Ovid to Focus on OV882, Potential RNA Therapy for Angelman

Ovid Therapeutics is stopping its clinical program for OV101 (gaboxadol), a candidate therapy for both Angelman and fragile X syndrome, in favor of focusing its resources on OV882, a potential RNA therapy for Angelman patients, it announced in a corporate update.

The decision to discontinue OV101 follows data from several clinical trials, including the Phase 3 NEPTUNE study (NCT04106557) in children with Angelman syndrome.

Despite being well-tolerated with no significant safety issues, efficacy outcomes seen with OV101 “do not support its further development in these conditions,” the update stated.

“While we are disappointed … our resources are now squarely focused on a very promising pipeline in rare neurological diseases, including Angelman syndrome,” said Jeremy M. Levin, chairman and CEO of Ovid Therapeutics.

“Ovid would like to thank everyone who participated in our OV101 clinical trials, including those with Angelman syndrome and Fragile X syndrome, families and investigators, to whom we remain committed to finding solutions,” he added.

OV101 intended to trigger the activation of specific receptors on the surface of nerve cells that bind the signaling molecule, or neurotransmitter, GABA (gamma-aminobutyric acid). This mode of action enhances tonic inhibition — a mechanism that decreases excessive nerve cell activity in the brain. As such, OV101 was expected to ease the symptoms of Angelman and fragile X.

The NEPTUNE study enrolled 97 Angelman children and adolescents, ages 4-12, who were given oral OV101 or a placebo once daily for 12 weeks. Children ages 2-3 were included for safety assessments.

The trial’s main goal was changes in participants’ overall scores on the Clinical Global Impression Improvement Angelman syndrome (CGI-I-AS) scale, a seven-point scale that assesses a patient’s condition across five key areas, specifically communication, fine and gross motor skills, behavior, and sleep.

Top-line results showed that OV101 did not meet its primary goal, with patients given OV101 showing a 0.7 point improvement compared with 0.8 points in those given a placebo.

Angelman syndrome, a genetic disorder, is caused by a loss-of-function mutation or deletion of the maternal UBE3A gene, which provides instructions for making a protein that is involved in nerve cell communication.

OV882 is a short hairpin RNA (shRNA) designed to target the cause of Angelman syndrome. It binds to and limits the levels of UBE3A-antisense, the molecule that causes Angelman by lying opposite of the UBE3A gene and stopping it from working properly. By restricting UBE3A-antisense expression, researchers hope to restore UBE3A gene function in patients.

Of note, shRNA refers to a lab-made strand of RNA — the intermediate molecular template between information contained within DNA and protein production.

Ovid has joined with researchers at the University of Connecticut (UConn) to advance an shRNA-based therapy for Angelman.

The research and clinical development of OV882 and other candidate therapies in Ovid’s pipeline will be supported by royalties from a recent agreement with Takeda Pharmaceuticals, it announced.

Takeda acquired the global rights to develop and commercialize the investigational oral therapy Soticlestat (OV935/TAK-935) for people with  developmental and epileptic encephalopathies (DEEs), including Dravet syndrome, Lennox-Gastaut syndrome, CDKL5 deficiency disorder, and Dup15q syndrome.

Under the agreement, Ovid is eligible to receive an upfront payment of $196 million, as well as up to $660 million in development, regulatory and sales milestones. If Soticlestat is approved, Ovid will be also eligible to collect up to 20% on its sales.