Challenges in Bringing a Treatment Forward in Angelman Syndrome


The behavioral director at the Angelman Syndrome Clinic at Massachusetts General Hospital offered insight into the challenges in studying a drug, such as gaboxadol, in Angelman syndrome.

Dr Christopher Keary

Christopher Keary, MD, associate program director, Autism Spectrum Disorder Fellowship, and behavioral director, Angelman Syndrome Clinic, Massachusetts General Hospital

Christopher Keary, MD

This year, Ovid Therapeutics has hit 2 major milestones with its investigational agent gaboxadol in the treatment of Angelman syndrome. The therapy, also known as OV101, was found to positively impact patients in a phase 2 study, and as a result, a phase 3 assessment has begun to explore it further.1,2

The highly selective extrasynaptic GABAA receptor agonist, global improvement was observed at week 12 with a once-daily, 15-mg dose compared to placebo, as measured by the Clinical Global Impressions-Improvement (CGI-I) scale (P = .0006). With the news of the start of the phase 3 NEPTUNE trial, NeurologyLive inquired with Christopher Keary, MD, to learn more about the treatment of this rare disorder.

Keary, the associate program director of the Autism Spectrum Disorder Fellowship and behavioral director of the Angelman Syndrome Clinic at Massachusetts General Hospital, offered insight into challenges in studying a drug in Angelman, as well as what the future plans are for gaboxadol.

NeurologyLive: Are there any challenges to studying a drug in Angelman which are specific to this condition?

Christopher Keary, MD: I think so. Angelman syndrome is a neurodevelopmental disorder—a lifelong neurodevelopmental disorder—with effects on a variety of different domains of function. It affects speech. It affects general cognition and learning, and motor function. It has effects on behavior and sleep. It really affects multiple different domains. And there are not great outcome measures that capture the totality of the areas that can be affected in Angelman syndrome, so I think this has a way of creating a barrier to doing research in this field. If you don't have these really great outcome measures that are designed for these rare neurodevelopmental disorders, that can have a chilling effect on doing research. That was part of the reason as to why, in the trial design, it was thought to use the CGI-I scale—to try and capture what clinicians who care for people with Angelman syndrome do in the office. They try to get a sense of whether the patient has improved or worsened meaningfully with a treatment. That's one.

It's a challenge in general, for rarer neurodevelopmental conditions, as there's more interest in finding treatments for some of these rare neurological conditions. How do we find good outcome measures? Many outcome measures of behavior are designed for subjects that have expressive verbal abilities. It is a challenge to measure behavioral outcomes in Angelman Syndrome where most subjects are minimally verbal.

How would you describe the outlook for OV101/gaboxadol as a potential therapy?

The data from STARS suggests a couple of things that are worth noting. First of all, it suggests favorable tolerability data, which is important because this is a patient population that tends to be very sensitive to medications and have major tolerability issues with medications, and that it might even be well-tolerated in other populations of neurodevelopmental disorders like autism. That's one important finding.

Another important finding is that there was a difference in the level of global improvement in individuals who took the study drug compared to those who didn't. This is suggestive of a clinically meaningful difference between being on the drug compared to placebo in blinded evaluators. This is really promising data in the absence of any current disease-modifying treatments in AS. We're eager to expand on research with NEPTUNE, and if the data supports it, bring it forward as a potential treatment.

Is there a planned next step for the development of this drug?

The open-label extension trial I mentioned before is the only currently planned study in Angelman. The sponsor is looking at the use of gaboxadol in a phase 2 trial in Fragile X syndrome. If the tolerability and efficacy data support it, I imagine the sponsor will move forward with seeking an indication for the drug in terms of treatment of Angelman syndrome, which would make it the first disease-modifying medication treatments for Angelman.

I envision study of gaboxadol in the future might include things like looking at which aspects of Angelman syndrome are most likely to improve with gaboxadol or if any subtypes or ages are more likely to respond than others. Those are, I imagine, the directions for the future. But in terms of current planned studies, the open-label trial is the only current one.

Transcript edited for clarity.


1. Ovid Therapeutics Announces First Patient Randomized in Pivotal Phase 3 NEPTUNE Trial of OV101 for the Treatment of Angelman Syndrome [press release]. New York, NY: Ovid Therapeutics; Published September 12, 2019. Accessed December 20, 2019.

2. Bird LM, Ochoa-Lubinoff C, Tan WH, et al. STARS: Results from a Safety and Efficacy Study of OV101 (Gaboxadol) in Adults and Adolescents with Angelman Syndrome. Presented at: 2019 American Academy of Neurology Annual Meeting. May 4-10, 2019; Philadelphia, PA.

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