Advances in the Pipeline for MASLD/MASH
In the final installment of the expert roundtable on MASLD/MASH, Drs Afdhal, Bansal, and Younossi discuss the most promising new candidate drugs in development for treatment, including some that may reverse fibrosis.
Nezam Afdhal, MD, is Chief of Gastroenterology and Hepatology at Beth Israel Deaconess Medical Center and a professor of medicine at Harvard Medical School in Boston, Massachusetts. Meena Bansal, MD, is Chief of the division of Liver Diseases and Director of the MASH Center of Excellence at Mt Sinai Medical Center in New York, New York. Zobair Younossi, MD, is chairman and professor of the Liver and Obesity Research Program at INOVA Health in Fairfax, Virginia, and chairman of the Global NASH Council.
CLINICAL PRACTICE SUMMARY
MASH (MASLD) Pipeline Update: Lanifibranor and FGF21 Agonists Advancing to Phase 3
- MASH/MASLD: Lanifibranor (pan-PPAR agonist); oral therapy; phase 2 completed → phase 3 pending: Lanifibranor is positioned for patients with lean MASLD/MASH, with a potential niche due to observed weight gain (primarily nonvisceral fat) alongside reduced visceral adiposity, which may affect patient acceptance.
- MASH with advanced fibrosis: FGF21 agonists (e.g., efruxifermin, Akero); endogenous hormone analogs with extended half-life; phase 2b data: FGF21 class shows strong antifibrotic potential, including reported reversal of cirrhosis in phase 2b. These agents may be prioritized upfront in patients at high risk of progression to cirrhosis to reduce downstream complications such as hepatocellular carcinoma.
- Care model (next 3–5 years): Combination and personalized therapy; chronic/lifelong treatment paradigm: Future management will likely involve induction with 2–3 agents followed by maintenance therapy, tailored to patient phenotype and disease activity.
TRANSCRIPT:
Dr Afdhal:
And I'm going to finish up with a two-minute section or a 3 or 4-minute section on new treatments. So we've got these 2 drugs and we've got a lot of new drugs in the pipeline. I think that the most exciting drugs that I'm going to ask our panel to talk about are really those that are more advanced, have finished phase 2, moving into phase 3, and they are drugs like lanifibranor, which is a pan-PPAR agonist and the FGF21 agonists of which there are multiple that are moving in towards phase 3. So I'm going to ask each to do quick comments on why do we need them? What will their role be and what do you think their target populations are going to be? So I'll start with Meena.
Dr Bansal:
Sure. So I think lanifibranor is another oral therapy. I think that it'll be a great drug. I think the sweet spot for this drug is going to be lean MASLD or MASH because there is a weight gain that you see with it, even though it's more of a weight gain in other parts of the body, but loss of visceral adiposity. It's still a hard sell to patients. That's my opinion. However, we'll see.
And I think the most promising class is the FGF21 class. It is an endogenous hormone that has effects on multiple target organs. And so I think it's going to be great. The drugs that are coming out, because the endogenous half-life is only 2 hours, all of the drugs that you're seeing are basically modulations to have them have a greater half-life.
I think that we've now seen for the first time a pharmacologic that reverses cirrhosis. So we saw that with the Akero drug, efruxifermin, where there is reversal of cirrhosis in phase 2b, but we look forward to the phase 3 studies. So I think exciting times, I think the FGF21s are going to be our best antifibrotic. And so those who are F3 kissing cirrhosis, you're going to want an FGF21 upfront. If you can prevent them from getting to cirrhosis, you decrease that HCC risk and all the other downstream outcomes.
Dr Afdhal:
Zobair?
Dr Younossi:
So I would say that I'm a big believer that you're going to do 2 things. One is that there's going to be combination. And the second is that there's going to be personalized treatment, meaning that you have to look at patient's profile and decide on what regimen would best fit the patient. So having these drugs would be great. I think the FGF21s will probably have a better antifibrotic effect, but in what we call hot fibrotic or hot fibrosis, you still have to have some activity going on. The pure antifibrotic, patients that have cirrhosis and don't have any activity, what used to call cryptogenic cirrhosis or cirrhosis that has very little fat and not in any evidence of MASH, you can't really get rid of those with anything that we have currently within the pipeline. So I think combination and then deciding on which drug and for how long.
The second thing is that you may want to actually start with 2 or 3 drugs as an induction. So you can actually get the process under control, but keep a patient on 1 or 2 drugs as maintenance because it's going to be long-term. In my view, it's going to be lifelong treatment. I don't think you're going to be able to stop these drugs. In fact, if you stop it, the process will take over and take off and you go back exactly where you started. So I think there's a lot of good things that's coming down the pike, but this is my 2 cents, at least how I see the future in the next 3 to 5 years.
Dr Afdhal:
Fantastic. Well, I think this has been a great conversation. I want to thank you both for participating. And I'd like to just say that we are really in the infancy of the treatment of MASH as one of the key factors in the cardiometabolic diseases that we face today. And I think that the future in terms of what is coming down the pipeline and the potential for development of targeted therapies is really, really going to be fantastic. We haven't talked about genetics, we haven't talked about genetic targeting. We haven't talked about a lot of exciting things that are coming, but clearly I think that there's a lot of hope for our patients with MASH-induced liver disease, and it's going to be an exciting next 10 years. Thank you.
