) could have potential here. In November 2023, 89bio announced positive topline data from its Phase IIb trial of pegozafermin. After 48 weeks, MASH patients with stage F2 or F3 fibrosis treated with the candidate saw sustained, statistically significant improvements across liver fat and noninvasive tests of liver injury/inflammation and fibrosis. Pegozafermin is “the first FGF21 analog candidate to demonstrate positive, sustained benefits over a 48-week period in patients with advanced NASH,” Hank Mansbach, the company’s chief medical officer, said in a statement at the time. (MASH used to be known by the name nonalcoholic steatohepatitis, or NASH.) Patients with stage F2 and F3 fibrosis are at high risk of progression to cirrhosis and increased risk of liver cancer, liver decompensation and death. Viking Therapeutics’ VK2809 Currently in Phase IIb trials, Viking Therapeutics’ VK2809 belongs to the same thyroid hormone receptor beta (THR-β) class as Rezdiffra. William Blair analysts Andy Hsieh and Alexandra Ramsey wrote in a March 2024 note that the drug could “potentially outshine Rezdiffra’s clinical profile.” Topline data presented in May 2023 showed VK2809 cleared the trial’s primary endpoint, significantly reducing liver fat in patients with biopsy-confirmed MASH. After 12 weeks, patients treated with 2.5 mg of Viking’s candidate saw a 45.3% decrease in liver fat content, compared to 3.7% in placebo comparators. Updated results from the Phase IIb study demonstrated “robust and comparable liver fat reductions among patients with or without type II diabetes, as well as patients with either F2 or F3 fibrosis,” Viking reported in November 2023. Viking expects 52-week biopsy results during the first half of this year. Aligos Therapeutics’ ALG-055009 Earlier this month, Aligos initiated dosing in the Phase IIa HERALD study of ALG-055009, also a THR-ß agonist. The placebo-controlled trial will enroll approximately 100 individuals with presumed MASH and F1–F3 fibrosis. So far in clinical trials, Blatt said ALG-055009 is showing up to 100-fold more potency than Rezdiffra. He added that, in contrast to Rezdiffra, the drug has linear and non-variable pharmacokinetics, “so it’s very well controlled.” With Rezdiffra, “the variation they see among these individuals is highly variable, so some people are getting the optimal dose, some people are getting underdosed [and] some people might be getting overdosed,” Blatt explained, even though they all got the same amount of the drug. He added that only about 25% of patients taking Rezdiffra had improvement in fibrosis because “you have a lot of patients who were underexposed to the drug, and they weren’t receiving the amount of drug that they needed.” Topline safety and efficacy data from the HERALD trial are expected in Q4, 2024. Heather McKenzie is a senior editor at BioSpace. You can reach her at heather.mckenzie@biospace.com. Also follow her on LinkedIn.

The FDA's approval for resmetirom sets the bar for many other candidates, including drugs leveraging the GLP-1 mechanism. The decades-long wait for an effective treatment for metabolic dysfunction-associated steatohepatitis (MASH) has ended, as the FDA has approved the first drug for the fatty liver disease. After a long and winding drug development path for the common disease, Madrigal Pharmaceuticals’ resmetirom, to be sold under the brand name Rezdiffra, has become the first MASH therapy to clear the FDA finish line. Thursday, the FDA approved the tablet drug for the treatment of MASH, also known as nonalcoholic steatohepatitis (NASH), with moderate or severe liver scarring, or fibrosis, consistent with stage F2 and F3 disease, according to a product label (PDF) posted on the FDA’s website. Rezdiffra emerged successful from a notorious drug development graveyard about four decades after the term NASH was first coined by researchers at Mayo Clinic. Its approval sets the bar for many other companies that are also eying the field, which is estimated to affect about 5% of adults in the U.S. “Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.” Madrigal is pricing Rezdiffra at the wholesale acquisition cost of $47,400 before any discounts. Previously, the influential cost watchdogs at the Institute for Clinical and Economic Review figured the drug would be cost-effective under common thresholds if its net price falls between $39,600 and $50,100 per year. In a major win for Madrigal, the FDA isn’t requiring a liver biopsy to determine a patient’s eligibility for Rezdiffra. Before the approval, a potential biopsy requirement served as a key point of debate among investors because the cumbersome and invasive procedure would have limited access to Rezdiffra.   A clinical feat Rezdiffra was the first drug to have met both goals of MASH resolution and fibrosis improvement in a phase 3 trial. Prior to Rezdiffra’s breakthrough, Intercept’s Ocaliva looked closest to being that first drug for MASH until the FDA struck it down for a second time in June 2023. The vast sea of MASH drug development had previously also sunk ships from the likes of Pfizer, Bristol Myers Squibb, Genfit, NGM Biopharmaceuticals and others. The current approval 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 80mg or 100mg 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 enjoyed 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. In the FDA’s approved label, Rezdiffra’s efficacy for each endpoint was presented by ruling from two pathologists. For improvement in liver fibrosis and no worsening of steatohepatitis, pathologist A found a 13% placebo-adjusted difference for Rezdiffra at 100mg, and the rate was 11% for pathologist B. Under the FDA approval, patients will get different dosages of Rezdiffra based on their body weight. For those weighing less than 100kg (220lbs.), the recommended dosage is 80mg. The other patients are supposed to take the 100 mg strength. Madrigal also provided additional safety data from the MAESTRO-NAFLD-1 trial, which the company believes resembles a real-world situation in which patients’ diagnoses are not confirmed by biopsies but instead noninvasive measures. There, the drug was found to be well tolerated, and offered significant improvements on some biomarkers such as liver fat and triglycerides. Physicians typically feel comfortable diagnosing MASH with noninvasive tools such as the FibroScan and therefore don’t routinely perform biopsies, Madrigal CEO Bill Sibold said in an interview with Fierce Pharma ahead of the approval. Plus, the biopsy procedure isn’t perfect for MASH because it only takes a thin slice of the liver, and it also comes with safety risks. With that considered, Madrigal wasn’t expecting a biopsy requirement from the FDA, or pushback from payers in reimbursement discussions, Sibold said. Based on a sans-biopsy-requirement label, analysts at Evercore ISI recently estimated that Rezdiffra could reach about $2.6 billion in global sales in 2030 and $5.5 billion at peak. That’s based on Madrigal’s estimate that about 315,000 U.S. patients who have MASH with significant fibrosis at stage 2 or 3 (F2 and F3) are currently being treated by specialists. Those F2 and F3 patients—plus about 5,000 to 7,000 high-volume, top-tier hepatologists and gastroenterologists—will be Madrigal’s key focus for the launch of Rezdiffra, Sibold said.    A specialty launch Sibold joined Madrigal in September after spending 12 years at Sanofi, most recently as executive vice president of specialty care and president of the French pharma’s North America business.  Sibold compared Rezdiffra to Dupixent, the blockbuster inflammatory disease drug that he managed, which delivered Sanofi 10.7 billion euros ($11.7 billion) in revenue last year. In Dupixent’s case, the dual inhibitor of IL-4/13 was the first biologic medicine approved for atopic dermatitis. Now, Rezdiffra is the first drug for MASH, another major market opportunity with significant unmet need. “Since there hasn’t been [a drug], we really get to shape the market and shape how you engage with the various stakeholders, and I love doing that,” Sibold said. Because Rezdiffra is the first MASH drug to hit the market, Madrigal has a lot of prep work to do. In a Feb. 29 note to clients, Evercore’s analysts said they expect to see a meaningful sales acceleration in the second year of the launch, after an initial phase for establishing infrastructure. “Just remember, there’s never, in the history of the country, a script been written for NASH,” Sibold said. “So there’s this notion of creating a pathway for patients to get through that.” In one important consideration, doctors will need to figure out how to process their existing patients. Initially, Madrigal will focus on educating doctors on both the disease and its medicine. The company will also work to have reimbursement policies in place and help practices navigate the prescription steps. “That is not a barrier to the ultimate success of the product, but it’s just a prerequisite for getting to that […] more established pathway,” Sibold said. By the CEO's estimate, it will take about 12 months before Madrigal can finish establishing the commercial foundation for Rezdiffra to ensure a “real rapid uptake," he said.   Prospect competitors behind the pioneer While Rezdiffra enjoys its first-mover advantage, other therapies have turned up promising preliminary clinical data in the hope of snatching meaningful market share. An estimated 100 million patients are projected to live with NASH in the U.S., France, Germany, Italy, Spain, the U.K., China and Japan by 2030. But researchers remain uncertain about how the disease’s prevalence will translate into a market for therapeutics, leading to wide variations in market size estimates, ranging from above $10 billion to more than $100 billion by 2030, according to a recent white paper from analytics firm IQVIA. Viking Therapeutics has VK2809, which, like Rezdiffra, is an oral thyroid receptor-beta agonist. In a midstage study, the drug led to an average relative change in liver fat of 51.7% after 12 weeks of treatment. The company has yet to report 52-week data on histologic response.  Meanwhile, both 89bio’s pegozafermin and Akero Therapeutics’ efruxifermin are FGF21 analogs given subcutaneously. Both have shown promising anti-fibrosis results in patients with F2 and F3 MASH, and phase 3 trials are either already underway or about to start.  Just before Rezdiffra’s approval, Ionis on Wednesday said a high dose of its antisense candidate ION224 helped 32% patients achieve a one-stage improvement in liver fibrosis without worsening steatohepatitis at week 51 in a phase 2 trial, compared to just 12.5% who received placebo. And then there’s the GLP-1 agonist class. Lilly in February reported positive phase 2 MASH data for its GIP/GLP-1 dual agonist tirzepatide in overweight or obese people, although the study wasn’t statistically powered to measure improvement in fibrosis. That drug is already approved in diabetes as Mounjaro and obesity as Zepbound. A few days ago, Boehringer Ingelheim touted what it called the best-in-class potential of its Zealand Pharma-partnered glucagon/GLP-1 agonist survodutide for MASH based on a phase 2 win. Detailed trial findings on the drug's statistically significant improvement in fibrosis remain under wraps.   RELATED: Prospective NASH market flips to overcrowded as Big Pharma GLP-1s cast shadow over biotech breakthroughs Sibold touted Rezdiffra’s advantage as a liver-directed medicine versus the more systemic approach with the GLP-1s, especially in patients with significant fibrosis. Madrigal plans to use its lead to establish deep roots in the community “in a way that will make it difficult for others to follow,” Sibold said. Eventually, Sibold expects Rezdiffra to be a foundational therapy which others will want to utilize in combinations rather than replace. While the company recognizes that combination treatments will be the future, it is right now focused on completing Rezdiffra’s existing trials, he said. As part of the accelerated approval, Madrigal has agreed to provide further evidence to confirm Rezdiffra’s benefits. That plan includes running the ongoing 54-month extension of MAESTRO-NASH that will measure disease progression and other outcomes such as liver transplants and development of cirrhosis. In addition, another study called MAESTRO-NASH Outcomes is evaluating Rezdiffra in patients with well-compensated NASH cirrhosis, which is a more advanced stage of the disease. If positive, the study could support the full approval of Rezdiffra and expand its patient base. Sibold said it’s hard to predict an exact timeline for a readout because the trial is event-driven, but he put it as a 2026 or 2027 event. While the long-term follow-up of MAESTRO-NASH lasts for 54 months, Sibold said Rezdiffra is expected to be a chronic treatment that patients continue to take until signs of the patient’s disease are gone and all the contributing factors such as obesity are removed. Editor's Note: The story has been updated with Rezdiffra's price.