8-K: Akero Therapeutics Reports Significant Histological Improvements in Phase 2b HARMONY Study at Week 96

Akero Therapeutics' Phase 2b HARMONY study of efruxifermin (EFX) shows statistically significant improvements in liver fibrosis and other key endpoints at 96 weeks, particularly with the 50mg dose.

Summary

• Akero Therapeutics announced positive topline results from its Phase 2b HARMONY study at week 96, evaluating efruxifermin (EFX) in patients with pre-cirrhotic MASH.
• The study met its primary endpoint at week 24, showing a one-stage improvement in fibrosis without worsening of MASH in 41% of the 50mg EFX group and 39% of the 28mg EFX group, compared to 20% for placebo.
• At week 96, the response rates for one-stage fibrosis improvement increased to 75% for the 50mg EFX group (p<0.001) and 46% for the 28mg EFX group (p=0.07), compared to 24% for placebo.
• A two-stage improvement in fibrosis without worsening of MASH was observed in 36% of the 50mg EFX group (p<0.01) and 31% of the 28mg EFX group (p<0.01), compared to 3% for placebo.
• The placebo-adjusted effect size for fibrosis improvement more than doubled for the 50mg EFX group between week 24 and week 96, increasing from 21% to 52%.
• Among patients who improved at week 24, 92% and 83% of the 50mg and 28mg EFX groups, respectively, remained responders at week 96, compared to 40% for placebo.
• In a subset of patients with advanced F3 fibrosis, 68% of the 50mg EFX group and 40% of the 28mg EFX group experienced at least a one-stage improvement in fibrosis without worsening of MASH, compared to 14% for placebo.
• EFX was generally well-tolerated, with the most frequent adverse events being mild gastrointestinal issues.
• The company is also progressing with the SYMMETRY study, with results expected in the first quarter of 2025.

Sentiment

Score: 9

Explanation: The document presents highly positive results from the HARMONY study, with statistically significant improvements in key endpoints and a strong safety profile. The magnitude of the treatment effect and the sustained response over time are very encouraging for the future of EFX.

Positives

• The 50mg EFX dose demonstrated a highly statistically significant improvement in fibrosis at week 96.
• The treatment effect of EFX was sustained and broadened over time, with a significant increase in the placebo-adjusted effect size.
• EFX showed a strong response in patients with advanced F3 fibrosis, a population at higher risk of progressing to cirrhosis.
• EFX was generally well-tolerated, with no deaths reported and manageable adverse events.
• The study showed improvements in multiple non-invasive markers of liver health and cardio-metabolic biomarkers.
• The results suggest that longer exposure to EFX has the potential to yield sustained fibrosis improvement.

Negatives

• The 28mg EFX dose did not achieve statistical significance for one-stage fibrosis improvement at week 96 (p=0.07).
• Some patients experienced gastrointestinal adverse events, such as diarrhea and nausea, although these were generally transient.
• Three patients treated with EFX were discontinued due to adverse events between week 24 and week 96.
• There were 15 serious adverse events reported, although they were generally balanced across dose groups.

Risks

• The study was not fully powered at week 96, which could affect the interpretation of the results.
• The placebo rate increased rather than decreased, which is unusual and could indicate variability in the patient population.
• The long-term effects of EFX are still being evaluated, and future studies are needed to confirm these results.
• The company's ability to fund operations and execute its strategy is subject to risks and uncertainties.
• Regulatory developments in the United States and foreign countries could impact the approval process for EFX.

Future Outlook

Akero is continuing its evaluation of EFX in patients with pre-cirrhotic MASH and cirrhosis due to MASH in its ongoing Phase 3 SYNCHRONY program, with two out of three studies actively enrolling. The company also anticipates reporting results from the SYMMETRY study in the first quarter of 2025.

Management Comments

• Stephen Harrison, M.D., stated that the results for 1-and 2-stage fibrosis improvement observed for 50mg EFX at week 96 are the largest response rates reported publicly to date for these endpoints in any MASH population.
• Andrew Cheng, M.D., Ph.D., stated that the statistically significant 2-stage improvement in fibrosis observed in approximately one in three EFX-treated patients sets EFX apart.
• Andrew Cheng, M.D., Ph.D., also noted that the results show that longer exposure to EFX has the potential to yield sustained fibrosis improvement.

Industry Context

These results are significant in the context of the MASH treatment landscape, where there are currently no approved therapies. The magnitude of the response observed with EFX, particularly the two-stage fibrosis improvement, positions it as a potential leader in the field. The results are being compared to other MASH treatments in development, such as Resmetirom, Semaglutide, Pegozafermin, Denifanstat, Tirzepatide and Survodutide.

Comparison to Industry Standards

• The 75% one-stage fibrosis improvement rate for the 50mg EFX group at week 96 is higher than the results reported for other MASH treatments in development, such as Resmetirom (26%), Semaglutide (24%), Pegozafermin (43%), Denifanstat (33%), Tirzepatide (22%) and Survodutide (18%).
• The 36% two-stage fibrosis improvement rate for the 50mg EFX group at week 96 is also higher than the results reported for Resmetirom (26%) and Semaglutide (10%).
• The study results suggest that EFX may offer a more robust and sustained treatment effect compared to other therapies in development.
• The results are being compared to other MASH treatments in development, such as Resmetirom, Semaglutide, Pegozafermin, Denifanstat, Tirzepatide and Survodutide, however, cross-trial comparisons are limited due to differences in trial design and patient populations.

Stakeholder Impact

• Shareholders are likely to react positively to the strong clinical results, potentially leading to an increase in the company's stock price.
• Patients with MASH may benefit from the development of EFX as a potential treatment option.
• Employees of Akero Therapeutics may be motivated by the positive results and the potential for EFX to become a successful therapy.
• The results may attract interest from potential partners or investors.

Next Steps

• Akero will continue to evaluate EFX in the ongoing Phase 3 SYNCHRONY program.
• The company expects to report results from the SYMMETRY study in the first quarter of 2025.
• The company will continue to monitor the safety and tolerability of EFX in ongoing clinical trials.

Key Dates

Keywords

efruxifermin, MASH, NASH, fibrosis, liver disease, clinical trial, HARMONY study, Akero Therapeutics, histological improvement, metabolic disease