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Ganaxolone in seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: a profile of its use in the USA

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Abstract

Ganaxolone (ZTALMY®), a synthetic neuroactive steroid that acts as a positive allosteric modulator of the synaptic and extrasynaptic gamma-aminobutyric acid (GABA)A receptor, is an effective and well tolerated, orally-administered adjunct to existing antiseizure treatments in patients 2 years of age or older with cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD)-associated seizures. CDD (a rare X-linked genetic disorder) is a severe developmental epileptic encephalopathy with onset in early infancy. In the randomized, double-blind, phase 3 Marigold trial, adjunctive ganaxolone significantly reduced the 28-day major motor seizure frequency from baseline compared with placebo in patients with CDD-associated refractory epilepsy. Preliminary results from the Marigold open-label extension suggest that the clinical benefits of ganaxolone in patients with CDD are maintained longer term. Ganaxolone is generally well tolerated; somnolence is the most frequent adverse reaction.

Plain Language Summary

Cyclin-dependent kinase-like 5 (CDKL5) deficiency disorder (CDD) is a rare, X-linked genetic disorder characterised by clinical features that include developmental delay and severe treatment-resistant epilepsy that begins soon after birth. Treatment of CDD is symptom based; antiseizure medications suitable for the seizure types seen in CDD are widely used, but no one agent has been associated with improved seizure control and treatment becomes less effective over time. Ganaxolone (ZTALMY®), an analog of the naturally occurring neuroactive steroid allopregnanolone, has recently been developed and is the first approved treatment for seizures associated with CDD. In the phase 3 placebo-controlled Marigold trial in patients aged 2–19 years, ganaxolone was more effective than placebo (as an addition to existing antiseizure treatment) in reducing the frequency of seizures in patients with CDD. The effectiveness of ganaxolone seems to be maintained during longer term treatment. Ganaxolone was generally well tolerated in patients with CDD; the most common adverse reaction was somnolence. Oral ganaxolone is an effective and well-tolerated adjunct to existing treatment options for patients with CDD-associated seizures.

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Acknowledgements

The manuscript was reviewed by: Y. Prashar, Department of Pharmacology, Rayat Institute of Pharmacy, Punjab, India; A. Strzelczyk, Epilepsy Center Frankfurt Rhine-Main, Department of Neurology, University Hospital Frankfurt, Frankfurt am Main, Germany. During the peer review process, Marinus Pharmaceuticals, Inc., the marketing authorization holder of ganaxolone, was also offered an opportunity to provide a scientific accuracy review of their data. Changes resulting from comments received were made on the basis of scientific and editorial merit.

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    Susan J. Keam & Zaina T. Al-Salama

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  1. Susan J. Keam
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Correspondence to Zaina T. Al-Salama.

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S.J. Keam is a contracted employee of Adis International Ltd/Springer Nature and declares no relevant conflicts of interest. Z.T. Al-Salama, a salaried employee of Adis International Ltd/Springer Nature and an editor of Drugs & Therapy Perspectives, was not involved in any publishing decisions for the manuscript and declares no relevant conflicts of interest. All authors contributed to the review and are responsible for the article content.

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Keam, S.J., Al-Salama, Z.T. Ganaxolone in seizures associated with cyclin-dependent kinase-like 5 deficiency disorder: a profile of its use in the USA. Drugs Ther Perspect 39, 81–88 (2023). https://doi.org/10.1007/s40267-022-00976-w

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