The study of an antisense oligonucleotide (ASO) therapy, which involved an increasing dose of STK-001 (Zorevunersen), produced encouraging results that offer hope to patients and their loved ones, the researchers said.
The phase 1/2a study was designed to allow participants to receive the treatment in a dose-escalating manner to ensure safety and tolerability as the primary endpoint, said lead author Joseph E. Sullivan, MD, FAES, professor of neurology and pediatrics at the University of California, San Francisco. The first dose started at 10 mg and then increased in a stepwise manner up to 70 mg, he said.
Researchers analyzed the safety, tolerability, and clinical impact of intrathecally (IT) administered STK-001 in 81 patients with DS between ages 2 and 18 years with recurrent seizures and a confirmed SCN1A variant. Their seizures were resistant to standard treatments, with ongoing convulsive seizures occurring despite the fact that 85 percent of participants took at least three antiseizure medications and 54 percent took four or more.
According to a press release from Stoke Therapeutics, which developed the treatment, there were median reductions of 85 percent (n=10) at three months and 74 percent (n=9) at six months after the last dose. Single and multiple doses of up to 70 mg of STK-001 were generally well tolerated, researchers wrote.
Patients treated with at least one initial dose of 70 mg “demonstrated substantial and sustained reductions in convulsive seizure frequency," according to the study abstract. Children receiving ongoing treatment in an open label extension demonstrated both reductions in seizure frequency and “clinically meaningful improvements" in both cognition and behavior measures after a year. Researchers hoped STK-001 would have this kind of impact, Dr. Sullivan said.
“There was hope based on the pre-clinical data in the mouse model that if we can up-regulate the amount of functioning NAV 1.1 channel, that not only would that translate into a significant reduction in seizures but also start to show some improvements in some of the other non-seizure related comorbidities as well as survival," he said.
In his presentation at CNS, Dr. Sullivan acknowledged that 30 percent of the patients experienced a study drug-related adverse event, most commonly elevated cerebrospinal fluid proteins (13.6 percent) and procedural vomiting (4.9 percent); 22% of patients experienced a treatment-emergent serious adverse event, although all but one were unrelated to the study drug.
The results could have important implications for other disorders, said Orrin Devinsky, MD, FAAN, a professor in the departments of neurology, neurosurgery, and psychiatry at NYU Grossman School of Medicine and an epileptologist at the Comprehensive Epilepsy Center at NYU Langone Health, who was not involved in the study.
“The initial data is very promising, and since this ASO promises to address the underlying problem—too little of the Nav1.1 protein produced by the SCN1A gene—it has the potential to be truly disease-modifying and provide benefits beyond seizure control, in other domains such as cognition and coordination," he wrote in an email. “Stopping seizures can improve cognition. Fenfluramine is a very effective drug to reduce convulsive seizures in Dravet syndrome patients and, likely through this reduction in seizures, led to significant improvements in cognition and behavior in many patients."
The next stage is a phase 3 trial with a larger cohort and a sham procedure in which patients will receive a lumbar puncture but no drug, said Dr. Sullivan. With most conventional anti-ASM trials, it takes about three months to know if the intervention is effective. It may take longer for the gene upregulation and protein production to happen with the ASO treatment, so it could take longer to understand the full benefit from a seizure and non-seizure comorbidity standpoints in the next phase of the study, he said.
“The primary endpoint is focused on seizure reduction, but we also want to understand if the development also improves in the group that's being treated, and that's also informing the clinical trial design in terms of the duration of the clinical trial," he said.
David A. Gloss, MD, FAAN, a neurologist specializing in epilepsy and neurophysiology at the NeuroMedical Center in Baton Rouge, LA, said that using STK-100 to replace a missing/malfunctioning protein makes a lot of sense physiologically, as it tries to improve the underlying abnormality. The challenge with ASO treatments is that they have not been tested on the wider population, focusing mainly on patients with rare diseases, so the true frequency and seriousness of adverse effects are not known very well.
However, he said, caregivers of those with Dravet syndrome should feel hopeful.
“There may be a new drug on the horizon," Dr. Gloss said by email. “This presentation combined four phase 1/2 trials, showing relative safety, but there are no guarantees that it will be able to come to market eventually."
Dr. Devinsky said many families are waiting and hoping for the next stage of the trial.
“The Dravet community of patients, families, physicians, and scientists are all rooting hard for this gene therapy to transform the landscape of care for this terrible and potentially deadly disease," he said.
https://journals.lww.com/neurotodayonline/blog/NeurologyTodayConferenceReportersCNSAnnualMeeting/pages/post.aspx?PostID=62
PL1-1. Safety and Clinical Effects of STK-001, an Antisense Oligonucleotide (ASO), in Children and Adolescents with Dravet Syndrome: Phase 1/2a End of-Study and Open-label Extension (OLE) Data Sullivan J (San Francisco, CA), Cross H, Laux L, Perry S, Desurkar A, Schreiber J, Roberts C, Knupp K, Wheless J, Wirrell E, Wang F, Parkerson K, Ticho B.
OBJECTIVE: DS is a severe and progressive genetic epilepsy that is typically caused by spontaneous, heterozygous loss of-function SCN1A gene mutations, which encode the Nav1.1 protein. STK-001 is an investigational ASO that exploits modulation of pre-mRNA to upregulate functional brain Nav1.1 expression by leveraging the wild-type copy of SCN1A to restore physiological protein levels.
METHODS: Phase 1/2a studies, MONARCH (US) and ADMIRAL (UK), with the SWALLOWTAIL (US) and LONGWING (UK), assessed safety, tolerability, plasma pharmacokinetics, CSF exposure, and clinical effect of intrathecally (IT) administered STK-001 in patients with DS aged 2-18y. Patients have disease onset <12 months old with recurrent seizures and confirmed SCN1A variant. Adverse Events were monitored continuously.
RESULTS: 81 patients received ≥1 dose of STK-001 (10-70mg/dose). Patients were highly refractory to standard treatments with ongoing convulsive seizures despite 85% taking ≥3 ASMs and 54% taking ≥4 ASMs. Patients treated with ≥1 initial dose of 70mg demonstrated substantial and sustained reductions in convulsive seizure frequency. Patients receiving ongoing OLE treatment (30 or 45mg/4 months) demonstrated durable reductions in convulsive seizure frequency and clinically meaningful improvements in multiple measures of cognition and behavior through month 12. Single and multiple doses of up to 70 mg STK-001 was generally well-tolerated across these studies.
CONCLUSIONS: STK-001 has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome.
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