Ovid Therapeutics and Takeda Pharmaceutical joined forces three years ago to develop a small molecule into a potential epilepsy drug. That research is starting to pay off as the companies now look ahead to pivotal studies testing that compound in several inherited forms of the disorder.
On Wednesday, New York-based Ovid (NASDAQ: OVID) reported Phase 2 results showing that the molecule, soticlestat, reduced the frequency of epileptic seizures in CDKL5 deficiency disorder (CDD) and chromosome 15q duplication (Dup15q) syndrome. The study was small and was not designed to show statistical significance. But combined with previously reported Phase 2 results in two other rare epilepsies, Dravet syndrome and Lennox-Gastaut syndrome, CEO Jeremy Levin says the company is ready to talk with the FDA about Phase 3 clinical trials.
“We’ll now definitely move it forward in Dravet and have the discussion with the FDA in Lennox-Gastaut,” Levin says. “And with the results in CDKL5 and Dup15q, we believe there is a route forward.”
Soticlestat is designed to target cholesterol 24 hydroxylate (24HC), an enzyme found only in the brain. According to Ovid, research has shown that elevated levels of this enzyme lead to increased activation of NMDA receptors, which are implicated in several neurological disorders, including epilepsy. The Ovid/Takeda drug is designed to block 24HC. By reducing levels of the enzyme, Levin says the once-daily pill is intended to tamp down signaling from the NMDA receptor and lessen stimulation of nervous system cells that cause inflammation.
“The dual action of this drug is to prevent the seizures at the NMDA receptor, and at the same time reduce inflammation and therefore tissue damage,” he says.
The clinical trial results Ovid released Wednesday are from an open-label Phase 2 study that enrolled 20 patients—12 with CDD and eight with Dup15q. Those patients were screened in four-to-six week period to establish a baseline for seizure frequency. They were then treated with the study drug for 20 weeks. Patients were permitted to be treated at the same time with other anti-epileptic drugs.
Soticlestat was well tolerated in both groups and no serious adverse events were reported. In the CDD group, the median reduction in motor seizure frequency was 14 percent during the 20-week study period and 24 percent during the 12-week maintenance period. All of the patients were rolled over into an extension study in which they continued to receive the drug. Ovid says that five of them have reached nine months of continuous treatment with the drug, achieving a median 50 percent reduction in motor seizure frequency.
In the Dup15q group, Ovid reported an average 13 percent increase in motor seizure frequency during the 20-week study period, and an average 12 percent increase in the 12-week maintenance period. But in the extension study, Ovid says the four patients who reached 9 months of continuous treatment with the drug showed an average 74 percent reduction in the motor seizure frequency. Levin says that one of the things that the companies have learned about the drug is that it needs time to take effect.
Soticlestat was discovered in the labs of Takeda (NYSE: TAK). Ovid licensed rights to the compound in 2017, but the deal called for both companies to share equally in the research and development costs. The Japanese pharmaceutical giant also took an equity stake in its partner and both companies will share in the profits of the drug’s sales if it reaches the market.
If Ovid and Takeda are able to commercialize their drug, they’ll compete against therapies from others that also address rare forms of epilepsy. In 2018, GW Pharmaceuticals (NASDAQ: GWPH) drug cannabidiol (Epidiolex) became the first FDA-approved treatment for both Dravet and Lennox-Gastaut. In June, the agency approved fenfluramine (Fintepla), a drug developed by Zogenix (NASDAQ: ZGNX), as a new Dravet treatment.
In CDKL5 deficiency, Ovid and Takeda are trailing Marinus Pharmaceuticals (NASDAQ: MRNS), whose drug ganaxolone takes a different approach by targeting the neurotransmitter GABA. In Phase 3 results released earlier this month, the Radnor, PA-based biotech said that patients treated with its drug experienced a 32.2 percent reduction in seizure activity compared to a 4 percent reduction in the placebo group. Based on those results, Marinus plans to seek FDA approval in mid-2021.
Levin says that soticlestat could have the advantage of addressing a mechanism that applies to multiple forms of epilepsy. In addition to the four types of epilepsy that Ovid and Takeda have tested so far, Levin says the drug has potential applications in developmental and epileptic encephalopathies, conditions that can develop early in life and lead to cognitive and developmental impairment. Some forms of these disorders have no approved treatments.
In addition to its epilepsy drug research, Ovid is also developing gaboxadol, an experimental treatment for Angelman syndrome, an inherited disorder that leads to developmental delays, cognitive difficulties, speech and balance problems, and seizures. There are no FDA-approved therapies for Angelman. Ovid is also evaluating the drug for Fragile X syndrome. Levin says Phase 3 data in Angelman are expected in the fourth quarter of this year.
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