Marinus Reports Several Positive Trial Updates on Antiseizure Medication Ganaxolone

Scott Braunstein, MD

In a recent company update, Marinus Pharmaceuticals reported that its phase 3 RAISE study (NCT04391569) assessing ganaxolone (Ztalmy) in patients with refractory status epilepticus (RSE) has exceeded its enrollment threshold required to conduct an interim analysis. Pending the study’s success, a potential new drug application (NDA) submission is planned for early 2025.¹

"We are thrilled to announce we have exceeded the enrollment threshold required to conduct an interim analysis in the Phase 3 RAISE trial in refractory status epilepticus, a life-threatening conditions,” Scott Braunstein, MD, chairman and chief executive officer at Marinus, said in a statement.¹ "With over 90 patients now randomized following several months of increasingly strong enrollment trends, we are on track to announce topline data in the second quarter, assuming efficacy criteria for the interim analysis are met."

The company noted several other positive updates, including an 85% completed enrollment for its phase 3 TrustTSC study (NCT05323734) assessing ganaxolone in tuberous sclerosis complex (TSC). Topline data for TrustTSC, a randomized, double-blind, placebo-controlled trial, is now anticipated in the first half of the fourth quarter of 2024. Marinus is also targeting a submission for a supplemental NDA to the FDA for TSC in the first half of 2025 with priority review expected.

"We also remain focused on advancing the Phase 3 TrustTSC trial in tuberous sclerosis complex and are confident that the new titration schedule is having the desired effect with the current discontinuation rate below 7%," Braunstein added.¹ "We continue to see steady adoption of Ztalmy in CDKL5 deficiency disorder and are eager to build on this momentum throughout 2024 as we grow the Ztalmy franchise and prepare for RSE and TSC data this year."

RAISE, a randomized, double-blind, placebo-controlled study, was expected to include approximately 125 patients with RSE who have failed benzodiazepines and 2 or more second-line intravenous (IV) antiepleptic drugs. The company now expects approximately 100 patients to be randomized by the conclusion of the interim analysis. Researchers will evaluate the efficacy and safety of IV ganaxolone by examining the proportion of patients with RSE who experience SE cessation within 30 minutes of treatment as well as the progression to IV anesthesia 36 hours following treatment initiation.

Ganaxolone is a synthetic neurosteroid that acts as a positive allosteric modulator of synaptic and extrasynaptic GABAA receptors. It exhibits antiseizure, anti-depressant, and anti-anxiety effects, and is noted to be generally safe and well-tolerated in adults. Ganaxolone is also currently being evaluated in the phase 3 RAISE II trial of patients with super RSE, with enrollment expected to be completed in the second quarter of 2024.

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In its release, Marinus noted that the company anticipates a proof-of-concept study with oral ganaxolone to treat a range of epileptic encephalopathies, including Lennox-Gastaut syndrome in late 2024. LGS, a severe form of epilepsy, has been typically treated with first-line valproate, followed by other anticonvulsant medications such as clobazam, felbamate, lamotrigine, rufinamide, topiramate, and cannabidiol (Epidiolex; GW Pharmaceuticals).

In March 2022, the FDA approved ganaxolone as the first treatment for seizures associated with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder, also known as CDD. The phase 3 MARIGOLD study (NCT03572933), a double-blind placebo-controlled trial that randomly assigned 101 patients, was the basis for the approval. In the trial, those who received ganaxolone experienced a median reduction of 30.7% in 28-day major motor seizure frequency, compared with a 6.9% reduction for those on placebo, meeting the trial’s primary end point with significance (P = .0036).²

Data from the open-label phase 2 CALM trial (NCT04285346) of ganaxolone, announced in August 2021, supported the therapy’s advancement to a phase 3 setting for TSC. In CALM, treatment with the therapy resulted in a median 16.6% reduction in 28-day seizure frequency relative to the 4-week baseline period, the primary end point. Ganaxolone was also well tolerated, with somnolence reported as the most common adverse event, which was consistent with previous trials.³

REFERENCES
1. Marinus Pharmaceuticals provides business update and reports fourth quarter and full year 2023 financial results. Marinus Pharmaceuticals. March 5, 2024. Accessed April 8, 2024. https://ir.marinuspharma.com/news/news-details/2024/Marinus-Pharmaceuticals-Provides-Business-Update-and-Reports-Fourth-Quarter-and-Full-Year-2023-Financial-Results/default.aspx
2. Marinus Pharmaceuticals Announces FDA Approval of ZTALMY® (ganaxolone) for CDKL5 Deficiency Disorder. News release. Marinus. March 18, 2022. Accessed April 8, 2024. https://www.businesswire.com/news/home/20220318005282/en/Marinus-Pharmaceuticals-Announces-FDA-Approval-of-ZTALMY%C2%AE-ganaxolone-for-CDKL5-Deficiency-Disorder
3. Marinus Pharmaceuticals report topline ganaxolone phase 2 open-label results in tuberous sclerosis complex and receives FDA orphan drug designation. News release. August 17, 2021. Accessed April 8, 2024 https://www.biospace.com/article/releases/marinus-pharmaceuticals-reports-topline-ganaxolone-phase-2-open-label-results-in-tuberous-sclerosis-complex-and-receives-fda-orphan-drug-designation/