STK-001 led to reductions in seizures, trial data shows

Therapy moves toward registrational trial with positive Phase 1/2 data

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Treatment with the investigational therapy STK-001 led to significant reductions in seizure frequency and clinically meaningful improvements in cognition and behavior for children and adolescents with Dravet syndrome, according to data from Phase 1/2 studies and their open-label extensions (OLEs).

Developer Stoke Therapeutics said that the findings are in “stark contrast” to recently collected natural history data showing that, despite treatment, Dravet patients on average don’t experience meaningful reductions in convulsive seizures and progressively fall behind their neurotypical peers in cognition and behavior.

The company now has plans to meet with regulatory authorities to discuss the design of a registrational Phase 3 clinical trial that could eventually support applications for the treatment’s approval. Updates on those discussions are expected later this year.

“STK-001 is the first medicine in development to demonstrate substantial and durable reductions in seizure frequency and improvements in multiple measures of cognition and behavior,” Edward M. Kaye, MD, CEO of Stoke, said in a company press release. “The totality of these data provide compelling evidence that support the potential for STK-001 to be a disease-modifying medicine for patients with Dravet syndrome by treating the underlying cause of the disease, rather than just the symptoms.”

Most cases of Dravet are caused by mutations in the SCN1A gene,  leading to a lack of the NaV1.1 sodium channel that’s important for regulating nerve cell signaling. Usually, patients have one affected copy of the SCN1A gene and another that’s normal.

STK-001 is designed to address this genetic cause of disease, leveraging the healthy copy of the gene to increase NaV1.1 production, thereby easing the hallmark Dravet symptoms of recurrent seizures and other behavioral abnormalities.

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STK-001 is being tested in 81 Dravet patients, ages 2-18

The therapy is delivered via injections directly into the spinal canal (intrathecal injection), where cerebrospinal fluid (CSF) — the fluid that surrounds the brain and spinal cord — resides.

STK-001 is being evaluated in a pair of open-label Phase 1/2a clinical trials involving 81 Dravet patients, ages 2-18 — MONARCH (NCT04442295), a U.S.-based study, and ADMIRAL (ISRCTN99651026), its U.K. counterpart.

In both MONARCH and ADMIRAL, trial participants received single or multiple injections of STK-001 (doses up to 70 mg) while continuing on their standard anti-seizure medications. Stoke notes that enrolled trial participants had highly refractory disease, with 85% of patients taking at least three other anti-seizure medications, and 54% taking at least four of them.

In the recent update, the company reported on 19 trial participants who received one to three infusions of STK-001 at its highest dose, 70 mg.

As reported in previous analyses, STK-001 at this dose led to the most substantial reductions in seizure frequency compared to rates prior to the study’s start (baseline).

Among 11 patients who received two or three injections, median seizure frequency was reduced by 85% compared to baseline three months after the last dose of STK-001 and by 74% after six months. More than 80% of these patients achieved at least a 50% reduction in seizures.

“A 50% reduction in seizures is an important measure of clinical efficacy, so an 80% reduction on top of any benefit patients may already be getting from their baseline anti-seizure regimen is profound,” said Joseph Sullivan, MD, a Dravet syndrome researcher at the University of California San Francisco.

For the remaining patients who received just one dose, seizures were reduced by 43% and 57% at three and six months after receiving it, respectively.

Open-label extension studies includes 68 participants

After the main trials, 74 participants opted to continue treatment in open-label extension (OLE) studies — SWALLOWTAIL (NCT04740476) for MONARCH participants and LONGWING (ISRCTN12811235) for ADMIRAL participants.

STK-001 is being given at a dose of 30 mg or 45 mg every four months for about one year. To date, 68 participants remain in the OLEs and 10 patients have received up to 10 doses of the medication.

Durable reductions in seizure frequency have continued to be observed among patients in the OLE who were given at least the 30 mg dose in the main trial, the company reports.

Moreover, clinically meaningful improvements in multiple measures of cognition and behavior compared to baseline have been observed after a year in the OLE.

“The further evidence of improvements in skills like communication, behavior, socialization and movement distinguish this approach from anything we have seen to date and mark our entry into a new era in the treatment of Dravet syndrome,” Sullivan said.

Across 81 treated patients, STK-001 has been generally well tolerated, with the most common side effects considered related to treatment being elevated CSF protein levels and procedural vomiting.

Based on the trial data, the U.S. Food and Drug Administration has cleared a dosing regimen of STK-001 where patients will receive three loading doses of the therapy (70 mg) followed by maintenance dosing at 45 mg. This is the intended dosing regimen for a future registrational trial.