Encoded Therapeutics’ Dravet Syndrome Gene Therapy ETX101 Cleared for Separate Clinical Trials in the US and Australia

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ETX101 consists of a transgene encoding a GABAergic regulatory element and an engineered transcription factor that is delivered via a nonreplicating, recombinant AAV9 vector.

Salvador Rico, MD, PhD, the chief medical officer of Encoded Therapeutics

Salvador Rico, MD, PhD
Credit: Encoded Therapeutics

Encoded Therapeutics’s ETX101, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat SCN1A+ Dravet syndrome, has received clearance from the FDA and the Australia Therapeutic Goods Administration for 2 separate clinical trials in each agency’s respective jurisdiction.1

The planned phase 1/2 US clinical trial (ENDEAVOR; NCT05419492) will seek to recruit patients aged 6 months to 3 years. It will take the form of a 2-part dose escalation study. In the first part, up to 2 dose levels of ETX101 will be evaluated in 4 participants. The second part of ENDEAVOR will consist of a double-blind, randomized dose-selection study. Participants in this portion may potentially be assigned to 1 of 3 cohorts in a 1:1:1 ratio, with a cohort for each of the 2 dose levels previously evaluated and a cohort for a sham delayed-treatment control. Although, if a recommendation to proceed with only 1 dose level is made based on the results of part 1, then part 2 may include only 2 equal-sized cohorts: a cohort for the selected dose level and a cohort for the sham delayed-treatment control. Part 1 of ENDEAVOR is anticipated to launch within the first half of this year. It will have an estimated total enrollment of 22 participants.

On the other hand, the planned phase 1/2 Australia clinical trial (WAYFINDER; NCT06112275) will seek to recruit patients aged 3 to less than 7 years. It will consist of a dose escalation design but has an estimated enrollment of only 4 patients in total. Two participants each will be assigned to 2 cohorts, one of which will treat patients at a lower dose level and one of which will treat patients at a higher dose level. WAYFINDER is likewise expected to launch in the first half of 2024.

“ETX101 represents a groundbreaking advancement in the therapeutic landscape for Dravet syndrome, with potential not only for seizure management but also for addressing the broader spectrum of nonseizure manifestations,” Salvador Rico, MD, PhD, the chief medical officer of Encoded, said in a statement.1 “ENDEAVOR and WAYFINDER are the first step in bringing a potentially one-time, disease-modifying gene therapy to the Dravet community, and we are excited to be partnering with leading experts in the care of patients with Dravet syndrome to begin clinical trials in the US and Australia in the coming months.”

Key Takeaways

  • Encoded Therapeutics’s ETX101, an investigational adeno-associated virus (AAV) vector-based gene therapy intended to treat SCN1A+ Dravet syndrome, has received clearance from the FDA and the Australia Therapeutic Goods Administration for 2 separate clinical trials in each agency’s respective jurisdiction.
  • The planned phase 1/2 US clinical trial (ENDEAVOR; NCT05419492) will seek to recruit patients aged 6 months to 3 years. On the other hand, the planned phase 1/2 Australia clinical trial (WAYFINDER; NCT06112275) will seek to recruit patients aged 3 to less than 7 years.
  • ETX101 consists of a transgene encoding a GABAergic regulatory element and an engineered transcription factor that is delivered via a nonreplicating, recombinant AAV9 vector.

ETX101 consists of a transgene encoding a GABAergic regulatory element and an engineered transcription factor that is delivered via a nonreplicating, recombinant AAV9 vector. The engineered transcription factor is intended to upregulate expression of the disease-targeted SCN1A gene, with the expectation that it will lead to increased production of NaV1.1 protein sodium channels in clinically relevant neurons.

ENDEAVOR and WAYFINDER are part of the company’s larger POLARIS program for Dravet syndrome, which also includes a biomarker discovery program dubbed ELUCIDATE, now-completed natural history study referred to as ENVISION (NCT04537832), and a drug development initiative referred to as Dravet ENGAGE.

In 2021, CGTLivespoke with Rico about the company’s plans for the development of ETX101. He spoke about the company's work in tackling Dravet from different angles and their emphasis on patient-focused drug development.2

“We are creating precision gene therapies capable of targeting disease mechanisms by replacing a gene, silencing gene expression, or creating patterns of gene expression through gene regulation,” Rico told CGTLive. “Our platform has huge potential because pediatric neurological disorders represent a significant proportion of the Global Burden of Disease because they contribute to premature mortality and years lived with disability... In the case of Dravet, parents of children with Dravet are not only caregivers, but also advocates and decision makers for their kids. So, it is imperative that we ask them what is important to them, because we want to design a clinical trial or clinical development program with them, not for them.

REFERENCES
1. Encoded Therapeutics Announces US IND Clearance and Australian CTA Approval for Dravet Syndrome Gene Therapy Candidate ETX101. News release. Encoded Therapeutics Inc. 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. Hood V. Natural history study of children with Dravet Syndrome begins. March 19, 2021. Accessed August 10, 2021. https://www.dravetfoundation.org/natural-history-study-of-children-with-dravet-syndrome-begins/
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