Authors :
Presenting Author: Kenneth Johnson, PharmD – Immedica Pharma
Kristina Lindsten, PhD – Immedica Pharma AB
Christine Ochoa Escamilla, PhD – Immedica North America
Joseph Hulihan, MD – Paradigm Neuroscience
Rajsekar Rajaraman, MD – David Geffen School of Medicine; UCLA Mattel Children’s Hospital
Mary Koenig, MD – The University of Texas Health Science Center at Houston
Rationale:
Ganaxolone, a neuroactive steroid that modulates both synaptic and extrasynaptic GABAA receptors, is approved in the US, Europe, and China for the treatment of seizures associated with CDKL Deficiency Disorder (CDD) in patients ≥ 2 years old. Marigold (NCT03572933) was the phase 3 pivotal trial for ganaxolone in CDD. Ganaxolone should be titrated gradually over 4 weeks to achieve individual clinical response and tolerability. Somnolence-related adverse events, which include somnolence, sedation, fatigue, and lethargy, are commonly reported during the up-titration of ganaxolone. A phase 2, open-label, proof-of concept study (TrustTSC-2001: NCT04285346) was conducted in Tuberous Sclerosis Complex (TSC) patients to evaluate the safety and efficacy of oral ganaxolone on seizure frequency. In this separate trial, somnolence-related adverse events were also commonly reported, so the phase 3 study (TrustTSC-3001: NCT05323734) progressed with a modified dose titration schedule. Here we present a post hoc analysis evaluating the somnolence-related adverse event profiles reported under the traditional and modified ganaxolone titration schedules.
Methods:
The TrustTSC phase 3 trial was designed with a modified titration schedule that was altered by using a lower initial dose, graded progression, and extending the up-titration time from 4 to 5 weeks, to reach the same target dose as stated in the current prescribing information. A comparison of the current recommended titration schedule for ganaxolone as evaluated in patients with CDD to the modified titration schedule adopted in the phase 3 TrustTSC trial can be found in Table 1.
Results:
The modified titration schedule did not impact ganaxolone exposure levels, and enabled patients to successfully titrate up to goal doses achieving effective plasma concentrations. Additionally, the onset of somnolence-related adverse events reported in the TrustTSC trial with the revised ganaxolone titration schedule was minimized when compared to the Marigold trial. No patients on modified titration schedule discontinued due to somnolence-related adverse events (see Table 2).
Conclusions:
The modified titration schedule is characterized by a progressively increased dose of ganaxolone over 5 weeks to the same target dose as stated in the current prescribing information. Adjusting the ganaxolone titration schedule minimized the occurrence of somnolence-related adverse events experienced by patients in the TrustTSC study. This modified titration schedule has the potential to improve ganaxolone tolerability with respect to the somnolence-related adverse events that have been associated with premature therapy discontinuation and/or interruption while not impacting ganaxolone exposure levels that have been shown effective in CDD patients.
Funding: Marinus Pharmaceuticals, Inc. an indirect wholly owned subsidiary of Immedica Pharma, AB.