Phase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy

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dc.contributor.authorSullivan, J.
dc.contributor.authorGunning, B.
dc.contributor.authorZafar, M.
dc.contributor.authorGuerrini, R.
dc.contributor.authorGecz, J.
dc.contributor.authorKolc, K.L.
dc.contributor.authorZhao, Y.
dc.contributor.authorGasior, M.
dc.contributor.authorAimetti, A.A.
dc.contributor.authorSamanta, D.
dc.date.issued2023
dc.description.abstractIntroduction: Protocadherin-19 (PCDH19)-clustering epilepsy is a distinct developmental and epileptic encephalopathy characterized by early-onset seizures that are often treatment refractory. Caused by a mutation of the PCDH19 gene on the X chromosome, this rare epilepsy syndrome primarily affects females with seizure onset commonly in the first year of life. A global, randomized, double-blind, placebo-controlled, phase 2 trial was conducted to evaluate the efficacy, safety, and tolerability of ganaxolone compared with placebo as adjunctive therapy to a standard antiseizure medication regimen in patients with PCDH19-clustering epilepsy (VIOLET; NCT03865732). Methods: Females aged 1–17 years with a molecularly confirmed pathogenic or likely pathogenic PCDH19 variant who were experiencing ≥12 seizures during a 12-week screening period were stratified by baseline allopregnanolone sulfate (Allo-S) levels (low: ≤2.5 ng/mL; high: >2.5 ng/mL) at screening and randomized 1:1 within each strata to receive ganaxolone (maximum daily dose of 63 mg/kg/day if ≤28 kg or 1800 mg/day if >28 kg) or matching placebo in addition to their standard antiseizure treatment for the 17-week double-blind phase. The primary efficacy endpoint was the median percentage change in 28-day seizure frequency from baseline to the 17-week double-blind phase. Treatment-emergent adverse events (TEAEs) were tabulated by overall, system organ class, and preferred term. Results: Of the 29 patients screened, 21 (median age, 7.0 years; IQR, 5.0–10.0 years) were randomized to receive either ganaxolone (n = 10) or placebo (n = 11). After the 17-week double-blind phase, the median (IQR) percentage change in 28-day seizure frequency from baseline was − 61.5% (− 95.9% to − 33.4%) among patients in the ganaxolone group and − 24.0% (− 88.2% to − 4.9%) among patients in the placebo group (Wilcoxon ranksum test, p = 0.17). TEAEs were reported by 7 of 10 (70.0%) patients in the ganaxolone group and 11 of 11 (100%) patients in the placebo group. Somnolence was the most common TEAE (40.0% ganaxolone vs 27.3% placebo); serious TEAEs were more common in the placebo group (10.0% ganaxolone vs 45.5% placebo); and 1 (10.0%) patient in the ganaxolone group discontinued the study versus none in the placebo group. Conclusions: Ganaxolone was generally well tolerated and led to a greater reduction in the frequency of PCDH19- clustering seizures compared to placebo; however, the trend did not reach statistical significance. Novel trial designs are likely needed to evaluate the effectiveness of antiseizure treatments for PCDH19-clustering epilepsy.
dc.description.statementofresponsibilityJoseph Sullivan, Boudewijn Gunning, Muhammad Zafar, Renzo Guerrini, Jozef Gecz, Kristy L. Kolc, Yufan Zhao, Maciej Gasior, Alex A. Aimetti, Debopam Samanta
dc.identifier.citationEpilepsy Research, 2023; 191:107112-1-107112-7
dc.identifier.doi10.1016/j.eplepsyres.2023.107112
dc.identifier.issn0920-1211
dc.identifier.issn1872-6844
dc.identifier.orcidGecz, J. [0000-0002-7884-6861]
dc.identifier.orcidKolc, K.L. [0000-0001-6247-5544]
dc.identifier.urihttps://hdl.handle.net/2440/141894
dc.language.isoen
dc.publisherElsevier BV
dc.rights© 2023 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
dc.source.urihttps://doi.org/10.1016/j.eplepsyres.2023.107112
dc.subjectSeizures; Pediatric; Safety; Encephalopathy; Ganaxolone
dc.subject.meshHumans
dc.subject.meshEpilepsy, Generalized
dc.subject.meshSeizures
dc.subject.meshPregnanolone
dc.subject.meshAnticonvulsants
dc.subject.meshTreatment Outcome
dc.subject.meshCluster Analysis
dc.subject.meshChild
dc.subject.meshFemale
dc.subject.meshProtocadherins
dc.titlePhase 2, placebo-controlled clinical study of oral ganaxolone in PCDH19-clustering epilepsy
dc.typeJournal article
pubs.publication-statusPublished

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