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Clinical Trial
. 2020 Mar;7(3):343-352.
doi: 10.1002/acn3.50998. Epub 2020 Feb 27.

Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome

Stéphane Auvin #  1   2 , Blandine Dozières-Puyravel #  1   2 , Andreja Avbersek  3 , David Sciberras  3 , Jo Collier  3 , Karine Leclercq  3 , Pavel Mares  4 , Rafal M Kaminski  3 , Pierandrea Muglia  3
Affiliations
Clinical Trial

Radiprodil, a NR2B negative allosteric modulator, from bench to bedside in infantile spasm syndrome

Stéphane Auvin et al. Ann Clin Transl Neurol. 2020 Mar.

Abstract

Objective: Infantile spasm syndrome (ISS) is an epileptic encephalopathy without established treatment after the failure to standard of care based on steroids and vigabatrin. Converging lines of evidence indicating a role of NR2B subunits of the N-methyl-D-aspartate (NMDA) receptor on the onset of spams in ISS patients, prompted us to test radiprodil, a negative allosteric NR2B modulator in preclinical seizure models and in infants with ISS.

Methods: Radiprodil has been tested in three models, including pentylenetetrazole-induced seizures in rats across different postnatal (PN) ages. Three infants with ISS have been included in a phase 1b escalating repeated dose study.

Results: Radiprodil showed the largest protective seizure effects in juvenile rats (maximum at PN12, corresponding to late infancy in humans). Three infants resistant to a combination of vigabatrin and prednisolone received individually titrated doses of radiprodil for up to 34 days. Radiprodil was safe and well tolerated in all three infants, and showed the expected pharmacokinetic profile. One infant became spasm-free and two showed clinical improvement without reaching spasm-freedom. After radiprodil withdrawal, the one infant continued to be spasm-free, while the two others experienced seizure worsening requiring the use of the ketogenic diet and other antiepileptic drugs.

Interpretation: Radiprodil showed prominent anti-seizure effect in juvenile animals, consistent with the prevalent expression of NR2B subunit of the NMDA receptor at this age in both rodents and humans. The clinical testing, although preliminary, showed that radiprodil is associated with a good safety and pharmacokinetic profile, and with the potential to control epileptic spasms.

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Conflict of interest statement

Stéphane Auvin has served as consultant or received honoraria for lectures from Advicenne Pharma, Biocodex, Eisai, GW Pharma, Novartis, Nutricia, Shire, UCB Pharma, Ultragenyx, Zogenyx. He has been investigator for clinical trials for Advicenne Pharma, Eisai, UCB Pharma and Zogenyx.

Blandine Dozières‐Puyravel has received honoraria for lectures from Eisai and UCB Pharma. She has been co‐investigator for clinical trials for Advicenne Pharma, Eisai, UCB Pharma and Zogenyx.

UCB biopharma was the clinical study sponsor. DS, JC, AA, RK, and PM are or were at the time this study was conducted full time employees of UCB Pharma, a pharmaceutical company active in the drug discovery, and development of new anticonvulsants.

Figures

Figure 1
Figure 1
Anticonvulsant effects of radiprodil in rodent seizure models. (A) Dose‐dependent protection against generalized clonic convulsions in the mouse audiogenic seizure model. (B) Age‐dependent protection against generalized tonic seizures in the rat pentyleneterazol (PTZ) model at three different postnatal (PN) periods.
Figure 2
Figure 2
Design of the phase Ib study.
Figure 3
Figure 3
Predicted and observed Radiprodil plasma concentrations. The curves represent the modeling‐based projected plasma concentrations (green curve is mean ± 95% confidence limits) for the mid dose selected for the clinical trial after 28 days of dosing. The individual data points are the observed concentrations for this dose in the first infant in the trial.
Figure 4
Figure 4
Interictal EEG recordings of the patients at baseline and at the end of maintenance period.
See this image and copyright information in PMC

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