New trials of Dravet syndrome gene therapy cleared in US and Australia

Phase 1/2 studies will test safety, efficacy of ETX101 in about 26 children

Andrea Lobo, PhD avatar

by Andrea Lobo, PhD |

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Encoded Therapeutics has received clearance from U.S. and Australian regulatory agencies to launch Phase 1/2 clinical trials testing ETX101, its Dravet syndrome gene therapy candidate, in infants and young children with the seizure disorder.

In the U.S., the company plans to begin ENDEAVOR (NCT05419492), which will be enrolling about 22 youngsters, in the first half of the year. Eligible patients will be ages 6 months to 35 months, or nearly 3 years old, and will be recruited at study sites in California and Texas.

Concurrently, the WAYFINDER trial (NCT06112275) will be conducted in Australia. This study will be enrolling an estimated 4 children, ages 3 to 7 years old, at a single site in Melbourne.

The launch of both trials follows the clearance of regulatory submissions in their respective countries, which sought to test the safety and early efficacy of the experimental gene therapy. An Investigational New Drug (IND) application was filed with the U.S. Food and Drug Administration (FDA), while a Clinical Trial Approval (CTA) scheme was submitted to the Australia Therapeutic Goods Administration.

“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 non-seizure manifestations,” Sal Rico, MD, PhD, Encoded’s chief medical officer, said in a company press release.

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Dravet syndrome gene therapy targets disease’s underlying cause

Dravet syndrome is a type of epilepsy characterized by episodes of frequent and prolonged seizures, usually starting in the first year of life. These seizures are difficult to control with any of the many existing medications for epilepsy. Due to the frequency of seizures, the disease also may lead to cognitive and developmental issues.

In most patients, the disease is caused by mutations in the SCN1A gene, resulting in the production of a nonfunctional sodium channel at the surface of nerve cells, particularly in GABA-producing neurons — a type of inhibitory nerve cell.

The deficient activity of sodium channels in these neurons is thought to reduce inhibitory signals in the brain, resulting in excessive neuronal activity that contributes to the development of seizures.

Although there are several therapies that can help control seizures, there are no disease-modifying treatments that have been approved as yet for the condition.

“Dravet syndrome is a devastating disorder that necessitates a paradigm shift from conventional symptomatic management towards precise and targeted interventions at the genetic level,” said Joseph Sullivan, MD, of the University of California, San Francisco (UCSF) and a principal investigator on the ENDEAVOR study. One of the U.S. study sites is at UCSF; the other site is at Cook Children’s Medical Center in Fort Worth.

ETX101 is a potential one-time, disease-modifying gene therapy targeting the underlying cause of Dravet syndrome. It is designed to restore the levels of the sodium channels in GABAergic neurons, by using a modified and harmless version of an adeno-associated virus (AAV) to deliver an engineered transcription factor to upregulate, or increase, the activity of the SCN1A gene. A transcription factor is a protein that regulates the activity of certain genes.

By targeting the underlying cause of Dravet syndrome, ETX101 has the potential to address the full scope of its symptoms.

I’m hopeful that gene therapy will not just alleviate symptoms but address the root cause of Dravet syndrome, marking a potentially transformative approach in our quest to address the ongoing medical burden of families living with Dravet syndrome.

Preclinical studies in a Dravet mouse model syndrome showed that a single administration of ETX101 increased sodium channel levels in GABAergic neurons, and reduced the frequency of seizures in mice. The treatment also lowered the risk of sudden unexpected death in epilepsy.

“I’m hopeful that gene therapy will not just alleviate symptoms but address the root cause of Dravet syndrome, marking a potentially transformative approach in our quest to address the ongoing medical burden of families living with Dravet syndrome,” said Sullivan, a professor of pediatric epilepsy, neurology and pediatrics at the UCSF Pediatric Epilepsy Center of Excellence.

The two new clinical trials are part of Encoded’s global clinical development program, POLARIS, which aims to assess the safety and efficacy of ETX101 in infants and young children.

The program also will evaluate the initial effects of the therapy on seizure burden, and potential long-term improvements in neurodevelopment, according to Encoded.

“ENDEAVOR and WAYFINDER are the first step in bringing a potentially one-time, disease-modifying gene therapy to the Dravet community,” Rico said.

Kartik Ramamoorthi, PhD, the company’s co-founder and CEO, said the launch of the two trials “strategically positions Encoded to achieve pivotal program milestones in 2024.”

“We look forward to sharing additional company updates in the coming months,” Ramamoorthi said.