Gaboxadol Moves Into Phase 3 in Angelman Syndrome


The behavioral director at the Angelman Syndrome Clinic at Massachusetts General Hospital discussed the phase 3 NEPTUNE trial of gaboxadol, also known as OV101.

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

Earlier this year, Ovid Therapeutics announced the initiation of a phase 3 pivotal trial of OV101, also known as gaboxadol, in the treatment of Angelman syndrome, a rare disease with no available treatments.1

Dubbed NEPTUNE, the phase 3 assessment is expected to read out topline data in mid-2020. The randomized, double-blind, placebo-controlled, clinical trial is designed to assess the effects of treatment with OV101 in oral, once-daily dosing versus placebo over 12 weeks. In phase 2, the therapy displayed overall improvement in patients, a feat yet achieved in the last 50 years.2

To find out more about this trial and the treatment, NeurologyLive spoke with Christopher Keary, MD, associate program director, Autism Spectrum Disorder Fellowship, and behavioral director, Angelman Syndrome Clinic, Massachusetts General Hospital.

NeurologyLive: What is the goal of the trial and what are you hoping to see?

Christopher Keary, MD: NEPTUNE, the current study, is a double-blind, placebo-controlled, multisite 12-week trial of OV101 or gaboxadol—you can use those terms interchangeably—in children with Angelman syndrome between the ages of 2 and 12 years old. So, the main goals of the trial are to look at the safety and tolerability of gaboxadol in ages 2 to 12 years old and to look at the efficacy gaboxadol as a treatment, as the potentially the first disease-modifying treatment, for Angelman syndrome.

We're hoping to see is that the trial is well-conducted. We're hoping to see that the drug is safe in patient populations with Angelman down to 2 years of age, and whether the efficacy data supports gaboxadol as the first potential disease-modifying drug treatment for Angelman syndrome.

The outcome measures to be looked at in this trial to support whether or not it's effective for Angelman, include measure of global improvement, called the Clinical Global Impressions-Improvement (CGI-I) scale, as well as the Vineland, a measure of sleep actigraphy, as well as some measures of quality of life and sleep habit questionnaires.

How will this build on existing data on OV101/gaboxadol?

Just to take a quick minute to review the data even before the previous trial, STARS, just to mention the animal data. Gaboxadol is a novel selective extrasynaptic GABAA receptor agonist. Its unique mechanism of action has been found to restore tonic inhibition in neurons in a mouse model of Angelman syndrome. Reduced tonic inhibition is proposed to be present in Angelman syndrome and contribute to the development of the disorder. That’s the animal model data and the data presented at AAN 2019 is the STARS data, which was a double-blind, placebo-controlled trial of 78 adults with Angelman syndrome. Data from that trial found good tolerability with the majority of adverse events (AEs) being mild. There were also significant differences in measures of global improvement between those taking gaboxadol once a day and those not taking any study drug—those taking placebo—as well as differences in sleep initiation and trend level improvements in gross motor function, as well as some parental reports of improvement in behavior. This data built the case to pursue further investigation of gaboxadol in Angelman syndrome.

Due to the absence of any current disease-modifying treatments for Angelman syndrome, the findings of STARS suggesting there was a difference in global improvement is a promising finding. This highlighted the importance of moving forward with a similar trial looking at safety and tolerability in children with Angelman.

Are there any particular aspects of this trial of note, whether a specific planned analysis or subgroup assessment?

Some special aspects of the trial are that we're going to be looking at are the pharmacokinetic (PK) properties of gaboxadol in children with Angelman. We'll be doing PK testing in subjects who take the study drug down to the ages of 2 years old. We have adult PK data for the study drug, in both adults with Angelman syndrome and neurotypical adults, but we don't have, you know, the same level of PK data in kids. So that's going to be a part of the trial.

PK data and safety data will first be analyzed in ages from 9 to 12, before moving on to recruitment for subjects between 4 and 8, and then before moving on to recruitment of subjects 2 to 3 to ensure safety and tolerability before we move on. The decision was made to use actigraphy to measure indexes of sleep, it being sort of the best way that we could do it rather than just using parental reports for sleep findings, to try and get the best data that we possibly could.

Have any adjustments been required since the original design was laid out?

Things have gone according to plan so far. The only major adjustments that we've made is that our subjects who participated in the adult trial, STARS, were eligible to then participate in a study called ELARA, which is an open-label trial, where subjects may maintain on the study drug for a period of years afterward. An amendment will allow subjects who participated and completed NEPTUNE to enroll into the open-label trial, ELARA.

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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