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Abstracts

A Novel Antisense Oligonucleotide for the Treatment of Early Onset SCN2A Developmental and Epileptic Encephalopathy: A First-in-Patient Report in a Preterm Infant with Refractory Status Epilepticus

Abstract number : 3.459
Submission category : 4. Clinical Epilepsy / 4C. Clinical Treatments
Year : 2023
Submission ID : 1444
Source : www.aesnet.org
Presentation date : 12/4/2023 12:00:00 AM
Published date :

Authors :
Presenting Author: Matias Wagner, MD – Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics and Comprehensive Epilepsy Center, Ludwig Maxmilians University Hospital, Munich, Germany

Claudio Nussbaum, PD Dr.med – Division of Neonatology, Department of Pediatrics, Ludwig Maximilians University Hospital, Munich, Germany; Geza Berecki, PhD – Ion Channels and Human Diseases Group, The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia; Andreas Flemmer, Prof Dr. med – Division of Neonatology, Department of Pediatrics, Ludwig Maximilians University Hospital, Munich, Germany; Silvana Frizzo, MD – Praxis Precision Medicines; Farina Heer, Student – Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics and Comprehensive Epilepsy Center, Ludwig Maxmilians University Hospital, Munich, Germany; Florian Heinen, Prof Dr. med – Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics and Comprehensive Epilepsy Center, Ludwig Maxmilians University Hospital, Munich, Germany; Robert Horton, MSc – Praxis Precision Medicines; Henry Jacotin, MD – Praxis Precision Medicines; William Motel, PhD – Praxis Precision Medicines; Brian Spar, BS – Praxis Precision Medicines; Martin Stuadt, Apl. Prof. Dr. med. – Center of Pediatric Palliative Care, Ludwig Maximilians University Hospital, Munich, Germany; Moritz Tacke, MD – Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics and Comprehensive Epilepsy Center, Ludwig Maxmilians University Hospital, Munich, Germany; Markus Wolff, MD – Swiss Epilepsy Center, Klinik Lengg AG, Zürich, Switzerland; Walid Fazeli, MD – Department of Pediatric Neurology, Children’s Hospital, University Hospital Bonn, Bonn, Germany; Steven Petrou, PhD – Praxis Precision Medicines; Marcio Souza, PharmD, MBA – Praxis Precision Medicines; Ingo Borggraefe, MD, PhD – Division of Pediatric Neurology, Developmental Medicine and Social Pediatrics, Department of Pediatrics and Comprehensive Epilepsy Center, Ludwig Maxmilians University Hospital, Munich, Germany

Rationale: Early onset SCN2A developmental and epileptic encephalopathy (SCN2A-DEE) is a rare, severe disorder caused by gain-of-function (GoF) mutations in the SCN2A gene encoding the voltage-gated sodium channel NaV1.2. Patients are at high risk of premature death and present with frequent, epileptic seizures, typically beginning within days of birth and often difficult to control with standard-of-care anti-seizure medications (ASMs). Comorbidities include profound global developmental impairment as well as movement disorders, gastrointestinal symptoms, severe irritability, variable sleep problems and frequent hospitalization, leading to a severely diminished quality of life.


Despite these pressing needs, drug development efforts for early onset SCN2A-DEE have been scarce. Preclinical findings suggest that gapmer antisense oligonucleotides (ASOs) that down regulate SCN2A expression may have potential to alter the disease course in patients. We describe the first clinical experience of intrathecally administered PRAX-222, a novel gapmer ASO, in an infant with early onset SCN2A-DEE and refractory status epilepticus (SE).

Methods: A preterm infant (29+4 weeks gestation; birthweight 1400g) diagnosed prenatally with the pathogenic SCN2A variant c.3986C >A p. (Ala1329Asp) presented with ongoing seizures since birth, confirmed by continuous EEG resembling SE. Anti-seizure treatment revealed only partial effect of high-dose sodium channel blockers (SCBs) and insufficient control of SE. Eligibility for PRAX-222 treatment was evaluated using in silico protein structural modeling and in vitro electrophysiology studies aiming to ascertain GoF status and inform dosing strategies.

Results: Voltage clamp experiments confirmed structural modeling predictions that the p.Ala1329Asp variant interferes with binding of the inactivation motif leading to impaired inactivation and increased persistent current. Dynamic action potential clamp experiments, performed to assess impact of the variant on intrinsic neuronal excitability, showed a large increase in action potential firing. Following confirmation of GoF status, treatment with PRAX-222 commenced, with the patient receiving a total of 6 doses over 17 weeks (1mg, 0.5mg, 1mg over the first five weeks; followed by 4mg, 8mg, 8mg at ~4-week intervals).

 
PRAX-222 treatment in combination with best standard-of-care ASMs (mainly SCBs) was well-tolerated with no severe or serious adverse events. Eight days after first administration, SE was interrupted intermittently and ultimately ceased following continued dosing. A >50% reduction in seizure frequency was observed during follow-up, with seizure symptoms being markedly attenuated.

Conclusions: First-in-patient findings highlight potential for PRAX-222 to be the first disease-modifying treatment for early onset GoF SCN2A-DEE, with early clinical experience in combination with SCBs indicating safety and a temporal association with seizure reduction including cessation of previous SE. Ongoing follow up will determine long-term effects of repeated PRAX-222 administration on seizure frequency and intensity, and associated comorbidities.

Funding: PRAX-222 made available under emergency use provision from Praxis Precision Medicines.

Clinical Epilepsy