TAK-935/OV935 is an investigational treatment for Dravet syndrome being jointly developed by Takeda Pharmaceuticals in Japan and elsewhere in Asia, and by Ovid Therapeutics in the U.S., Canada, Europe, and Israel. The U.S. Food and Drug Administration (FDA) granted TAK-935/OV935 orphan drug status in 2017.
How TAK-935/OV935 works
Dravet syndrome is a serious disorder characterized by seizures that usually begin in the first year of life. In many cases, these seizures do not improve with anticonvulsant medications. The disease is caused by mutations in the SCN1A gene, which is thought to result in overactive signaling in the brain.
TAK-935/OV935 inhibits an enzyme called cholesterol 24-hydroxylase (CH24H). CH24H is expressed in the brain, where it plays a role in cholesterol metabolism. CH24H recently has been shown also to be involved in regulating a signaling molecule called glutamate. Glutamate is one of the main chemical signals in the brain, and it can increase the initiation and spread of seizure activity. High levels of CH24H activate glutamate signaling pathways, so by inhibiting CH24H, TAK-935/OV935 should be able to reduce the number and severity of seizures. Preclinical studies of TAK-935/OV935 showed promising results.
TAK-935/OV935 in clinical trials
Two Phase 1 clinical trials tested the safety and pharmacokinetics (absorption and metabolism) of multiple increasing doses of TAK-935/OV935 in healthy participants.
One Phase 1 clinical trial (NCT02201056) enrolled 48 volunteers in six groups. In each group, six participants received a single dose of TAK-935/OV935, and two participants received a placebo. The first group received 15 mg, while the other groups received 50, 200, 600, 900, or 1,350 mg of TAK-935/OV935. Trial results were presented at the 2017 American Epilepsy Society meeting and showed that TAK-935/OV935 was safe and well-tolerated up to a single dose of 1,350 mg. The most common side effects were headaches and nausea, and no severe adverse events were reported.
A second Phase 1 clinical trial (NCT02539134) enrolled 40 healthy volunteers. Participants were randomly assigned to one of five groups receiving either 100, 300, 400, or 600 mg of TAK-935/OV935 once per day, or 300 mg of TAK-935/OV935 twice per day. Results were presented at the 2017 American Epilepsy Society meeting and showed that TAK-935/OV935 was well-tolerated up to 400 mg once per day, with the most common side effects being headaches and attention disturbances. Two participants discontinued treatment at the highest doses tested due to adverse events. One participant on 600 mg of treatment reported acute psychosis, and one on 300 mg of treatment twice per day reported confusion. Both events were resolved after treatment was discontinued.
A multicenter Phase 1/2 clinical trial (NCT03166215) is now recruiting patients with epilepsy across the U.S. The trial will include an initial one-month baseline period followed by a one-month double-blind, dose-escalation phase. The purpose is to characterize the safety and tolerability of multiple doses of TAK-935/OV935 in adult participants with developmental or epileptic encephalopathies including Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex.
About 20 participants are expected to be enrolled, with half of the patients randomly assigned to either TAK-935/OV935 or placebo groups. Patients will receive a placebo or a low dose of TAK-935/OV935 twice daily on days 1 to 10, then a medium dose of TAK-935/OV935 on days 11 to 20, and a high dose from days 21 to 30. The treatment and the placebo will be in tablet form, taken either orally or through a gastrostomy tube, which is inserted through an incision in the abdomen and provides medication directly to the stomach.
The optional second half of the trial will be open-label. Patients will receive a medium dose of TAK-935/OV935 twice daily from days 31 to 40, followed by a low dose of TAK-935/OV935, a medium dose, and then a high dose twice daily from days 31 to 85. At the end of the second half of the trial, the dose of TAK-935/OV935 will be decreased before dosing is discontinued. Treatment also will be delivered in tablet form, either orally or through a gastrostomy tube.
The study’s primary outcome is to characterize the safety and tolerability of TAK-935/OV935. Secondary outcomes include assessment of standard laboratory safety values and evaluation of the treatment’s pharmacokinetics.
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