8-K/A: DURECT Announces Phase 3 Trial Design for Larsucosterol in Alcohol-Associated Hepatitis

DURECT Corporation has finalized the design for its Phase 3 trial of larsucosterol for severe alcohol-associated hepatitis, following a Type B meeting with the FDA under Breakthrough Therapy designation.

Summary

• DURECT Corporation has announced the design of its Phase 3 registrational trial for larsucosterol, a potential treatment for severe alcohol-associated hepatitis (AH).
• The trial design was agreed upon with the FDA following a Type B meeting under the Breakthrough Therapy designation.
• The Phase 3 trial will enroll approximately 200 patients in the U.S. and will assess the 90-day survival rate as the primary endpoint.
• Topline results from the trial are expected within two years of trial initiation.
• The trial protocol is based on data from the Phase 2b AHFIRM trial, where larsucosterol showed a reduction in 90-day mortality in U.S. patients by 57% and 58% at 30mg and 90mg doses respectively, compared to placebo.
• The FDA has agreed that a single Phase 3 trial will be sufficient for a New Drug Application (NDA) submission, which can be done as a rolling submission due to the Breakthrough Therapy designation.
• The company is in discussions with clinical sites and hepatologists to streamline the trial initiation process.
• The trial will be a randomized, double-blind, placebo-controlled, multi-center study, with patients randomized 1:1 to either 30mg larsucosterol or placebo, in addition to standard of care.
• Patients will be followed for up to 180 days to collect additional safety and outcomes data.
• The company notes that the mortality rate for AH is approximately 30% at 90 days, highlighting the urgent need for effective therapies.

Sentiment

Score: 8

Explanation: The document is positive due to the progress in the Phase 3 trial design, the Breakthrough Therapy designation, and the promising results from the Phase 2b trial. However, the need for funding and the inherent risks of clinical trials temper the overall sentiment.

Positives

• The FDA has agreed to the Phase 3 trial design, indicating a positive regulatory pathway.
• Larsucosterol has shown promising results in the Phase 2b AHFIRM trial, with significant mortality reductions in U.S. patients.
• The Breakthrough Therapy designation allows for a rolling NDA submission, potentially accelerating the approval process.
• The company has a strong network of clinical sites and investigators ready to participate in the Phase 3 trial.
• The trial design incorporates feedback from the FDA, increasing the likelihood of a successful outcome.
• The 90-day survival endpoint is considered clinically meaningful and has a high probability of success based on previous data.

Negatives

• The company needs to secure sufficient funding to initiate the Phase 3 trial.
• The numerical improvement in the primary endpoint of mortality or liver transplant at 90 days in the AHFIRM trial did not achieve statistical significance for either dose of larsucosterol.
• The trial is limited to U.S. patients, which may not fully represent the global AH population.
• The trial is dependent on the availability of patients and the ability to enroll them in a timely manner.

Risks

• Future clinical trials may not confirm the results from the AHFIRM trial, including geographic or other segmentations.
• The company may not be able to raise sufficient capital to commence or complete the Phase 3 trial.
• The FDA may require additional clinical trials before approving larsucosterol.
• The Breakthrough Therapy designation may not expedite the approval process.
• The company faces risks related to cash resources, capital requirements, and continued listing on Nasdaq.
• There is a risk that larsucosterol may never be approved for the treatment of AH.

Future Outlook

The company plans to initiate and enroll patients in the Phase 3 trial in 2024 and expects to present topline data in the second half of 2026, subject to obtaining sufficient funds. They aim to confirm the efficacy and safety of larsucosterol to support an NDA filing with the FDA.

Management Comments

• James E. Brown, D.V.M., President and Chief Executive Officer of DURECT, stated that they are pleased with the collaborative interactions with the FDA and believe the 90-day survival endpoint provides the greatest probability of success.
• Norman Sussman, M.D., FAASLD, Chief Medical Officer of DURECT, noted the urgent need for an effective therapy to reduce the high mortality rate of AH and believes larsucosterol has the potential to save lives.

Industry Context

This announcement is significant in the context of the rising cases of alcohol-associated hepatitis and the lack of FDA-approved therapies. DURECT's progress with larsucosterol, particularly with the Breakthrough Therapy designation, positions them as a potential leader in this therapeutic area.

Comparison to Industry Standards

• The 90-day mortality rate for AH is approximately 30%, which highlights the severity of the condition and the need for effective treatments.
• Current treatments, such as corticosteroids, have limitations and have not shown to improve survival at 90 days or one year.
• Liver transplantation is an option, but it is limited by organ availability and high costs, exceeding $875,000 per transplant.
• The AHFIRM trial showed a 57% and 58% reduction in 90-day mortality in U.S. patients with 30mg and 90mg doses of larsucosterol, respectively, compared to placebo, which is a significant improvement compared to standard of care.
• Other companies are also developing treatments for AH, but DURECT's Breakthrough Therapy designation and Phase 3 trial design put them in a competitive position.

Stakeholder Impact

• Shareholders may see a positive impact due to the progress of larsucosterol and its potential for market approval.
• Patients with severe alcohol-associated hepatitis may benefit from a new treatment option.
• Clinical sites and investigators will be involved in the Phase 3 trial.
• Employees of DURECT will be involved in the execution of the trial and the regulatory process.

Next Steps

• Initiate and enroll patients in the Phase 3 trial of larsucosterol in AH.
• Report topline data within two years of trial initiation.
• Continue discussions with the FDA under the Breakthrough Therapy designation.
• File a New Drug Application (NDA) as a rolling submission.

Key Dates

Keywords

larsucosterol, alcohol-associated hepatitis, AH, Phase 3 trial, FDA, Breakthrough Therapy, mortality, epigenetic therapy, clinical trial, liver disease