89bio’s PhII data add to quick succession of NASH readouts as field seeks turnaround

89bio said its drug was better than placebo at lessening fibrosis without worsening nonalcoholic steatohepatitis, or NASH, in two of three dose groups.

The San Francisco biotech said it thinks the Phase IIb data pave the way for a potential Phase III, following in the footsteps of another biotech in its drug class, Akero Therapeutics. To fund a late-stage study, CEO Rohan Palekar told Endpoints News 89bio “would need to raise additional capital,” with the company having about $188 million at the end of last year.

Both 89bio and Akero are making analogs of FGF21 — a hormone normally produced in the liver at low levels to manage energy and lipid metabolism and insulin sensitivity — in the hopes of treating the fatty liver disease. They’re attempting to wade into a disease that has tripped up biopharmas for years but might soon see the first two treatment approvals, with Intercept awaiting an FDA decision in June and Madrigal Pharmaceuticals headed to the regulator next year. Akero previously said it would meet with the FDA this month to discuss a late-stage trial after reading out a positive Phase IIb last September.

For 89bio’s Enliven study, 27% of patients receiving the investigational drug pegozafermin at 44mg every two weeks experienced a decrease of at least one stage of fibrosis with no worsening of NASH, the biotech said Wednesday, compared to 7% of those on placebo. For those who got 30mg every week, 26% of patients saw that improvement. Those pegozafermin groups came in at a p-value of 0.008, which the company said was “high statistical significance.” About 22% of the 15mg group saw that improvement, for a p-value of 0.1.

On the other primary endpoint, looking at NASH resolution without a worsening of liver fibrosis, 89bio said 26% of those on the 44mg dose every two weeks met that bar compared to 2% on placebo. The weekly 30mg group saw 23% meet that endpoint, and 37% did so in the weekly 15mg set of patients. P-values were 0.0005 for 44mg, 0.0009 for 30mg and less than 0.0001 for 15mg.

The potential Phase III dosing regimen hasn’t been determined yet, but Palekar said an every-two-week injection is more ideal for patients than a weekly one, especially given the chronic nature of NASH.

Hank Mansbach

The data, with more to be submitted to a medical conference and journal, are likely to draw fine-combing from other NASH drug developers, physicians and investors as the analysis of two primary endpoints came from 192 of 219 patients dosed. The 27-patient difference came after the biotech changed from consulting one pathologist to having three independent pathologists score each liver biopsy slide, which CMO Hank Mansbach called a “much more precise approach” that resulted in those patients no longer meeting the histological inclusion criteria. “Insight from the landscape about how” NASH trials were being conducted led to the adjustment, he said in an interview.

“There is a large variability when a pathologist reads that slide, and in some ways, this has plagued some of the prior studies in NASH,” Palekar said in a separate interview.

The biotech homed in on the prospectively identified population of those with F2 and F3 stages of fibrosis, or liver scarring, which are the “population of interest for regulatory submission,” Mansbach said. Other NASH drug trials have looked at patients with additional stages of fibrosis, but they typically isolate data from the F2 and F3 group, he noted.

On the safety front, 89bio said five patients on pegozafermin versus none on placebo discontinued because of treatment-related adverse events. The biotech said the most frequently reported side effects were grade 1 or 2 diarrhea, nausea or increased appetite at mild to moderate levels. One drug-related serious adverse event occurred in which a patient experienced “uncomplicated pancreatitis associated with gallbladder sludge” after receiving one dose in the 44mg every-two-week group.

Liver fat levels dropped more for patients on 44mg every two weeks and 30mg weekly. 89bio reported 54% and 52% declines for those groups, respectively, versus 14% for the patients on placebo. Liver damage was also lower on the study drug than placebo.

Up next, 89bio plans to meet with regulators in the US and Europe to discuss a Phase III clinical trial, Palekar said. To fund that, the biotech will need more capital, he noted, as current funds are also being directed toward an upcoming Phase III that will test pegozafermin in patients with severe hypertriglyceridemia. The FDA approved the late-stage study after 89bio presented data last year on the condition, which can lead to cardiovascular disease.

As 89bio gears up for the next stage, patients and the field await an FDA decision on Intercept’s obeticholic acid. The agency will convene its outside advisors on May 19. Mansbach, the 89bio CMO, said a thumbs up from the experts and a subsequent approval for Intercept’s treatment candidate would be “very welcomed certainly by patients as well as by physicians” because it would be the first treatment approved for the indication.

Meanwhile, multiple other biotechs are in the mid-and-late stages of NASH drug development, with Inventiva working on Phase III studies of its drug lanifibranor and HighTide Therapeutics reeling in $107 million to help support a Phase IIb trial. Chemomab Therapeutics, when presenting Phase IIa results in January, said it’d focus on other diseases because of the cash required for running later-stage studies in NASH.

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