Encoded cleared to test ETX101 for Dravet syndrome in UK

Developer was cleared in US, Australia to begin two similar studies

Margarida Maia, PhD avatar

by Margarida Maia, PhD |

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Encoded Therapeutics has been cleared by the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) to begin clinical testing of ETX101, an investigational one-time gene therapy for children with Dravet syndrome.

A Phase 1/2 clinical study dubbed EXPEDITION will test how safe ETX101 is and how well it works in four children, ages 6 months to 4 years, with Dravet syndrome. The trial is expected to begin this year.

The decision comes on the heels of U.S. and Australian regulators giving the green light to begin ENDEAVOR (NCT05419492) and WAYFINDER (NCT06112275), similar studies that will run parallel as part of a global program called POLARIS.

The clearance by the U.K. regulator “marks the third regulatory approval for ETX101 as we advance our global clinical development program, POLARIS,” Sal Rico, MD, PhD, chief medical officer of Encoded, said in a company press release. “We believe ETX101 has the potential to deliver transformative benefit in multiple disease domains and have designed our clinical program to efficiently assess its impact on affected infants and young children.”

Most people with Dravet carry mutations in the SCN1A gene, which codes for part of a sodium channel called NaV1.1. This channel is found in the brain, where it helps nerve cells pass signals between one another.

While it’s not fully understood how the mutations in the SCN1A gene cause seizures, it’s thought they impair the activity of a type of inhibitory neuron, or  nerve cell, resulting in the nervous system being overly activated, resulting in the seizures. While some neurons send signals that activate other neurons (excitatory), some are inhibitory and send signals that silence other neurons.

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What does ETX101 do in Dravet syndrome?

ETX101 is designed to deliver a transcription factor — a protein that acts as a molecular switch that controls the activity of genes in a cell — directly into the brain. The gene coding for that transcription factor is packaged aboard a viral delivery vehicle called AAV9, which is harmless to humans.

The therapy is delivered via an intracerebroventricular infusion, or directly into the ventricles, the fluid-filled spaces, of the brain.

Once ETX101 reaches cells in the brain, the gene gets unloaded from the delivery vehicle. The cells can then produce the transcription factor on their own. This is expected to increase the activity of SCN1A and restore the function of the NaV1.1 sodium channel, easing symptoms by targeting the root cause of the disease.

“The relentless and devastating nature of this condition underscores the critical importance of developing therapies that not only alleviate symptoms but also target the underlying mechanisms,” said Andreas Brunklaus, MD, PhD, principal investigator in the EXPEDITION study. “EXPEDITION represents a significant stride forward in our collective pursuit of new treatments that can truly make a difference in the lives of people affected by Dravet syndrome.” Brunklaus is also a consultant pediatric neurologist at the Royal Hospital for Children, Glasgow.

ETX101 has been granted rare pediatric disease status in the U.S. and orphan drug status for treating Dravet syndrome caused by mutations in the SCN1A gene in both the U.S. and the European Union.