FDA Clears IND for Gene Therapy Candidate ETX101 in Dravet Syndrome


Encoded Therapeutics plans to initiate clinical trials assessing its gene therapy candidate ETX101 for the treatment of SCN1A+ Dravet syndrome during the first half of 2024.

 Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF

Joseph Sullivan, MD

Credit: UCSF

According to a recent announcement, the FDA has cleared Encoded Therapeutics’ investigational new drug (IND) application for ETX101, an AAV9-mediated candidate gene regulation therapy, for the treatment of SCN1A+ Dravet syndrome (DS). The company plans to initiate the phase 1/2 clinical trial ENDEAVOR (NCT05419492), a 2-part dose escalation study in US, to assess the therapy in patients between the ages of 6 months to 3 years with SCN1A+ DS in the first half of 2024.1

In Part 1 of ENDEAVOR, investigators will evaluate up to 2 doses of ETX101 in 4 participants to assess the safety and tolerability of the agent, exploring preliminary efficacy and therapeutic dose selection. The first part is expected to start in the first half of 2024 and Part 2 is planned following demonstration of safety and efficacy in Part 1, a design the company aligned with the agency on for the trial. The gene therapy is designed to selectively upregulate expression of the SCN1A gene in GABAergic inhibitory interneurons and potentially address the underlying cause of the condition.

Top Clinical Takeaways

  • Encoded Therapeutics' ETX101, a gene therapy for SCN1A+ Dravet syndrome, has received FDA clearance for phase 1/2 clinical trials in the US and Australia.
  • The clinical trials, ENDEAVOR and WAYFINDER, are part of the global program POLARIS, aiming to assess the safety, efficacy, and potential long-term improvements of ETX101.
  • The gene therapy, designed to upregulate SCN1A gene expression, holds promise as a potentially one-time, disease-modifying treatment for Dravet syndrome.

“I was very excited to hear this program will be able to get started in the US as it is a novel approach and includes the youngest patients with DS. There is still a huge unmet need for all aspects of the syndrome. While the newly approved antiseizure medications have really helped many patients reduce their seizure frequency the majority still continue to have seizures and we are really striving for as close to seizure freedom as possible,” principal investigator Joseph Sullivan, MD, director of the Pediatric Epilepsy Center at UCSF, told NeurologyLive®.

READ MORE: Updated Guidelines Published to Improve Care in Specialized Epilepsy Centers

In addition to the accepted IND, the Australia Therapeutic Goods Administration approved the gene therapy to be initiated in clinical trials under the Clinical Trial Approval (CTA) scheme. In Australia, the company plans to investigate ETX101 in the phase 1/2 trial WAYFINDER (NCT06112275), in patients between the ages of 3 and 7 years, concurrently with ENDEAVOR. WAYFINDER is also dose escalation study and up to 2 doses of ETX101 will be assessed in the same number of participants as ENDEAVOR.

“Beyond seizures however, what really needs to be addressed are the various comorbidities that are seen to varying extents in every patient. It is the opinion of our community that the only way to address these are to address the underlying cause and restore normal SCN1A channel expression,” Sullivan told. “Assuming the interventions do in a human what they have been shown to do in animal models, gene therapies are well positioned to address the underlying cause and by doing so is going to be critical to altering the natural history of DS.”

ENDEAVOR and WAYFINDER are part of the company’s global clinical development program POLARIS, which aims to investigate the safety and efficacy of ascending doses of ETX101 in pediatric patients. The company noted that POLARIS will assess the initial effects of ETX101 on seizure burden in participants as well as potential long-term improvements in neurodevelopment. POLARIS is based on patient-focused treatment development initiatives like Dravet ENGAGE, the multipronged biomarker discovery project ELUCIDATE, and the recently completed natural history study ENVISION. Encoded noted these initiatives instructed the design for POLARIS and highlighted the need for disease-modifying therapies in this patient population.

"We are thrilled to have reached this significant milestone and for the opportunity to bring a one-time, potentially disease-modifying gene therapy to pediatric patients living with DS. Gene therapy development is uniquely complex, and I am proud of our dedicated team for their commitment and exceptional work in bringing ETX101 to this pivotal stage," Kartik Ramamoorthi, PhD, cofounder and chief executive officer at Encoded Therapeutics, told NeurologyLive. "Despite approval of multiple new antiseizure medications, findings from our natural history study (ENVISION) of pediatric patients with SCN1A+ DS, indicate that patients continue to endure an unacceptably high seizure burden and experience early and global neurodevelopmental stagnation."

In July 2020, the FDA granted ETX101 Orphan Drug Designation and Rare Pediatric Disease Designation for the treatment of SCN1A+ DS as well as received Orphan Designation by the EMA.2 The company noted that it will provide additional updates on its research pipeline in addition to news on the clinical progress with ETX101 for DS later in 2024. Ramamoorthi added by saying, "By targeting the root cause of the disease, we believe ETX101 has the potential to address the broader spectrum of both seizure-related and nonseizures symptoms. This could lead to significant improvements in the lives of pediatric patients with DS and their families."

"We believe there is significant potential and need for innovative platforms like Encoded’s to deliver transformative gene therapies for genetically-driven seizure disorders, such as DS, as well as for more prevalent epilepsy conditions," Ramamoorthi told. "More than 30% of patients living with epilepsy are unable to achieve adequate seizure control with currently available treatments, with resulting impacts on psychosocial functioning, cognitive abilities, quality of life and mortality. Genetic medicine approaches targeting specific genes or dysregulated pathways hold tremendous potential for a transformative impact on the lives of affected patients."

1. Encoded Therapeutics Announces US IND Clearance and Australian CTA Approval for Dravet Syndrome Gene Therapy Candidate ETX101. News Release. Encoded Therapeutics. Published February 6, 2024. Accessed February 6, 2024. https://encoded.com/press-releases/encoded-therapeutics-announces-us-ind-clearance-and-australian-cta-approval-for-dravet-syndrome-gene-therapy-candidate-etx101/
2. Encoded Therapeutics Announces $135 Million Series D Financing to Support First Clinical Trials in SCN1A+ Dravet Syndrome and Advance Preclinical Pipeline of Gene Therapies for Debilitating Neurological Disorders. News Release. July 22, 2020. Accessed February 6, 2024. https://encoded.com/press-releases/encoded-therapeutics-announces-135-million-series-d-financing-to-support-first-clinical-trials-in-scn1a-dravet-syndrome-and-advance-preclinical-pipeline-of-gene-therapies-for-debilitating-neurologic/
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