Rare Daily Staff

RNA-based medicines biotech Stoke Therapeutics reported highlights from five presentations being made at the American Epilepsy Society 2021 Annual Meeting related to the ongoing clinical development of STK-001, potentially the first disease-modifying therapy to target the underlying cause of Dravet syndrome.

Dravet syndrome is a severe and progressive genetic epilepsy characterized by frequent, prolonged, and refractory seizures beginning within the first year of life. It is difficult to treat and has a poor long-term prognosis. Complications of the disease often contribute to a poor quality of life for patients and their caregivers. The effects of the disease go beyond seizures and often include intellectual disability, developmental delays, movement and balance issues, language and speech disturbances, growth defects, sleep abnormalities, disruptions of the autonomic nervous system and mood disorders.

The disease is classified as a developmental and epileptic encephalopathy due to the developmental delays and cognitive impairment associated with the disease. Compared with the general epilepsy population, people living with Dravet syndrome have a higher risk of sudden unexpected death in epilepsy, or SUDEP. There are no approved disease-modifying therapies for people living with Dravet syndrome. One out of 16,000 babies are born with Dravet syndrome, which is not concentrated in a particular geographic area or ethnic group.

Stoke is initially using its TANGO (Targeted Augmentation of Nuclear Gene Output) research platform to target diseases in which one copy of a gene functions normally and the other is mutated, also called haploinsufficiencies. In these cases, the mutated gene does not produce its share of protein, resulting in disease. Using the TANGO approach and a deep understanding of RNA science, Stoke’s antisense oligonucleotides (ASOs) bind to pre-mRNA and help the functional (or wild-type) genes produce more protein. TANGO aims to restore missing proteins by increasing—or stoking—protein output from healthy genes, thus compensating for the mutant copy of the gene.

STK-001 is an investigational antisense oligonucleotide (ASO) for the treatment of Dravet syndrome currently being evaluated in ongoing clinical trials, which the company believes has the potential to be the first disease-modifying therapy to address the genetic cause of Dravet syndrome. STK-001 is designed to upregulate NaV1.1 protein expression by leveraging the non-mutant (wild-type) copy of the SCN1A gene to restore physiological NaV1.1 levels, thereby reducing both occurrence of seizures and significant non-seizure comorbidities. Stoke has generated preclinical data demonstrating proof-of-mechanism and proof-of-concept for STK-001. STK-001 has been granted orphan drug designation by the FDA as a potential new treatment for Dravet syndrome.

The MONARCH study is a phase 1/2a open-label study of children and adolescents ages 2 to 18 who have an established diagnosis of Dravet syndrome and have evidence of a pathogenic genetic mutation in the SCN1A gene. The primary objectives for the study are to assess the safety and tolerability of STK-001, as well as to determine the pharmacokinetics in plasma and exposure in cerebrospinal fluid. A secondary objective is to assess the efficacy as an adjunctive antiepileptic treatment with respect to the percentage change from baseline in convulsive seizure frequency over a 12-week treatment period. Stoke also intends to measure non-seizure aspects of the disease, such as quality of life, as secondary endpoints. Stoke plans to enroll approximately 90 patients in the study across 20 sites in the United States.

Although the phase 1/2a MONARCH study of STK-001 was not powered to show statistical significance, Stoke reported that 70.6 percent (12/17) of patients treated with single doses (10mg, 20mg, 30mg) or multiple doses (20mg) of STK-001 experienced a reduction from baseline in convulsive seizure frequency measured from Day 29 to Day 84 after receiving their first dose of STK-001 and all patients ages 2-12  experienced a reduction from baseline in convulsive seizure frequency measured from Day 29 to Day 84. Reductions in seizure frequency were also observed among patients ages 13-18 and across all cohorts median reductions of 17 percent to 37 percent from baseline in convulsive seizure frequency from Day 29 to Day 84 were observed. STK-001 was well tolerated with no safety concerns related to the study drug.

Patients who participated in the MONARCH study are eligible to continue treatment in SWALLOWTAIL, an open label extension study designed to evaluate the long-term safety and tolerability of repeat doses of STK-001. Enrollment and dosing in SWALLOWTAIL are underway.

“STK-001 is designed to target the underlying cause of Dravet syndrome to potentially address both seizures and non-seizure comorbidities,” said Barry Ticho, chief medical officer of Stoke Therapeutics. “These initial data give us confidence that STK-001 is having an effect on the disease. Based on our pharmacokinetic model, we believe that sustained higher exposure levels in the brain may lead to greater reductions in seizure frequency and potentially also improvements in some of the non-seizure comorbidities.”

Photo: Barry Ticho, chief medical officer of Stoke Therapeutics

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