The U.S. Food and Drug Administration (FDA) will allow an additional higher dose of STK-001 to be added to the Phase 1/2a MONARCH trial, which is evaluating the potential therapy’s safety and tolerability in treating children and adolescents with Dravet syndrome.
The FDA had previously placed higher doses of the therapy on a partial clinical hold, meaning they could not be tested in the trial. Now, Stoke Therapeutics, the treatment’s maker, will move forward with dosing participants at three levels in the ongoing study (NCT04442295), which continues to enroll new patients.
“There is an urgent need for more effective medicines for people who are living with Dravet syndrome, so we are pleased to be moving ahead quickly with our plans to continue dosing children and adolescents in this important Phase 1/2a study of STK-001,” Edward M. Kaye, MD, CEO of Stoke Therapeutics, said in a press release.
The higher dose will be added to the single ascending dose (SAD) portion of the study, previously called Part A. This part of the trial will now evaluate three doses: 10 mg, 20 mg and 30 mg. Doses above 30 mg remain on the FDA’s partial clinical hold.
MONACH is enrolling children and adolescents with Dravet syndrome, ages 2–18, at 13 testing sites across the U.S. Participants must currently be on anti-epileptic therapies, and have taken at least two anti-epileptic medications but stopped due to ineffectiveness or side effects.
A single dose of STK-001 will be administered to all participants, by injection into the spinal cord, following one month of patient monitoring by the study’s researchers. The children and adolescents then will continue to be monitored for harmful side effects, called adverse events, for six months.
The researchers also will measure STK-001 levels in the patients’ blood and cerebrospinal fluid, the liquid surrounding the brain and spinal cord. Seizure frequency, changes in quality of life, and any differences in clinical status also will be assessed.
STK-001 is an antisense oligonucleotide that restores normal levels of the NaV1.1 sodium ion channel protein in nerve cells by increasing its production from a patient’s one functional copy of the SCN1A gene. The other copy is mutated in people with Dravet, which leads to the syndrome’s severe form of epilepsy.
Subject to FDA review, the company also is preparing to add a multiple ascending dose (MAD) portion to the trial to replace its original Part B. MAD protocols seek to establish the best doses and dosing intervals of a compound by analyzing the pharmacokinetics and pharmacodynamics of multiple doses. Pharmacokinetics is how a medication moves through the body, while pharmacodynamics is what the medicine does to the body.
The company decided to add a MAD portion after a repeat-dose toxicology study found no adverse effects in non-human primates. These studies are performed to characterize potential harmful effects that come from repeated exposure to a medicine.
The trial dosed its first patient in August, when just the two lower doses had been approved for testing. The FDA had placed its hold on higher doses in March, pending additional pre-clinical safety testing at doses higher than the current no observed adverse effect level (NOAEL) — the highest dose at which no adverse effect is seen.
In this pre-clinical testing, hind limb weakness and convulsions appeared at some higher doses. However, these occurred at doses well above the corresponding human levels and in a higher concentration than would be administered in a clinical setting. Also of note, hind limb weakness is a known effect of delivering antisense oligonucleotides to primates by a spinal tap, but is not known to occur in humans.
The company found no correlation between those adverse effects and the compound’s mechanism of action.
Stoke expects to have preliminary safety and pharmacokinetic data in 2021.
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