Retatrutide

For years, drug developers working to treat an advanced form of fatty liver disease known as MASH were chasing wide-open terrain. There were no products on the market, millions of potential patients and a high bar on the science to get a successful drug. Then, in June, Eli Lilly reported that its blockbuster weight loss drug tirzepatide might be an effective treatment for the condition. Last week, Novo Nordisk released a study showing that its weight loss drug semaglutide also improved MASH in patients . It’s planning to apply for an FDA approval next year. MASH (metabolic dysfunction-associated steatohepatitis) is often associated with obesity, and the apparent success of the widely available (and cheaper) GLP-1 drugs has raised the question about how much room there will be for MASH-targeting drugs. The answer, however, appears to be that there’s still an opportunity. Last week, the first company to bring a MASH drug to market reported third-quarter sales of $62.2 million, well above Wall Street expectations. It’s a fraction of what the weight loss products are selling, but it was enough to send the company’s stock up by almost half. On a call with investors Thursday, Madrigal Pharmaceuticals executives said many of their patients are also on weight loss drugs, and they don’t expect patients to have to try a GLP-1 before moving to a MASH therapy. “We’ve had ongoing dialogue with payers now for well over a year,” Madrigal CEO Bill Sibold said. “They understand the profile of the product and what it can offer.” At the same time, biotechs developing the MASH drugs have begun to tweak their development strategies to prove that their liver-targeting candidates work in conjunction with the weight loss drugs, especially as more patients show up in trials already on the therapies. And early batches of data released by biotechs in the space suggest there are benefits to combining the treatments. Sagimet Biosciences, for example, has a once-daily, oral MASH drug named denifanstat that’s set to enter Phase 3 before the end of the year . In the company’s Phase 2b study that read out this year, about 10% of patients were on a GLP-1 receptor agonist. CEO David Happel estimates that rate could jump to as much as 50% in a Phase 3 trial, and a survey of clinicians published by Cantor Fitzgerald in late June found that about a third of patients with advanced MASH are already on GLP-1s. “We were able to show a highly statistically significant improvement in fibrosis in those patients that frankly exceeded what either molecule alone could achieve,” Happel said in an interview with Endpoints News . None of the four patients on a GLP-1 who were given placebo demonstrated an improvement in either resolution of MASH without worsening of fibrosis or improvement in fibrosis without worsening of MASH. Five of 12 patients that were given the study drug showed MASH resolution and fibrosis improvement, respectively, though the MASH resolution results weren’t statistically significant. Those sorts of data are just beginning to emerge, now that companies developing MASH drugs are starting to study what happens when patients are on GLP-1s — and whether some patients might benefit more than others. “Until now, we have put all these patients in one population to examine, so there is little granularity in the treatment of the patients so far,” said Frank Tacke, director of hepatology at Charité – Universitätsmedizin Berlin, who’s consulted for numerous pharmas, including Novo Nordisk and Madrigal. “If we want to position whatever drug we would like to develop in patients with MASH, it will be in an environment where GLP-1s are one of the main drugs to treat the comorbidities,” Tacke said. Akero Therapeutics has performed similar analyses as Sagimet with its experimental MASH drug efruxifermin, currently in Phase 3. The drug is an analogue of fibroblast growth factor 21 (FGF21), a protein which fights against fat-induced toxicity and its effect on cellular distress. In a Phase 2 trial cohort, Akero studied 31 people on GLP-1s who had type 2 diabetes and MASH, adding either efruxifermin or a placebo. In the group, the majority of patients who added efruxifermin saw significant improvement to key markers of the disease. “The two in combination are really making substantial differences to the liver,” Akero chief development officer Kitty Yale said of the effect of the weight loss drugs and Akero’s experimental medicine. Other results, presented earlier this year, found that efruxifermin improved patients’ fibrosis across two dose levels at the 96-week mark compared to placebo. One reassurance for the companies developing MASH drugs is that the weight loss treatments, while effective in treating obesity, don’t appear to be a cure for the liver disease. Data from Eli Lilly at this year’s European Association for the Study of the Liver annual meeting showed that tirzepatide met the primary endpoint of wiping out fat cells in the liver compared to placebo. The company said the drug demonstrated the potential to be “clinically meaningful” at improving fibrosis, but that the study was not powered for the endpoint. And in a 2021 trial, Novo Nordisk failed to show a significant difference between semaglutide and placebo. “While these medications can be very helpful for the treatment of MASH, they’re not a complete panacea,” said Sidney Barritt, director of hepatology at the University of North Carolina’s liver center. Lilly is still mulling whether to launch a pivotal trial of tirzepatide in MASH, or wait to test a successor weight loss drug — if the better bet is retatrutide — in the disease. A spokesperson for the company said it “plans to continue conversations with the FDA on the next steps for tirzepatide for the treatment of MASH.” As for Novo, investors described the new data as roughly in line with expectations. Analysts at Leerink Partners said the GLP-1s don’t appear to be a ‘silver bullet’ for MASH and believe that combination use will be the standard of care. “For NASH stocks — we believe this outcome removes a potential overhang / worst-case scenario where [semaglutide] showed ‘game-changing’ fibrosis improvement,” the analysts wrote. Investors agreed and Madrigal’s stock climbed after the readout. There could be a handful of reasons for why the obesity drugs don’t solve MASH, Barritt explained, including that GLP-1 receptors aren’t located in the liver. The benefits are indirect, with improvements in weight through decreased appetite that naturally improve MASH — to a point. It’s also possible that a 52-week endpoint that some MASH trials implement may be a bit too soon for GLP-1s to show a full effect. Other trials have a longer, 72-week endpoint. “I think there’s going to be a market for these combination therapies in the future,” said Brian Ting, a transplant surgeon and gastroenterology specialist at the Tulane Transplant Institute. Reynald Castañeda contributed reporting.