Given the limited effectiveness of current therapies to treat Dravet syndrome and the significant burden of symptoms, much hope lies in the potential of targeted genetic therapies to treat Dravet syndrome at the root cause and modify the course of the disease. In the majority of cases, patients with Dravet syndrome carry mutations in the SCN1A gene that cause the loss of function of one copy of the gene. This type of genetic disorder is called a haploinsufficiency. Despite some significant barriers, progress in basic science has provided the knowledge and tools to enable the development of novel genetic approaches to overcome this haploinsufficiency in Dravet syndrome. Work in preclinical animal and cell models provides a proof-of-concept that these genetic approaches may indeed be able to modify the course of Dravet syndrome. In the fall of 2020, the first patient with Dravet syndrome received an experimental genetic-based therapy call STK-001, an antisense oligonucleotide that works by increasing the productivity of the healthy copy of the gene by targeting RNA; data outputs from this ongoing clinical study are promising regarding the relative safety and first insights into efficacy to reduce seizures and impact cognitive domains. Earlier this month, announcements indicated that another genetic-based therapy candidate for Dravet syndrome, ETX101, may be entering human trials in the near future.
On February 6th, Encoded Therapeutics announced via a press release that they have received Investigational New Drug (IND) clearance from the US FDA as well as approval under the Clinical Trial Approval (CTA) from the Australian Therapeutic Goods Administration. This means they are now able to move towards initiating clinical trials for ETX101 in the United States and Australia. ETX101 has been developed as a one-time gene regulation therapy for SCN1A+ Dravet syndrome. ETX101 consists of a specialized genetic material called an engineered transcription factor that increases the expression of the SCN1A gene, leading to normalized levels of the encoded sodium channel. In ETX101, the engineered transcription factor is under the control of the cell-selective regulatory element, which targets the therapy to the cells in the brain that appear to be most impacted in Dravet syndrome. The genetic material is packaged and delivered using an adeno-associated viral capsid called AAV9 that has previously been used in other clinical applications. In preclinical mouse models of Dravet syndrome, ETX101 reduced seizures and increased survival. Subsequent studies in non-human primates have provided additional insight into the safety profile and brain distribution following dosing with ETX101. Now, following these clearances, ETX101 will be evaluated for the first time in patients with Dravet syndrome.
In the first half of 2024, Encoded aims to begin the ENDEAVOR clinical trial in the United States and the WAYFINDER clinical trial in Australia.
- ENDEAVOR is a two-part, Phase 1/2 clinical trial in US patients aged 6 months to <3 years with SCN1A+ Dravet syndrome. Part 1 of ENDEAVOR will evaluate up to two different dose levels of ETX101 in 4 participants. The primary aims will be to evaluate the safety and tolerability of ETX101 as well as preliminary efficacy, and additionally to contribute to therapeutic dose selection. Part 2 of ENDEAVOR is planned to proceed following evidence of safety and efficacy in Part 1.
- WAYFINDER is a Phase 1/2 clinical trial in Australian patients aged 3 to <7 years with SCN1A+ Dravet syndrome. WAYFINDER will evaluate up to two different dose levels of ETX101 in 4 participants. The primary aims will be to evaluate the safety and tolerability of ETX101 as well as preliminary efficacy, and additionally to contribute to therapeutic dose selection.
ENDEAVOR and WAYFINDER are part of the global clinical development program, POLARIS. The development of POLARIS has been informed by initiatives Encoded Therapeutics has deployed including Dravet ENGAGE, a patient-focused drug development initiative; ELUCIDATE, a biomarker discovery effort; and ENVISION, a prospective natural history study.
This announcement marks a major step forward to a future with targeted, disease-modifying therapies for Dravet syndrome, and we are grateful to the dedication of companies like Encoded Therapeutics to developing such therapies for those living with rare genetic diseases. These clinical advancements also sit on the shoulders of the broad community of scientists and researchers that have discovered the genetic cause, developed models, and uncovered so much knowledge about the mechanisms behind Dravet syndrome. It also rests on the tireless efforts of the patient-family community, from raising awareness and funds for research into Dravet syndrome to participating in countless research efforts. It is still important to temper excitement, as this is still an experimental therapy and only the clinical trials can provide the data to understand how safe and effective this will be in humans. However, I do think we can continue to be hopeful that this is one more step in the right direction towards a future with therapies that can address the symptoms of Dravet syndrome more fully.
And in the meantime, we can continue to focus on building our community and advancing research, which history now exemplifies can lead to incredible progress for Dravet syndrome.
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Want to learn more?
Clinicaltrials.gov listings for ENDEAVOR and WAYFINDER, including additional study details and study site locations:
- US: https://clinicaltrials.gov/ct2/show/NCT05419492
- Australia: https://clinicaltrials.gov/ct2/show/NCT06112275
More about ETX101 from Encoded Therapeutics:
- https://encoded.com/programs/etx101-for-dravet-syndrome/
- Informational Video: https://youtu.be/QcyMq5_c9ME?si=f8rc_nhiaRpqUald
Study of ETX101 in mouse model of Dravet syndrome upregulates SCN1A, reduces seizures, and increases survival:
- Tanenhaus A, Stowe T, Young A, et al (2022) Cell-Selective Adeno-Associated Virus-Mediated SCN1A Gene Regulation Therapy Rescues Mortality and Seizure Phenotypes in a Dravet Syndrome Mouse Model and Is Well Tolerated in Nonhuman Primates. Hum Gene Ther 33:579–597. https://doi.org/10.1089/hum.2022.037
Dravet ENGAGE study of caregivers’ perspectives and needs
- Juandó-Prats C, James E, Bilder DA, et al (2021) DRAVET ENGAGE. Parent caregivers of children with Dravet syndrome: Perspectives, needs, and opportunities for clinical research. Epilepsy Behav 122:108198. https://doi.org/10.1016/j.yebeh.2021.108198
Overview of advances in the gene therapy space for Dravet syndrome
Clinical Trials and Pipeline of Therapies for Dravet syndrome:
