New data from Ovid Therapeutics’ Phase 2 STARS trial shows that treatment with oral candidate OV101 once daily at a dose of 15 mg significantly improves sleep and motor skills in adult and adolescent Angelman patients.
Alex Kolevzon, MD, professor of psychiatry and pediatrics at the Icahn School of Medicine at Mount Sinai, presented the results in a scientific poster titled “Topline Results From a Phase 2 Adult and Adolescent Angelman Syndrome Clinical Trial: A Randomized, Double-Blind, Safety and Efficacy Study of Gaboxadol (OV101),” during the 65th American Academy of Child and Adolescent Psychiatry Annual Meeting, in Seattle, Washington.
OV101, also called gaboxadol or THIP, is a small molecule derived from a compound called muscimol, which is naturally found in a mushroom (Amanita muscaria). It binds and selectively activates GABAA receptors located on the surface of nerve cells and restores tonic inhibition, i.e., the brain’s ability to filter real nerve signals. Perturbations in this process, mainly caused by mutations in the UBE3A gene, are thought to underlie Angelman syndrome.
The Phase 2 STARS trial (NCT02996305) recruited 88 Angelman patients — 66 adults and 22 adolescents, ages 13 to 49 — at 13 sites in the U.S. and Israel.
Patients were randomly given either OV101, administered orally as a once-daily dose of 15 mg (at night) or twice daily — 10 mg in the morning and 15 mg at night — or a placebo (control). Treatment was maintained for 12 weeks.
Previous data showed that OV101 had a favorable safety profile and was well-tolerated through the 12-week treatment. At the end of the treatment, patients who had received OV101 showed statistically significant improvements — measured by a physician-rated clinical global impression of improvement (CGI-I) — at the two doses tested, relative to placebo controls.
CGI-I is a seven-point scale that assesses changes in a patient’s condition after the start of treatment, including all global neurological deficits.
The new data shows OV101’s effects in key clinical features of Angelman syndrome, namely sleep and motor function. Additional parameters evaluated included patients’ behavior and quality of life.
Researchers evaluated the time it takes to fall asleep (latency), mean daytime sleepiness and changes in sleep efficiency in 39 patients who were able to wear an actigraphy watch — a non-invasive way to monitor human rest/activity cycles.
Latency to sleep was improved in patients who received OV101 15 mg once daily compared to placebo — OV101-treated patients fell asleep 25 minutes faster than controls.
Patients’ sleep time was more efficient (increase of 3.65 percent) and the need to sleep during the day was reduced by almost 1 hour (50 minutes) in the group of patients treated with OV101 15 mg once daily compared to the placebo group.
By the end of the treatment, patients’ overall sleep was improved with the once-daily dose of OV101. The twice-daily dose of OV101 showed no differences from the placebo group.
Fifty-four percent and 36 percent of the patients in the OV101 15 mg dose group showed improvement in overall motor response at week 12, as shown by an increase of three or more points in the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III) motor scale. This test examines all the facets of a child’s (1 to 42 months) development.
No changes were observed in fine motor skills, such as the ability to control small movements of hands and fingers, as well as the small muscles of the face, mouth (tongue) and feet.
Patients’ mobility, measured with the Pediatric Evaluation of Disability Inventory-Computer Adaptive Test (PEDI-CAT), significantly improved in the OV101 15 mg group relative to controls. Daily activity remained similar between both groups.
In the Zeno Walkway test — a 20-foot-long walkway used to monitor walking in people with neurological disorders and injuries — patients in the 15 mg dose of OV101 showed statistically significant improvements in mean cadence (rate at which an individual walks) and stride velocity compared to controls.
The new analysis showed that patients who had already shown improvement in the CGI-I in the previous analysis now showed improvement in their communication skills and had reduced anxiety, as measured by the Parent Global Impression (PGI) scale.
No differences were found between OV101 and the placebo group in two other behavior scales, the Aberrant Behavior Checklist (ABC) and the Anxiety, Depression, and Mood Scales (ADAMS).
Patients’ quality of life, measured using three scales — the Short-Form Health Survey (SF-36), EuroQoL 5-Dimension, and the Patient-Generated Index (PGI) — remained similar between the OV101-treated group and the placebo group.
“Angelman syndrome is an extremely complex disorder in which any given patient may present with a variety of symptoms with different degrees of severity,” Kolevzon said in a press release. “These additional data from the STARS trial are encouraging, particularly the efficacy signals observed across the domains of sleep and motor, which appear to have driven the overall improvements seen in CGI-I.”
An open-label, 1-year extension study, called ELARA, will be open to Angelman syndrome patients who have participated in a prior OV101 clinical trial. The ELARA trial will assess the long-term (1 year) safety and efficacy of a 15 mg, once-daily dose of OV101.
“There are no established tools or endpoints to measure a drug’s effect on signs and symptoms of Angelman syndrome, and the information gained from the Phase 2 STARS trial establishes the potential of OV101 to offer a clinically meaningful benefit specific to people living with Angelman syndrome,” Kolevzon said.
“STARS was informed by extensive collaboration with the Angelman community,” said Jeremy Levin, DPhil, MB, BChir, chairman and chief executive officer of Ovid Therapeutics.
“The data presented today contribute to a greater understanding and appreciation of the outcomes observed after administration of OV101 on key clinical aspects of Angelman syndrome. These results, together with those reported in August 2018, will help inform our discussions with the FDA when we meet with them later this year,” Levin said.