FGF21

iStock, Elena Merkulova Akero Therapeutics, 89bio, Boston Pharmaceuticals and more are working to bring novel treatment options for metabolic dysfunction-associated steatohepatitis to a market that could reach $16 billion by 2033. It’s been a little more than a year since the FDA approved Madrigal Pharmaceuticals’ Rezdiffra as the first treatment for the liver disease metabolic dysfunction-associated steatohepatitis. After earning $180 million in full-year 2024 sales , Madrigal expects Rezdiffra to reach blockbuster status in the coming years. With an estimated 22 million Americans living with metabolic dysfunction-associated steatohepatitis (MASH)—previously known as nonalcoholic steatohepatitis (NASH)—there is a growing pipeline of potential therapies, and several companies are expecting Phase III readouts in 2025. Rather than relying on one strategy, the leading candidates are approaching the disease from different angles. This could allow more assets to carve out a share of a market that is expected to be worth $16 billion by 2033 . Rezdiffra’s early success, along with clinical research suggesting that GLP-1 drugs could also have therapeutic potential in MASH, has analysts optimistic about the growth potential of the space. “That’s why Rezdiffra has been so heavily watched and why there are so many drugs in development for MASH,” Edward Nash, senior biotechnology analyst at Canaccord Genuity, told BioSpace . “It’s thought of as having the potential to be the next type 2 diabetes for the industry. It’s that big of a metabolic disease, and it offers multi-billion dollar opportunities for many different treatment mechanisms.” Here, BioSpace looks at five candidates that could soon emerge on the market. 89bio’s Pegozafermin Fibroblast growth factor 21 analog Currently undergoing Phase III trials , 89bio’s pegozafermin is part of a class of treatments for MASH that mimics the activity of fibroblast growth factor 21 (FGF21), a hormone produced by the liver that acts as a metabolic regulator. According to Nash, FGF21 analogs have generated the most attention because they’ve shown a “really strong ability to reduce liver fibrosis,” which is damage to the liver caused by the chronic inflammation associated with MASH. So far, pegozafermin is no exception. Phase IIb trial results showed the candidate managed at least one-stage fibrosis improvement at two different dosage levels (30 mg weekly and 44 mg every-other week) without worsening of MASH. In addition, MASH resolution without worsening of fibrosis was managed at 26% and 23%, dependent on the dosage. Rohan Palekar, CEO of 89bio, pointed to a recent peer-reviewed publication where pegozafermin was ranked as the most efficacious drug for fibrosis improvement and MASH resolution among all approved or investigational MASH drugs. “A key distinction is that pegozafermin has also shown a favorable safety and tolerability profile, with few gastrointestinal side effects and no clinically significant effect on bone density,” Palekar told BioSpace in an email. Akero Therapeutics’ Efruxifermin Fibroblast growth factor 21 analog Akero finds itself in a similar position to 89bio, with a FGF21 analog in Phase III trials. However, the biotech’s path to this point, at least from a shareholder perspective, has been more tumultuous. Akero’s stock price sunk in October 2023 after efruxifermin missed its primary endpoint of 36-week fibrosis improvement in a Phase IIb trial. The drug’s prospects were saved five months later when the biotech was able to show in 96-week data that fibrosis was significantly improved in patients with MASH. “Unlike other MASH drugs that target [a] specific pathway, efruxifermin delivers sustained FGF21 signaling to both liver and adipose tissue, aiming to correct metabolic imbalances that drive disease progression,” Kitty Yale, chief development officer at Akero, told BioSpace over email. “While some obesity drugs aid weight loss, they may not directly target the liver, limiting their impact on fibrosis.” The biotech has a Phase III program comprising three ongoing clinical trials aimed at supporting future regulatory applications of efruxifermin for patients with compensated cirrhosis due to MASH and with pre-cirrhotic MASH, Yale added. Boehringer Ingelheim, Eli Lilly, Novo Nordisk: Survodutide, Tirzepatide, Semaglutide GLP-1 agonists A fierce competition is underway between weight loss rivals, as GLP-1 drug developers attempt to differentiate their treatments . One strategic angle has been to target MASH as an additional indication to support the drugs’ widespread use. According to Nash, an approval in MASH would boost GLP-1s’ appeal for physicians because it would allow them to address three metabolic diseases—type 2 diabetes, obesity and MASH—with the same treatment. Boehringer Ingelheim, Eli Lilly and Novo Nordisk have all adopted this approach. Boehringer and Novo Nordisk have progressed survodutide and semaglutide , respectively, through to Phase III trials, and Lilly posted positive Phase II trial results for tirzepatide in June 2024. Of the GLP-1s currently being studied for MASH, Nash suggested that semaglutide is the closest to potential FDA approval, projecting that an approval could come by the end of 2025 or in the early part of 2026. While clinical trials have indicated that GLP-1s can reduce fat in the liver, that does not necessarily indicate that fibrosis will also be reduced, Nash cautioned. Due to this limitation, GLP-1 drug developers will likely explore combination therapies, which could see other approaches to MASH combined with GLP-1 medicines, he added. Both Palekar and Yale said they are exploring using their MASH candidates in conjunction with GLP-1s. Boston Pharmaceuticals’ Efimosfermin Alfa Fibroblast growth factor 21 analog Boston Pharmaceuticals’ FGF21 analog is a little bit different. A fusion protein based on human IgG and FGF21, efimosfermin alfa is longer-acting than other late-stage rivals in the MASH pipeline, with Boston exploring a once-monthly regimen for the drug. In November 2024, the potential treatment elicited a one-stage improvement in fibrosis without worsening of MASH in a Phase II trial . The biotech plans to advance efimosfermin into Phase III trials in the fourth quarter of this year, according to CEO Sophie Kornowski. Similar to other companies working in the space, the next stage of trials will assess how efimosfermin pairs with incretin treatments for diabetes, such as GLP-1s, Kornowski told BioSpace via email. Nash likened Boston’s dosing to approaches in immunology and inflammation, where when rival drugs’ clinical outcomes are similar and the longer dosing schedule drugs are preferred. Margaret Koziel, chief medical officer at Boston, told BioSpace by email that efimosfermin’s increased half-life is enabled by “several point mutations and an additional disulfide bond that prevents proteolytic degradation.” Viking Therapeutics’ VK2809 Thyroid hormone receptor agonist Adopting a similar approach to Madrigal, Viking has a thyroid hormone receptor agonist as its lead candidate for MASH. The biotech posted positive Phase IIb data in November 2024 showing that up to 75% of patients treated with VK2809 reached MASH resolution without fibrosis worsening. A further 57% showed at least a one-stage improvement in fibrosis without deterioration of MASH. Like Rezdiffra, VK2809 is a small molecule, oral treatment. In Phase II studies, Viking carried out both a daily and an every-other-day dosing schedule. In full-year results released in February 2025 , Viking stated that it considered its drug candidate “best-in-class” but only noted that it is “currently evaluating potential next steps” for VK2809. Should the development of VK2809 prove successful, the biotech could explore trialing the treatment alongside its own GLP-1 treatment candidate, VK2735, providing Viking with an in-house combination therapy. Despite this healthy roster of candidates, Nash said it is unlikely that any of them will be able to fully displace Rezdiffra. “Given their lead over the competitive landscape and being on the market first, Madrigal is going to have entrenched itself by the time competitors arrive,” he concluded. “Plus, it’s a safe drug—so, it’s a nice, solid foundational drug to have on the market.”

The once-fledgling field of MASH drug developers is now one of the few areas of consistency in the biotech industry. And another late-stage startup is gaining traction. Boston Pharmaceuticals, advancing a once-monthly liver disease drug, is exploring both an IPO and an acquisition, looking to capitalize after a successful mid-stage trial and a comparable company’s positive data. “We are focusing on being de-risked and fast, but we’re also doing [a] dual track,” Boston Pharma CEO Sophie Kornowski told Endpoints News in an interview. “It’s important for us to have smart investors at the table. You want to maximize the asset for the patients.” Mayank Mamtani, senior managing director and group head of healthcare at B Riley Securities, compared Boston to the cardiometabolic biotech Carmot Therapeutics. In 2023, that company raised $150 million in May, filed paperwork to go public in mid-November, and was swiftly acquired by Roche two weeks later. “They could kind of do these parallel processes and see what makes sense from a timeline to value creation,” he said in an interview. Boston’s plans underscore just how much momentum biotechs have gained by looking to treat metabolic dysfunction-associated steatohepatitis, a form of advanced fatty liver disease also known as NASH. A few years ago, the treatment landscape was a graveyard. Now, there’s an approved drug in Madrigal’s once-daily pill Rezdiffra, and a number of followers that confidently feel there’s enough of the market that awaits them. Boston Pharma launched 10 years ago with $600 million when megarounds genuinely were a dime a dozen. It had the backing of Gurnet Point Capital, led then by current Biogen CEO Chris Viehbacher, and was helmed by former Eli Lilly executive Robert Armstrong. Not unlike many bright-eyed biotechs, Boston Pharma wanted to win at everything. It strove to have 20 clinical assets, and licensed a handful from GSK and Novartis in 2018. Another asset separately licensed from the Swiss pharma in 2020 was what became efimosfermin alfa, now the only asset in its clinical pipeline. Kornowski, a dealmaker in her own right after previously leading Roche’s BD team, said “the economics are really favorable to Boston Pharmaceuticals.” Board chairman Elias Zerhouni told Endpoints that when he got involved, he convinced investors that the company had to focus. “You can’t afford to not be best-in-class in at least one category, if not two,” he recalled telling Ernesto Bertarelli, an Italian billionaire whose asset management firm includes Gurnet Point. So the company focused on the MASH treatment. Boston Pharma reported Phase 2 data in November showing statistically significant improvements in both fibrosis without worsening of MASH, and resolution of MASH without worsening of fibrosis. Fibrosis is a type of liver scarring that’s a hallmark of the disease. Its drug got another boost after Akero Therapeutics reported in late January that its own candidate with a similar mechanism was able to better reverse advanced fibrosis in patients compared to placebo. Zerhouni says that those data not only validated the broader FGF21 class, but they informed how vital the duration of therapy is. “They set up a threshold for everybody,” he said. “We think we have what it takes to equal or better this particular threshold that they came up with.” Akero is testing its drug as a once-weekly treatment, and fellow FGF21-targeting biotech 89bio is testing weekly or every two-week dosing. Mamtani compared Boston’s once-monthly efimosfermin alfa to Amgen’s obesity drug MariTide, which is similarly leaning on convenience to compete with other weight loss drugs. “Longer-acting mechanism, very potent fat reduction, less drug exposure, maybe that bone [toxicity] risk can be kind of ruled out,” Mamtani said. “So those are things that, from a clinical profile standpoint, make the case” for the drug, he added. Boston Pharma has some catching up to do, with Akero and 89bio both in Phase 3 studies. It expects to work with the FDA on trial plans by the middle of this year and could start its Phase 3 study in patients with F2 or F3-stage fibrosis as early as the third quarter of this year. A separate trial arm, in more severe F4 patients, would launch “very soon after that,” according to Zerhouni. That program will also include a subgroup analysis for patients who enter the study on a GLP-1 drug, a key feature that some other MASH biotechs have already incorporated into their trials. Akero found that the combination of its drug and GLP-1s made “substantial differences to the liver,” according to an exec in an earlier interview . Boston did not include a similar subgroup analysis in its Phase 2 study. For Kornowski, keeping up with competitors isn’t daunting. “I’m extremely motivated to do it well, and to do it fast,” she said.

- Funding will advance development of Rejuvenate’s one-time gene therapy RJB-0402 for the treatment of desmoplakin gene variant arrhythmogenic cardiomyopathy SAN DIEGO--(BUSINESS WIRE)-- Rejuvenate Bio, announced today that the California Institute for Regenerative Medicine (CIRM) has awarded the company a $4M grant to complete IND-enabling activities for the development of RJB-0402 for the treatment of desmoplakin gene variant arrhythmogenic cardiomyopathy (DSP ACM). RJB-0402 is a novel systemically administered investigational AAV8 gene therapy that drives liver specific expression of FGF21 protein, targeting multiple key pathological drivers of DSP ACM. Since the DSP gene is too large for gene replacement therapy, novel strategies are needed to treat DSP ACM. FGF21 has known salutary effects on cardiac dysfunction as well as ventricular arrhythmias, adipogenesis, inflammation, and fibrosis, all of which are DSP ACM hallmarks. Furthermore, clinical efficacy of RJB-0402 in DSP ACM may form the basis for the treatment in other forms of ACM. “DSP ACM is a rare, severe, life-threatening, and debilitating disease that typically manifests in young adults as a high risk of life-threatening ventricular arrhythmias, sudden cardiac death, and progression to heart failure,” said Dan Oliver, CEO & Co-Founder, Rejuvenate Bio. “There is currently no disease modifying therapy for patients with this disease, and our gene therapy RJB-0402 addresses a significant unmet medical need.” “The funding and strategic support from CIRM will accelerate development of our gene therapy candidate RJB-0402 into clinical trials for DSP ACM patients in desperate need of new therapies,” said Noah Davidsohn, Ph.D., Chief Scientific Officer & Co-Founder, Rejuvenate Bio. “We are confident that RJB-0402, a one-time gene therapy, could be a transformative regenerative medicine and the first disease modifying therapy to address the unmet medical need of DSP ACM patients, and the recent funding from CIRM will enable us to initiate our first in human clinical trial.” Nonclinical proof-of-concept studies in the ACM mouse model showed that RJB-0402 significantly improved cardiac structure, function, and markedly reduced the arrhythmia burden, normalizing premature ventricular contractions (PVCs) to wild type levels. The clinical relevance of these efficacy signals provides a scientific rationale for further development as a therapeutic with the potential to meaningfully impact patients’ survival, symptoms, and quality of life. “Our goal is to move the most promising research forward,” said Dr. Abla Creasey, Vice President of Therapeutics Development at the California Institute for Regenerative Medicine (CIRM). “A one-time gene therapy treatment for patients with this rare cardiac disease DSP ACM, would have significant impact for patients with this degenerative disorder. We look forward to supporting Rejuvenate Bio in bringing this regenerative therapy to patients with this degenerative disease.” About Desmoplakin Arrhythmogenic Cardiomyopathy (DSP ACM) DSP ACM is a severe, life-threatening, and debilitating, rare autosomal recessive disease that results in ventricular arrhythmias that are often life threatening and progressive cardiac dysfunction caused by fibrofatty replacement of ventricular myocardium which can lead to heart failure for which no disease modifying therapies exist. While more than 10 different genes have been implicated in this heterogeneous disease, the majority involve one or more variants in desmosomal genes which are key components of the cardiac intercalated disc that are essential for the electrical and mechanical coupling of cardiomyocytes. These multiprotein complexes work together to provide cardiac mechanical integrity and strength as well as electrical communication and synchronization. While the exact prevalence of DSP ACM is unknown, it is estimated to affect an estimated 30,000-50,000 people in the United States. About Rejuvenate Bio Rejuvenate Bio is a biotechnology company dedicated to developing novel gene therapies for chronic age-related diseases. Rejuvenate Bio has built a gene therapy pipeline with huge potential in chronic disease by utilizing clinically validated gene targets and a delivery approach that ensures well tolerated, durable expression. Founded on scientific research developed at the Wyss Institute at Harvard Medical School, Rejuvenate Bio has developed groundbreaking therapies to treat chronic age-related disease in both humans and animals. The company is headquartered in San Diego, CA. For more information, visit . About California Institute for Regenerative Medicine (CIRM) At CIRM, we never forget that we were created by the people of California to accelerate stem cell treatments to patients with unmet medical needs, and act with a sense of urgency to succeed in that mission. To meet this challenge, our team of highly trained and experienced professionals actively partners with both academia and industry in a hands-on, entrepreneurial environment to fast track the development of today’s most promising stem cell technologies. With $5.5 billion in funding and more than 150 active stem cell programs in our portfolio, CIRM is the world’s largest institution dedicated to helping people by bringing the future of cellular medicine closer to reality. For more information go to .