ETX101 Durability Signal Promising, But Single-Arm Design and Data Opacity Leave Payer Path Unresolved

Encoded to Present Positive ETX101 Gene Therapy Data for Dravet Syndrome

Encoded Therapeutics Inc. announced that new results from its POLARIS clinical program for ETX101, an investigational AAV9-based gene regulation therapy for SCN1A+ Dravet syndrome, will be presented at the 16th European Epilepsy Congress on September 7, 2026, in Athens, Greece. The presentation will feature up to 117 weeks of follow-up data, demonstrating substantial and sustained seizure reductions and clinically meaningful neurodevelopmental gains in children living with Dravet syndrome following a single dose of ETX101.

• The upcoming presentation will detail up to 117 weeks of follow-up data from the POLARIS Phase 1/2 program for ETX101. These results highlight substantial and sustained reductions in seizures, alongside clinically meaningful neurodevelopmental improvements observed in children affected by SCN1A+ Dravet syndrome after receiving a single dose of the gene therapy.
• ETX101 is an AAV9-based gene regulation therapy designed to increase the expression of the SCN1A gene, aiming to restore sodium channel function in inhibitory interneurons. This targeted approach addresses the underlying genetic cause of Dravet syndrome, offering the potential to treat the full spectrum of symptoms, including seizures, cognitive, communication, behavioral, and motor impairments.
• ETX101 has garnered significant regulatory support, receiving multiple designations from the FDA, including Breakthrough Therapy, Regenerative Medicine Advanced Therapy, Fast Track, Rare Pediatric Disease, and Orphan Drug. Additionally, it was selected for the FDA’s CMC Development and Readiness Pilot (CDRP) program and granted Orphan designation by the European Medicines Agency (EMA).

The Persistent Challenges in Treating SCN1A+ Dravet Syndrome

Despite meaningful advances in the pharmacological management of SCN1A+ Dravet syndrome, the condition remains profoundly difficult to treat. Approved anti-seizure medications (ASMs) reduce seizure burden but fall short of achieving complete seizure freedom or preventing cognitive decline, and disease-modifying therapies remain in early stages of development.

• Pharmacoresistance and polypharmacy burden: Seizures in Dravet syndrome are highly drug resistant, requiring multiple ASMs. Initial broad-spectrum agents such as valproate (VPA) and clobazam (CLB) are generally insufficient to control seizures, necessitating escalation to adjunct therapies including stiripentol (STP), cannabidiol (CBD), and fenfluramine (FFA). Managing polypharmacy introduces clinically significant drug-drug interactions — for example, STP combined with CLB increases plasma concentrations of CLB and its active metabolite norclobazam, potentially increasing somnolence; CBD has a bi-directional interaction with CLB producing increases in plasma concentrations of 7-OH-CBD and norclobazam; and CBD is associated with elevations of liver transaminases, particularly in patients taking concomitant VPA.

• Risk of seizure exacerbation with certain ASMs: Non-selective sodium channel blockers can exacerbate symptoms in patients with Dravet syndrome, given that the underlying SCN1A haploinsufficiency leads to hypoexcitability of GABAergic interneurons. This constrains the therapeutic options available and requires careful agent selection.

• Incomplete understanding of chronic disease mechanisms: Early studies established that Nav1.1 loss preferentially impairs GABAergic interneuron function, particularly parvalbumin-positive fast-spiking interneurons (PVINs). However, the impaired action potential generation observed in PVINs during early development has been shown to normalize by postnatal day 35 in mouse models, suggesting that a transient impairment of PVINs contributes to epilepsy onset but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome. This implies that the pathomechanisms driving chronic seizures remain incompletely characterized.

• Multisystem comorbidities beyond seizure control: Dravet syndrome is now recognized as a multisystem disorder with widespread developmental consequences. Children frequently exhibit cognitive impairment, motor and speech delays, and neuropsychiatric comorbidities such as anxiety, attention deficits, and autistic traits. Current treatments fail to prevent cognitive decline, and sudden unexpected death in epilepsy (SUDEP) remains a frequent and serious risk. Effective management strategies beyond seizure control — encompassing cognitive preservation and SUDEP prevention — represent a critical unmet need.

• Disease-modifying therapy remains nascent: Disease-modifying approaches targeting the underlying SCN1A haploinsufficiency are at their beginning. Antisense oligonucleotides have so far proven to be the most successful within disease-modifying therapy, but require further refinement of methodology of application and delivery to target cells, as well as additional testing of effectiveness outside of TANGO technology. The full potential of gene therapy has yet to be explored, with high capacity adenoviral vectors capable of incorporating the SCN1A gene only recently prepared. CRISPR-derived platforms and genome-editing strategies also face significant translational challenges, including efficient and cell-type-specific delivery, long-term safety, and the risk of network-level side effects in the epileptic brain.

• Absence of head-to-head comparative data for approved add-on ASMs: The comparative efficacy and safety of stiripentol, cannabidiol, and fenfluramine as add-on therapies have not been evaluated in head-to-head trials. Indirect comparisons suggest fenfluramine and stiripentol have comparable efficacy, but fenfluramine appeared to be safer in terms of less frequent serious treatment-emergent adverse events (TEAEs), while cannabidiol had relatively lower efficacy and was associated with serious TEAEs. The trial on stiripentol had limited sample size, explaining wide confidence intervals for comparative outcomes, and a head-to-head trial between these agents has been identified as a critical need.

Targeting the Genetic Root of SCN1A+ Dravet Syndrome with ETX101

Dravet syndrome (SCN1A+) is driven at its genetic root by loss-of-function mutations — most commonly heterozygous — in SCN1A, the gene encoding the voltage-gated sodium channel Nav1.1. Nav1.1 haploinsufficiency selectively impairs the excitability of GABAergic inhibitory interneurons, particularly parvalbumin-expressing fast-spiking interneurons (PVINs) and somatostatin-expressing interneurons in the neocortex. Electrophysiological recordings in neocortical slices from Scn1a⁺/⁻ mice have revealed that both interneuron subtypes exhibit increased threshold and rheobase for action potential generation, decreased action potential frequency within trains, and more frequent firing failure. Critically, specific heterozygous deletion of Nav1.1 in forebrain GABAergic neurons is sufficient to reproduce all manifestations of Dravet syndrome in mice, confirming that interneuron dysfunction is a primary pathogenic driver. The deficit in somatostatin-expressing interneurons further causes significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons, resulting in substantial disinhibition of cortical output.

Beyond this initial interneuron dysfunction, the disease course involves broader network and homeostatic alterations. In the CA1 hippocampal microcircuit, homeostatic synaptic changes have been identified in both CA1 pyramidal neurons and stratum-oriens interneurons, consistent with reduced excitation and inhibition onto CA1 pyramidal neurons and increased release probability at the CA1-SO synapse. These findings suggest global neuronal alterations within the CA1 microcircuit extending beyond the direct impact of Nav1.1 dysfunction. Furthermore, PVIN dysfunction has been shown to be transient: impaired action potential generation observed in PVINs during early development normalizes by postnatal day 35, with axon initial segment elongation suggesting a reorganization of axonal sodium channels as a compensatory mechanism. This implies that a transient impairment of PVINs contributes to epilepsy onset, but is not the mechanism of ongoing, chronic epilepsy in Dravet syndrome.

Genetic and molecular modifiers further shape disease severity and progression. The same SCN1A mutation can produce phenotypes ranging from mild GEFS+ to severe Dravet syndrome, and studies using a R1648H knock-in mouse model demonstrated that short repeated seizures at the age of disease onset transformed a mild/asymptomatic phenotype into a severe Dravet syndrome-like phenotype — including frequent spontaneous seizures and cognitive/behavioral deficits — exclusively in Scn1a⁺/⁻ mice, not in wild-type animals. This indicates a clear interaction between seizures and the mutation for the development of a severe phenotype generated by pathological remodeling, including increased excitability of hippocampal granule cells. At the molecular level, transcriptome analysis of DS-patient iPSC-derived GABAergic cells revealed dysregulation of genes governing chromatin structure, mitotic progression, neural plasticity, and excitability, with marked upregulation of the transcription factors FOXM1 and E2F1. Additionally, the GABA-A receptor subunit gene Gabra2 has been identified as a strain-specific genetic modifier of the Scn1a⁺/⁻ phenotype, with pharmacological manipulation via clobazam demonstrating dose-dependent protection against hyperthermia-induced seizures.

Promising Safety and Efficacy from ETX101's POLARIS Program

The available studies on fenfluramine in Dravet syndrome provide robust efficacy and safety data across randomized controlled trials, real-world programs, and long-term extension analyses. The knowledge base does not have sufficient information on this aspect. regarding SCN1A+ genotype-specific stratification — none of the studies below report outcomes restricted to SCN1A-positive patients or reference ETX101 or the POLARIS program.

The studies below reflect fenfluramine trials in Dravet syndrome broadly, as that is what the available literature covers.

The knowledge base does not have sufficient information on this aspect.

Assessing the Long-Term Durability of Response for ETX101

Published data on long-term outcomes in Dravet syndrome (DS) — predominantly in SCN1A mutation-positive patients — spans three approved antiseizure medications (ASMs): stiripentol, cannabidiol (CBD), and fenfluramine. A 12-year prospective observational study of stiripentol (2003–2015; n=41; median treatment duration 37 months, range 2–141 months) found that 20 out of 41 patients achieved ≥50% long-term reduction in generalized tonic-clonic seizure frequency, 11 out of 23 achieved ≥50% reduction in focal seizure frequency, and 11 out of 26 achieved ≥50% reduction in status epilepticus frequency. The most common adverse events were anorexia, weight loss, sedation, and behavioural changes; one patient developed recurrent pancreatitis on concurrent valproate. For fenfluramine, an open-label extension (OLE) study enrolling 232 patients demonstrated a median decrease in convulsive seizure frequency of -66.8% (range = -100% to 234.9%; P < .001) over a median treatment duration of 256 days (range = 46–634 days), with similar reductions in patients <6 years (-75.7%) and ≥6 years (-64.7%). A subsequent OLE analysis of 327 patients (median treatment duration 23.9 months, range 0.2–42.6 months) further supported durability, with no systematic loss of efficacy observed in long-term DS cohorts per a meta-analysis of 20 studies (4 randomized, 16 observational) comprising 1,387 patients, which reported pooled ≥50% responder rates of 64.8% (95% CI 56.1–72.7) and seizure freedom in 11.4% (95% CI 7.2–17.6).

Cardiovascular safety has been a particular focus for fenfluramine given its historical association with cardiac valvulopathy at weight-loss doses. Across both OLE studies — enrolling 232 and 327 patients respectively — serial transthoracic echocardiography performed at standardized intervals found no cases of valvular heart disease (VHD) or pulmonary artery hypertension (PAH), with the larger cohort representing up to 42.6 months of exposure. A pooled mortality analysis across 732 persons with DS treated with fenfluramine (1,185.3 person-years of exposure) reported an all-cause mortality rate of 1.7 per 1,000 person-years (95% CI, 0.4 to 6.7) and a SUDEP rate lower than the all-cause estimate of 15.8 per 1,000 person-years (95% CI, 9.9 to 25.4) and SUDEP estimate of 9.3 (95% CI, 5.0 to 17.3) reported for persons with DS receiving standard-of-care, though further studies were noted as warranted to confirm whether fenfluramine reduces SUDEP risk and to elucidate potential mechanisms.

Beyond seizure control, natural history data underscore persistent non-seizure deficits. Cognitive slowing becomes evident during the second year of life in all DS cases, with early appearance of absences and myoclonic seizures associated with the worst cognitive outcome; statistical analysis failed to reveal differences in cognitive outcome with regard to the presence and type of SCN1A mutation. In adulthood, overall seizure frequency — particularly myoclonic, atypical absence, and focal seizures with impaired awareness — tends to decrease, and adults show a notable reduction in status epilepticus, especially after 30 years of age, though behaviour problems persist and are associated with lower health-related quality of life. A comprehensive 2024 review noted that natural history studies continue to underscore persistent deficits in cognitive development and quality of life, and highlight suboptimal long-term seizure control despite the use of the three approved ASMs.

Dravet Syndrome: ETX101's Long-Term Data Signals a Paradigm Shift

Dravet syndrome represents one of the most challenging pediatric epilepsies, characterized by severe, refractory seizures and significant neurodevelopmental delays stemming from SCN1A haploinsufficiency. For years, treatment has focused on managing symptoms, often with limited success. The emerging data for ETX101, an AAV9-based gene regulation therapy, signals a potential paradigm shift, moving towards a disease-modifying approach.

The reported sustained seizure reductions and clinically meaningful neurodevelopmental gains over an impressive 117-week follow-up period are particularly compelling. This suggests that ETX101 is not merely suppressing seizures but may be addressing the underlying neurological dysfunction, offering a chance for children to achieve developmental milestones previously out of reach. This long-term efficacy and impact on neurodevelopment could position ETX101 as a foundational therapy, differentiating it from other gene-targeted approaches and conventional treatments.

However, as with any novel gene therapy, critical considerations remain:

• Long-term Safety: While preclinical data showed a favorable safety profile, the potential for delayed immunogenic responses or other adverse events associated with AAV9 delivery and sustained transgene expression requires ongoing vigilance.

• Durability: The 117-week data is encouraging, but the ultimate long-term durability of a single-dose therapy in a lifelong condition will be crucial for its clinical utility.

• Patient Heterogeneity: Understanding the therapy's consistent efficacy and safety across the diverse spectrum of SCN1A+ Dravet syndrome patients, including those with different genetic variants or disease stages, will be vital.

Ultimately, the continued positive trajectory of ETX101 could validate the broader AAV9 gene regulation platform, potentially accelerating the development of similar targeted therapies for other severe neurological disorders. This represents a significant step forward in precision medicine for genetic epilepsies.