Akero’s FGF21 analog yields 63 percent to 72 percent relative hepatic fat reduction in Phase 2a study; the company awaits biopsy data hoping to see a fibrotic benefit. Also, Genfit says COVID-19 pandemic should not significantly delay its Phase 3 NASH readout.
FGF21 analogs comprise one of the more crowded classes in nonalcoholic steatohepatitis (NASH) drug development, with major players like Merck & Co. (NYSE: MRK) and Bristol Myers Squibb (NYSE: BMY) in the field, but Akero Therapeutics (NASDAQ: AKR) may be moving to front of the pack with Phase 2a data for its drug showing an ability to produce relative hepatic fat reduction ranging from 63%-72%.
On 31 March, the recently-turned-public firm revealed that its BALANCED study met its primary endpoint of hepatic fat reduction from baseline compared to placebo, with 28mg, 50mg and 70mg doses of the once-weekly injectable all hitting that mark. Akero licensed AKR-001 from Amgen (NYSE: AMGN), after that firm made the compound available for out-licensing following Phase 1 investigation in type 2 diabetes.
Jefferies analyst Michael Yee said in a same-day note that the data “suggests some of the best initial data in the field with 75%-85% responders and even the lowest dose is very strong.” Akero is continuing to develop the dataset – patients who achieved at least 30 percent liver fat reduction from baseline were eligible for an end-of-treatment biopsy and the company has completed 25 out of 50 planned. From the histology, the biotech hopes to assess AKR-001’s potential antifibrotic benefit.
Yee said the data seen already help de-risk the drug and show that it is quite active in NASH patients. “We believe the next Phase 2 data coming will further confirm the drug works and will have good fibrosis data (key investor focus),” he wrote. “We look forward to that data with the caveat the numbers are semi-small [and there was] a somewhat short time to allow fibrosis changes.”
In an interview, Akero CEO Andrew Cheng said the data released on 31 March are the primary endpoint data based on MRI-PDFF scans, but that the biopsy data will offer additional information on safety as well as fibrosis effect. Jefferies anticipates the biopsy data to emerge around June.
The 80-patient study enrolled patients with fibrosis scores ranging from F1 to F3; Cheng said approximately 63 percent to 65 percent of the sample were more advanced patients with F2 or F3 fibrosis. For relative reduction in fat from baseline, the placebo arm showed no reduction in hepatic fat, while the 28mg arm showed a 63 percent reduction, the 50mg arm a 71 percent reduction and the 70mg arm a 72 percent reduction (p<0.001 for all three treatment arms.)
Measuring absolute fat reduction, the 28mg dose produced a 12.3 percent reduction, the 50mg dose a 13.4 percent reduction and the 70mg dose a 14.1mg reduction (p<0.001 for each), compared to 0.3 percent for placebo. The responder rate – patients achieving 30 percent reduction or greater from baseline – was 84 percent in the lowest dose, 85 percent in the middle dose, and 75 percent in the highest dose.
DATA COMPARE WELL WITHIN FGF21/FGF19 CLASSES
Jefferies’ Yee called the results “high-end data vs. others” noting that FGF21 analogs tested in NASH generally yielded response rates of about 55 percent. NGM Biopharmaceuticals’ (NASDAQ: NGM) aldafermin (NGM-282), an FGF19 analog, produced a 66 percent response rate in Phase 2, but also met a composite endpoint by resolving NASH and reducing fibrosis scores by one stage or better in 22 percent of patients in a Phase 2 study of patients with F2/F3 fibrosis scores. BMS, Merck, Boehringer Ingelheim International and Novo Nordisk (NYSE: NVO) are among the other firms advancing FGF21 candidates for NASH, along with the lesser known 89bio (NASDAQ: ETNB).
“I think it’s accurate to say that these are the most robust responses within the FGF21 class to date,” Cheng said, while conceding that he was making cross-study comparisons to candidates like BMS’ pegbelfermin and Merck’s MK-3655. “We did not test them head-to-head, and of course these are compounds that are in early-stage development,” he added.
The exec told Scrip that Akero wants to see the biopsy data before determining which dose will advance to Phase 2b, adding that it’s possible more than one dose could be investigated in that study. “We’re only looking at one side of the story and we want to see the totality of the data before we make a decision on dose range,” he explained. “Certainly, the 63 percent reduction [with 28mg] was impressive for us given that it’s roughly one-third of the 70mg dose, yet [showed] very little difference.”
The study also yielded a statistically significant reduction in alanine aminotransferase (ALT), a standard marker for liver safety, for all three doses compared to placebo. Safety was in line with what Amgen saw in previously testing the compound in type 2 diabetes, Akero said.
Investors responded positively to the news, with Akero’s share price finishing 31 March up 23.4% to $21.20. The company raised $92m in an oversubscribed initial public offering last June.
No clinical update these days is complete without mention of the impact of the COVID-19 pandemic, and Akero reported that this will impact the way it conducts the remaining biopsies for BALANCED as well as planned 20-week safety follow-up visits. The company also has postponed until the second half of the year an additional cohort to test AKR-001 in NASH patients with compensated cirrhosis (F4 fibrosis scores).
GENFIT DOES NOT EXPECT MAJOR DELAY IN REPORTING PHASE 3 DATA
Genfit (NADAQ: GNFT) also addressed the coronavirus pandemic’s impact in a statement on 31 March, saying that it does not affect the outbreak to significantly affect the planned readout of its Phase 3 RESOLVE-IT study of elafibranor in NASH, expected during the second quarter. The dataset locked at the end of February and the French firm has said it will wait for some guidance from the US Food and Drug Administration before unblinding the data.
SVB Leerink analyst Thomas Smith said on 31 March that this FDA feedback, which Genfit expects imminently, might lead the company to elevate some exploratory endpoints addressing metabolic parameters in RESOLVE-IT to be secondary endpoints. This might include lipid levels and changes in HbA1c, the analyst said.
Genfit said it considered the benefits for NASH patients in light of the risks posed by the COVID-19 outbreak and will continue an extension phase of RESOLVE-IT. Through its contract research organization, Genfit is implementing safety measures such as virtual clinic visits, local laboratory assessments, home delivery of the study drug and halting the screening of new patients.
The firm is also halting all Phase 1 trials, including pharmacokinetic, food effect and bioequivalence studies that will be needed to complete the planned new drug application for elafibranor. “Management anticipates that these studies could likely be restarted within about one month following abatement of the COVID-19 pandemic concerns,” Leerink’s Smith noted.
Genfit halted a pair of Phase 2 studies as well, one for PK and pharmacodynamics in pediatric patients and another to assess the drug’s effect on hepatic fat. Finally, Genfit has put on hold its Phase 2 NASH combination study and a planned Phase 3 study in primary biliary cholangitis.
The company said its supply chain currently is unaffected by the pandemic and it has enough elafibranor on hand to cover clinical trial needs into mid-2021 and expects no issues with raw material supply or batch production.