Durect Transforming AH Treatment with Larsucosterol’s Promise

In this interview, Jim Brown, CEO of Durect Corporation, shared insights into the treatment of Alcohol-Associated Hepatitis (AH) with Moe Alsumidaie. Brown discussed Durect’s innovative drug, larsucosterol, which has shown promising results in clinical trials. This conversation explores the mechanisms, clinical trial outcomes, and plans for larsucosterol, offering a glimpse into the potential transformation of AH treatment.

Moe: Alcohol-associated hepatitis (AH) is often misunderstood. Can you explain its symptoms and current treatment options?

Jim Brown: Absolutely. AH is an acute condition triggered by binge drinking, affecting even young individuals without cirrhosis. Symptoms include flu-like signs, jaundice, and high bilirubin levels. The mortality rate is about 30% within 90 days, and current treatments are limited to supportive care and sometimes steroids, which don’t significantly improve long-term survival. This stark contrast to chronic alcohol-induced cirrhosis highlights the urgent need for effective interventions in AH. The lack of awareness and effective treatment options makes it a critical area for medical advancement. We focus on addressing this gap with an innovative solution that has potential to impact patient outcomes.

Moe: How does larsucosterol work, and what benefits does it offer AH patients?

Jim Brown: Larsucosterol is an epigenetic modulator, meaning that it influences the expression of multiple genes without changing the DNA sequence. DNA hypermethylation, the addition of methyl groups to DNA, is an example of epigenetic dysregulation linked to cellular dysfunction and has been reported in AH. Larsucosterol specifically inhibits enzymes that add methyl groups to the DNA, called methyltransferases. Reducing DNA hypermethylation in AH patients may mitigate abnormal gene expression, ultimately helping stabilize multiple organ systems, including the liver, kidneys, and lungs. Remarkably, in our clinical studies a single or double dose of larsucosterol improved survival rates in patients with AH. This approach is akin to reprogramming the cellular environment to promote healing and resilience, a concept gaining traction in treating complex diseases. The ability to intervene at the epigenetic level offers a novel therapeutic pathway that could redefine how we approach acute liver conditions. By focusing on the root cause of the disease, we aim to provide a more effective and lasting solution for patients.

Moe: Can you share key findings from your Phase 2 study on larsucosterol?

Jim Brown: Our Phase 2b study, conducted during the pandemic, involved 307 patients and showed a 58-57% reduction in mortality at 90 days in the U.S. cohort and a 35-41% reduction in mortality when including all geographies. Despite challenges, such as varying healthcare systems and patient demographics, these results highlight larsucosterol’s potential to save lives in a condition with no effective treatments. The study’s success, particularly in the U.S., additionally underscored the importance of timely intervention and consistent healthcare practices. The data validate our approach and sets a new benchmark for what can be achieved in AH treatment, offering hope to thousands of patients who currently face limited options. This breakthrough is a testament to the potential of innovative therapies in transforming patient care.

Moe: What are the next steps for larsucosterol’s development and regulatory path?

Jim Brown: We have Breakthrough Therapy Designation from the FDA, facilitating a faster review process. Our Phase 3 trial will focus on the U.S., ensuring treatment within 10 days of hospitalization and site-specific randomization to minimize bias. If successful, this could lead to approval and a significant impact on AH treatment. The breakthrough designation is a testament to the FDA’s recognition of the unmet need and the potential of larsucosterol to address it. This pathway accelerates the development process and provides us with critical guidance and support, enhancing our ability to bring this life-saving treatment to market. We are committed to navigating this path efficiently to meet the urgent needs of AH patients.

Moe: What learnings from the Phase 2b trial will guide your Phase 3 study design?

Jim Brown: Key lessons include the importance of timely treatment, conducting trials in regions with uniform healthcare provision, and site-specific randomization, to ensure balanced patient demographics and healthcare practices. These strategies aim to enhance the reliability and applicability of our Phase 3 results. The pandemic taught us the value of adaptability and precision in trial design, and we are leveraging these insights to optimize our approach. By focusing on the U.S. initially, we can control for variables that might otherwise skew results, ensuring that our findings are robust and reflect the drug’s true potential.

Moe: How will you manufacture and distribute larsucosterol to meet demand?

Jim Brown: We are already at full commercial-scale production, with three years of stability data. This readiness, combined with the FDA’s support, positions us well to swiftly meet demand upon approval, addressing a significant unmet need in AH treatment. Our proactive approach to manufacturing ensures that we can deliver larsucosterol efficiently and effectively, minimizing delays and maximizing impact. This strategic foresight is crucial in a field where time is of the essence, and lives are at stake. We are committed to ensuring that our supply chain is robust and responsive to the needs of patients and healthcare providers.

Moe: Are there plans to explore larsucosterol’s efficacy in other conditions?

Jim Brown: Yes, we’ve explored its potential in various models, including acetaminophen toxicity, stroke, and sepsis, showing multi-organ protection. While AH is our current focus due to its high mortality and lack of treatments, larsucosterol’s broad applicability in acute conditions is promising for future research. The drug’s ability to modulate the epigenome opens many therapeutic possibilities, offering hope for conditions that have long eluded effective treatment. As we continue to explore these avenues, we remain committed to advancing the science and improving patient outcomes. We aim to leverage this innovative approach to benefit as many patients as possible.