By Jia Jie Chen

Pictured: Stocks trending down/iStock, lerbank
Shares of Akero Therapeutics crashed this week after the biotech released data from a late-stage trial of its lead candidate, efruxifermin, in nonalcoholic steatohepatitis. Although the Phase IIb study met multiple secondary endpoints, the effect on the primary endpoint was not considered statistically significant.
The SYMMETRY trial compared 182 patients with compensated cirrhosis—also known as F4 fibrosis—who were treated with efruxifermin (EFX) with a placebo control group. The data showed that 22% of patients treated weekly with 28 mg of efruxifermin (EFX) saw at least a one-stage improvement in liver fibrosis with no non-alcoholic steatohepatitis (NASH) worsening, while 24% of those treated with 50 mgs of EFX achieved this result; this compared to 14% of patients in the placebo arm who experienced similar improvement. The differences between the placebo group and both experimental arms were not statistically significant, with p-values at 0.38 and 0.28, respectively.
This murky primary endpoint data caused other companies with drugs in the same pharmacologic class as EFX, such as 89bio, to lose investors as well. For Akero, a thorough reassessment of this data and overall strategy is crucial to regaining investor trust.
From a statistical significance standpoint, the company must determine whether there is a way to reinterpret the existing data and if further trials will be needed.
First, Akero needs to consider the logic of using only the NASH Clinical Research Network (CRN) scoring rubric to determine whether or not fibrosis stage improvement has occurred. While using only one guideline for scoring helps to standardize the calculations, without other fallback scoring systems in place, identifying the precise location of the data quality issue becomes more difficult. Although using NASH CRN scoring has its strengths, such as separating pathologists’ pattern-based diagnoses from the liver feature-based score, there are also weaknesses, including an inability to measure speed of disease progression.
Second, Akero should confirm whether the three pathologists hired to calculate the NASH CRN score were adequately trained. In SYMMETRY, two pathologists were utilized to individually determine NASH CRN scores. If the scores differed, a meeting was held to calculate a consensus score, and if there was no consensus, the third pathologist would come up with an adjudicated score. The NASH CRN scoring rubric was designed mainly for expert academic hepatopathologists, and it is unclear whether community-based general pathologists use the scoring guidelines in the same way. While the SYMMETRY readout report states that the “pathologists underwent protocol-specific training to align on NASH-CRN scoring interpretation,” their academic backgrounds are unclear, which could be a confounder.
Finally, Akero must strategically factor other late-stage contenders into its market position. In its competitive intelligence reporting, Akero covered six other companies working on NASH treatments but left out other late-stage contenders such as Terns Pharmaceuticals, Madrigal Pharmaceuticals and Viking Therapeutics. Of these, Madrigal’s resmetirom is the most direct competitor. In Phase III, resmetirom delivered statistically significant positive results in two primary endpoints in pre-cirrhotic patients: NASH resolution with no worsening of fibrosis and one or more fibrosis stage improvement with no worsening of NAFLD activity score (NAS). In Phase IIb trial data reported in September 2022, Akero also demonstrated statistical significance in both primary and secondary endpoints in this patient population. Still, as resmetirom is orally administered once per day and EFX is injected subcutaneously once per week, patients are more likely to prefer resmetirom based on route of administration alone, which could cut into Akero’s potential revenues.
As confounding as it sounds, Akero’s path to reassuring investors is time-sensitive. At this point, the company not only needs to convince investors that EFX can meet primary endpoints statistically in the F4 fibrosis indication, but must also contend with a future competitor like Madrigal, which could reach the market first. The FDA is expected to make a decision on resmetirom in March 2024.