Ganaxolone Demonstrates Seizure Improvement in Tuberous Sclerosis Complex

Joseph Hulihan, MD

Newly announced data from the open-label phase 2 CALM trial (NCT04285346) of ganaxolone (Marinus Pharmaceuticals) showcased the agent’s ability to effectively treat seizures associated with tuberous sclerosis complex (TSC) and supported advancement of the drug to a phase 3 setting. The company also announced that the FDA has granted ganaxolone orphan drug designation for treatment in TSC.¹

Ganaxolone, a positive allosteric modulator of GABAA receptors, resulted in a median 16.6% reduction in 28-day seizure frequency relative to the 4-week baseline period, the primary end point. The investigational drug also was generally well-tolerated among patients, with somnolence reported as the most common adverse event (AE), consistent with previous trials. One treatment-related serious AE of seizure was reported as well.

Seizure reductions of at least 50% or more were recorded in 30.4% of patients. Additionally, among a subgroup of 19 individuals with focal seizures, data showed a median 25.2% reduction in seizure frequency.

"We believe the totality of the data is encouraging and supports advancing to phase 3. There was notable activity in focal seizures, a meaningful 50% response rate, and consistent results in this refractory patient population, including patients on both cannabidiol and everolimus," Joseph Hulihan, MD, chief medical officer, Marinus, said in a statement.¹ "We look forward to initiating our phase 3 trial and adding to the body of evidence that supports ganaxolone’s potential as an innovative treatment option for rare epilepsies."

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Marinus also announced TrustTSC, a global phase 3 randomized, double-blind, placebo-controlled trial, that will evaluate adjunctive ganaxolone in approximately 160 patients with TSC and is expected to begin enrollment during Q4 2021. Investigators will use percent change in 28-day TSC-associated seizure frequency as the primary end point.

Patients included in the open-label phase 2 study were on a stable regimen of antiseizure medications, either everolimus (Afinitor; Novartis) or cannabidiol (CBD; Epidiolex; GW Pharmaceuticals) for at least 1 month period to the screening visit. Achievement of at least 50% reduction in TSC-associated seizures was found in 36.4% of patients on concomitant everolimus and 25% in patients on concomitant CBD.

CALM, a 2-part proof-of-concept trial, included 23 patients with TSC aged 2 to 32 years old with a diagnosis of TSC and/or a mutation in either the TSC1 or TSC2 gene. Part A consisted of a 4-week baseline period followed by a 12-week treatment period where patients were treated with up to 600 mg of ganaxolone oral liquid suspension 3 times a day.

Those in Part A who responded well to ganaxolone will be given an option to stay on the therapy through the Part B. There, patients will undergo a 24-week open-label extension period, followed by a 2-week taper period and a 2-week safety follow-up visit. The differences between the 2 parts include length of treatment, less frequent assessments, and the ability to alter drug doses based on investigator evaluation of the patient’s clinical course during Part B.

Ganaxolone has been studied in more than 1800 pediatric and adult subjects across various indications at therapeutically relevant dose levels and treatment regimens for up to more than 2 years. Most notably, in September 2020, Marinus announced positive topline results of its phase 3 MARIGOLD clinical trial (NCT03572933) of ganaxolone in treating children and young adults with CDKL5 deficiency disorder. The investigational agent had significant median reductions of 32.2% in 28-day major motor seizure frequency compared to 4.0% reduction for those in the placebo group (P = .002), warranting a potential new drug application, which the company submitted on August 3, 2021.^2,3

REFERENCES

1. 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 August 18, 2021. 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/

2. Ganaxolone Achieves Primary Endpoint in Phase 3 Trial for CDKL5 Deficiency Disorder (CDD), a Rare Form of Genetic Epilepsy. News release. Radnor, PA. Marinus Pharmaceuticals. September 14, 2020. Accessed August 18, 2021. biospace.com/article/releases/ganaxolone-achieves-primary-endpoint-in-phase-3-trial-for-cdkl5-deficiency-disorder-cdd-a-rare-form-of-genetic-epilepsy

3. Marinus Pharmaceuticals Submits New Drug Application (NDA) to FDA for Ganaxolone for the Treatment of Seizures Associated with CDKL5 Deficiency Disorder and Provides Pipeline Update. News release. Radnor, PA. Marinus Pharmaceuticals.August 3, 2021. Accessed August 18, 2021. businesswire.com/news/home/20210803005573/en/Marinus-Pharmaceuticals-Submits-New-Drug-Application-NDA-to-FDA-for-Ganaxolone-for-the-Treatment-of-Seizures-Associated-with-CDKL5-Deficiency-Disorder-and-Provides-Pipeline-Update