89bio recently revealed the initiation of the Phase III ENLIGHTEN-Cirrhosis trial of its flagship FGF21 analog, pegozafermin, in patients with metabolic dysfunction-associated steatohepatitis (MASH) with compensated cirrhosis. The announcement followed the November release of strong results for pegozafermin in F4 patients, albeit with a very small sample size. Clinical Trials Arena spoke to 89bio’s chief medical officer Hank Mansbach about the news, discussing potential strengths that the asset could have over its competitors.
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The ENLIGHTEN-Cirrhosis trial is the first clinical trial of pegozafermin in MASH F4, following past trials that focused more on MASH F2-3 patients. As a result, Mansbach was first asked about the differences between conducting a trial in MASH F4 and in MASH F2-3.
“We are conducting two studies, one called ENLIGHTEN-Fibrosis, which is in the non-cirrhotic population, and then ENLIGHTEN-Cirrhosis, which we announced earlier this week, is starting in the cirrhotic population,” he said. “In the non-cirrhotic studies, there are many examples of Phase III programs, some of which have been different; the most recent one was successful.”
However, Mansbach went on to note that the situation was quite different for cirrhotic trials.
“There’s also a number of ones that ultimately were unsuccessful in the cirrhotic population… As of now, there haven’t been any successful trials,” he added. “So as we designed ENLIGHTEN-Cirrhosis, the study in the F4 population, we tried to look at what we thought might have gone well and what might have been some areas of improvement. We ended up with a design that looks at 760 patients, approximately double-blind, placebo-controlled.”
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He explained the decision for the trial to have two primary endpoints: a histological one at month 24, focusing on fibrosis regression, and one at month 60, which addresses clinical outcomes.
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By GlobalData“The point of the histology is to potentially lead to accelerated approval in the US or conditional approval in Europe,” he said. “But it’s important to be able to convert that to full approval in both regions, and for that, we need clinical outcomes.”
He went on to note that the clinical outcomes measure was important in non-cirrhotic trials as well, in order to convert the accelerated approval to full approval.
Mansbach was then asked about the emerging treatment paradigm in MASH, led by the recently approved THR-β agonist Rezdiffra. He noted that there was no direct data comparing pegozafermin to Rezdiffra based on Phase III results, but there were some indications that pegozafermin could have advantages over its established competitor.
“In Phase II results from Rezdiffra, the fibrosis improvement Δ relative to placebo appears to be somewhat more muted relative to what we’ve observed with pegozafermin in Phase II, but I caution again, this is not a direct comparison,” he noted. “In F4, fibrosis regression, of course, is going to be very important, and if we’re able to demonstrate significant improvement relative to placebo and a Δ like we’ve observed in Phase II in the non-cirrhotic population, we think we will have a very important new therapy for patients.”
Mansbach went on to address suggestions that certain approved drugs, including Rezdiffra in MASH and various GLP-1 agonists in obesity, could reduce the potential market for pegozafermin by halting the progression of MASH before the development of advanced fibrosis.
“As to whether there’ll be a reduction in the number of patients progressing into F4, it’s hard to know, to be honest. The placebo-corrected improvement in fibrosis with Rezdiffra’s Phase III was relatively modest. So right now, the more important thing is that it’s going to lead to more patients being diagnosed and treated with MASH. That will probably be more important than any reduction in the actual absolute numbers,” he said.
“There are GLP-1 therapies that are revolutionizing obesity care and have been on the market for diabetes for a long time. From our standpoint, they are likely to end up as background therapy for patients with MASH because many patients with MASH have diabetes or obesity. At the time a physician is choosing to treat advanced fibrosis, which I’ll define as F3 or potentially even F4, they are more likely to be looking for an agent that has a more robust effect on fibrosis; at the moment, the GLP-1-based therapies have not demonstrated the ability to have a robust benefit on fibrosis.”
He further noted that both the ENLIGHTEN-Cirrhosis and ENLIGHTEN-Fibrosis trials would include data for patients taking background GLP-1 agonist therapies as part of their standard of care.
89bio’s most direct competitor, Akero, which is developing the FGF21 analog efruxifermin, recently had a setback in its Phase IIb SYMMETRY trial, after the asset failed to achieve statistical significance. Mansbach commented on efruxifermin’s situation.
“Even the Akero team at this point is saying they probably looked a little early; they look at 36 weeks for fibrosis regression,” he said. “In our Phase III program, we are going to do the repeat biopsy of 24 months to allow a long enough time for fibrosis regression to be done and to be more robustly demonstrated than what Akero looked at in their Phase II study.”
He then went on to distinguish pegozafermin from its in-class rival, noting advantages in safety and dosing regimen.
“There’s similarities and differences between… efruxifermin and pegozafermin—both are potent FGF21 analogs; they both show very robust effects on fibrosis and on MASH resolution,” he added. “From a differentiation perspective, pegozafermin has continually shown better tolerability, relative to Akero, specifically on [gastrointestinal (GI)] tolerability, which we think is important as patients need to stay on these therapies chronically. And secondly, we offer an every two-week option, again, which is important for patients who are going to be on chronic dosing—Akero at the moment with efruxifermin is once a week only.”
On the third major FGF21 analog in development, Boston Pharma’s BOS-580, Masbach raised similar criticisms.
“We’ve only seen non-invasive test data from the Boston Pharma compound; their GI tolerability looks to be relatively poor at the moment,” he said. “We need to see more data to understand what the differentiations are going to be.”
Masbach then justified the decision to choose a month 24 readout for ENLIGHTEN-Cirrhosis, given the previous encouraging results at week 48, stating that there would not be any other time points introduced to the trial design to measure fibrosis regression.
“Regression in F4 will only be measured at month 24. I think it’s important to note that in F4, in those patients that are more advanced, the scarring of their liver has progressed substantially relative to the F2/F3 population, and it takes longer to rewind the clock, if you will,” he said. “We arrived at the 24 months based on looking at clinical trial data from the previous programs, consulting with experts, and consulting with regulators as to what would be the most likely time point to enhance the probability of success for our study.”
Lastly, Masbach assuaged safety concerns about FGF21 analogs causing bone loss, suggesting these had not been an issue for pegozafermin yet.
“Any bone effects, we’ve not observed in our study,” he claimed. “We’ve reported at week 48 that there were no clinically meaningful or statistically significant effects on bone in our ENLIVEN study. We continue to monitor that; if there are longer-term effects, they might be modest, and there are many ways in which physicians could be able to manage those.”
Pegozafermin appears to be increasingly well-positioned to be a major player within the MASH therapy space. Though numerous other assets are still vying for the same market, its consistently impressive efficacy and safety data have set it apart from the competition. However, it remains to be seen whether the results presented so far will be confirmed in the new Phase III trial.
