The company’s decision is based on an end-of-Phase 2 meeting with the U.S. Food and Drug Administration. If successful, the Phase 3 study, named NEPTUNE, will support a new drug application for OV101 in Angelman. Ovid expects to start enrollment in the second half of 2019.
“It is important to acknowledge that while this meeting was a milestone for Ovid, and provides a clear path forward, it is an even more momentous one for the Angelman syndrome community,” Jeremy Levin, Ovid’s chairman and CEO, said in a press release. “With the thoughtful assistance and clear direction from the FDA, we now move forward to a pivotal trial that we hope will result in the first approved medicine for individuals living with this disorder.”
According to Amit Rakhit, MD, Ovid’s chief medical and portfolio management officer, the meeting with the FDA was “productive and helped us understand the FDA’s expectations for a pivotal trial of OV101 in Angelman.” Juvenile toxicology studies and pharmacological data provide the basis to start the trial in younger patients, he said.
“This trial is not only an important next step of our OV101 strategy, but also part of our overall mission to bring medicines to people who have no or limited treatment options,” he added.
A process called tonic inhibition enables the brain to differentiate between excitatory and inhibitory neurological signals without being overloaded. Its disruption is regarded as the underlying cause of certain neurodevelopmental disorders, including Angelman and fragile X syndrome, as the brain loses the ability to separate important information from background noise.
OV101 is a small molecule derived from a naturally occurring compound called muscimol that selectively activates GABAA receptors located on the surface of nerve cells but away from the site where these cells communicate — called a synapse. According to Ovid, OV101 is believed to be the first compound targeting disrupted tonic inhibition.
Recently presented data from Ovid’s 12-week Phase 2 STARS trial (NCT02996305) showed that treatment with 15 mg of OV101 once daily significantly improved sleep and motor skills in adult and adolescent Angelman patients.
The double-blind study enrolled 88 patients (66 adults and 22 adolescents), who were randomly assigned to receive either once-daily OV101 at night (15 mg), twice-daily OV101 (10 mg in the morning and 15 mg at night), or a placebo. Previous results showed that OV101 had a favorable safety profile and was well-tolerated.
Both doses led to statistically significant improvements over placebo at the end of treatment, as assessed with the seven-point Clinical Global Impression of Improvement (CGI-I) scale, which addresses changes in condition, including all global neurological deficits.
Ovid and the FDA agreed that the upcoming Phase 3 trial will be designed as a single, 12-week, randomized, double-blind trial of once-daily OV101. It will enroll approximately 50-60 pediatric Angelman patients ages 4 to 12 years, who will either receive the treatment candidate or placebo.
The study’s primary objective will be changes in overall CGI-I scores. Based on its discussions with the FDA, the company will develop a framework to ensure uniform use of the CGI-I by focusing on specific symptoms relevant to both Angelman patients and their caregivers. Further details will be shared once the NEPTUNE trial starts.
“Angelman syndrome is a rare disease, and until now, there have been no medicines that specifically treat AS. There were not even any good tests to tell us if a new drug was helping people with AS. The Ovid trial has changed everything. It gives us hope — hope for families and even hope for other researchers who are developing new drugs for this rare disease,” Terry Jo Bichell, outgoing director of the Angelman Biomarkers and Outcome Measures Alliance, as well as a parent of a son with Angelman syndrome and a scientific expert, said to Angelman Syndrome News.
Ovid is also about to start ELARA, a one-year, open-label extension study for Angelman patients who have completed a prior OV101 trial. Participants will receive once-daily dosing. ELARA will explore the treatment’s long-term safety and tolerability in addition to its efficacy. The company is also evaluating options for patients younger than 4 years of age.
The FDA granted orphan drug and fast track designations for OV101 as a treatment for Angelman and fragile X syndrome. Preclinical studies showed that the investigational therapy eased symptoms of both disorders. Assessments in more than 4,000 patients showed that OV101 has favorable safety and bioavailability — the proportion of the therapy that reaches circulation in the body.
Ovid recently started a Phase 2 trial called ROCKET (NCT03697161) to evaluate the safety, tolerability, and efficacy of OV101 in adolescents and young adults with fragile X syndrome. Patient enrollment is ongoing; more information is available here.