8-K: Marinus Pharmaceuticals Announces Mixed Results from Phase 3 RAISE Trial, Prioritizes ZTALMY

Marinus Pharmaceuticals' Phase 3 RAISE trial for IV ganaxolone in refractory status epilepticus met one co-primary endpoint but failed on the other, leading the company to prioritize its ZTALMY franchise.

Summary

• Marinus Pharmaceuticals announced topline results from its Phase 3 RAISE trial evaluating IV ganaxolone for refractory status epilepticus (RSE).
• The trial met its first co-primary endpoint, showing a statistically significant proportion of patients achieving status epilepticus cessation within 30 minutes of initiating IV ganaxolone compared to placebo, with 80% vs 13% respectively.
• However, the trial failed to meet the second co-primary endpoint, which was the proportion of patients not progressing to IV anesthesia for 36 hours, with 63% in the ganaxolone arm compared to 51% in the placebo arm.
• The company noted an imbalance in baseline characteristics between the treatment arms, with the ganaxolone arm having a higher proportion of patients with more severe conditions.
• Despite the mixed results, preliminary EEG analysis showed that patients receiving IV ganaxolone had a median reduction in seizure burden of 88% compared to 38% for placebo through 36 hours.
• Marinus will continue to prioritize the ZTALMY franchise and expects topline data from the Phase 3 TrustTSC trial in the first half of Q4 2024.
• The company projects its cash runway extends into Q2 2025 due to recent cost reduction plans and financing activities.

Sentiment

Score: 5

Explanation: The sentiment is neutral to slightly negative. While the company achieved one co-primary endpoint and has positive financial metrics, the failure to meet the other co-primary endpoint in the RAISE trial and the imbalance in baseline characteristics are concerning. The focus on ZTALMY is a positive, but the future of IV ganaxolone in RSE is uncertain.

Positives

• IV ganaxolone demonstrated a statistically significant rapid cessation of status epilepticus within 30 minutes.
• EEG analysis showed a substantial reduction in seizure burden with IV ganaxolone.
• The company achieved profitability on the ZTALMY commercial investment in Q1 2024, ahead of schedule.
• Marinus has a strong cash position with a runway into Q2 2025.
• The company has completed enrollment for the Phase 3 TrustTSC trial.
• ZTALMY U.S. net product revenue is expected to be $33M $35M for 2024.

Negatives

• The RAISE trial failed to meet its second co-primary endpoint regarding progression to IV anesthesia.
• There was an imbalance in baseline characteristics between the treatment arms, with the ganaxolone arm having more severe cases.
• The company noted that patients were enrolled late in their course of status epilepticus, on average 38 hours after onset.
• The incidence of hypotension was more common in the IV ganaxolone arm.

Risks

• The failure to meet one of the co-primary endpoints in the RAISE trial may impact the regulatory path for IV ganaxolone in RSE.
• The imbalance in baseline characteristics between treatment arms could confound the assessment of IV ganaxolone's efficacy.
• There are risks associated with the commercialization of ZTALMY, including market acceptance and payer coverage.
• The company's future success depends on the results of ongoing and planned clinical trials.
• There are risks associated with the development of new formulations of ganaxolone or prodrugs.
• The company's cash runway is projected to last until Q2 2025, which may require additional financing in the future.

Future Outlook

Marinus plans to continue analyzing the full RAISE dataset and engage with the FDA to discuss a potential path forward for IV ganaxolone in RSE. The company will prioritize the ZTALMY franchise and expects topline data from the Phase 3 TrustTSC trial in the first half of Q4 2024. Marinus also intends to continue offering IV ganaxolone for patients with super refractory status epilepticus under emergency investigational new drug applications.

Management Comments

• Scott Braunstein, M.D., Chairman and Chief Executive Officer of Marinus, stated that the RAISE trial findings provide valuable insights that will guide ongoing research and development.
• Joseph Hulihan, M.D., Chief Medical Officer of Marinus, noted that patients were enrolled late in their course of status, with study drug initiated, on average, 38 hours following onset.
• Dr. Hulihan also expressed disappointment with the imbalance in baseline characteristics between the two treatment arms.
• Aatif M. Husain, M.D., Epileptologist, Neurologist, Professor at Duke University Medical Center, stated that objective measures such as EEG should be considered in future trials to assess control of status epilepticus.

Industry Context

The announcement comes in the context of ongoing efforts to develop effective treatments for refractory status epilepticus, a condition with high morbidity and mortality. The mixed results highlight the challenges in treating this complex disorder. The company's focus on the ZTALMY franchise reflects a strategic shift towards a more established product while continuing to explore the potential of ganaxolone in other indications.

Comparison to Industry Standards

• The RAISE trial is the first randomized Phase 3 trial in patients with refractory status epilepticus, making direct comparisons challenging.
• The 80% cessation rate within 30 minutes for IV ganaxolone is a positive result compared to typical outcomes with standard treatments, but the failure to meet the second co-primary endpoint is a setback.
• The company's focus on EEG monitoring aligns with a growing recognition of the importance of objective measures in assessing seizure control, as opposed to relying solely on proxy measures like the use of IV anesthesia.
• The company's ZTALMY product is approved for CDKL5 deficiency disorder, a rare genetic epilepsy, and the company is now expanding into Tuberous Sclerosis Complex, another rare genetic epilepsy, which is a similar strategy to other companies in the rare disease space such as Ultragenyx and BioMarin.
• The company's collaboration agreements with Orion Corporation and Tenacia Biotechnology for ganaxolone in Europe and China respectively are similar to other pharmaceutical companies that seek to expand their global reach through partnerships.

Stakeholder Impact

• Shareholders may react negatively to the mixed results of the RAISE trial.
• Patients with refractory status epilepticus may have limited access to IV ganaxolone in the near term.
• Patients with CDKL5 deficiency disorder and Tuberous Sclerosis Complex may benefit from the continued development and commercialization of ZTALMY.
• Employees may be affected by the company's cost reduction plans.

Next Steps

• Marinus will continue to analyze the full RAISE dataset.
• The company plans to engage with the U.S. Food and Drug Administration to discuss a potential path forward for IV ganaxolone in RSE.
• Marinus expects to present the RAISE data at an upcoming medical meeting.
• The company will continue to offer IV ganaxolone for patients with super refractory status epilepticus under emergency investigational new drug applications.
• Marinus will continue to prioritize the ZTALMY franchise and expansion opportunities in highly refractory, chronic epilepsies.
• The company expects topline data from the Phase 3 TrustTSC trial in the first half of Q4 2024.
• Marinus is targeting submission of a U.S. sNDA for TSC in April 2025 with priority review expected.

Key Dates

Keywords

Ganaxolone, Status Epilepticus, Refractory Status Epilepticus, ZTALMY, Epilepsy, Seizure Disorders, Clinical Trial, RAISE Trial, TrustTSC Trial, CDKL5 Deficiency Disorder, Tuberous Sclerosis Complex