Experimental Agent Offers First Hope for Rare Genetic Disorder

Caroline Cassels

May 13, 2019

PHILADELPHIA — An experimental agent offers the first glimmer of hope for improving the lives of patients with Angelman syndrome (AS), a rare genetic disorder for which there are no approved therapies and that carries a high, unmet medical need.

In the first industry-sponsored AS drug trial, the randomized, placebo-controlled study showed that OV101 (Gaboxadol, Ovid Therapeutics) was safe and helped alleviate many common symptoms of the disease in adolescents and adults.

Dr Alexander Kolevzon

"We found this was a safe and well-tolerated drug with no differences across [study] groups in terms of the tolerability of the medicine," study investigator Alexander Kolevzon, MD, Seaver Autism Center for Research and Treatment, Department of Psychiatry, Icahn School of Medicine, New York City, told reporters attending a press briefing here at the American Academy of Neurology (AAN) 2019 Annual Meeting.

He added that beyond safety and tolerability, the investigators also examined a number of "exploratory outcomes." They found that the drug was effective in improving several key domains that characterize the disease, including behavioral and emotional problems, impaired motor function, dysregulated sleep, and "even perhaps communication behaviors," as measured by the Clinical Global Impressions–Improvement (CGI-I) scale.

"Happy Puppet Syndrome"

The estimated prevalence of AS is 1 in every 12,000 to 20,000 live births. It is a complex neurologic condition characterized by seizures, severe intellectual impairment, and motor and gait impairment. Despite these challenges, many AS patients live a typical life span.

The disorder is caused by impaired expression of the ubiquitin protein ligase E3A gene (UBE3A) in the brain, which causes aberrant increases in γ-amniobutric acid (GABA) uptake, resulting in reduced extrasynaptic GABA.

Reduced extrasynaptic GABAergic neurotransmission results in decreased tonic inhibition. On the basis of data from animal studies of AS, it is presumed that this is the underlying neuropathology.

In addition to intellectual disability and motor and gait impairment, AS patients, said Kolevzon, suffer from hyperexcitability, which is often described as "happy puppet syndrome."

AS has been recognized for almost 50 years, said Kolevzon, yet there are no disease-modifying treatments for these patients. To date, management has been aimed at symptom control with antiepileptic medications for seizures, benzodiazepines to treat disordered sleep, and mood disorder medications to manage behavior.

For the study, the researchers took what Kolevzon described as a "genetics first" approach.

"Having identified the gene, there is some understanding of what the underlying biology is, and it seems to relate to deficits in tonic inhibition — so it is a GABAergic-driven disease state. GABA is the primary inhibitory neurotransmitter of the brain and sits in balance with the primary excitatory nerve neurotransmitter, which is glutamate — so what we think this compound is doing is actually reversing the deficits in tonic inhibition and restoring that state to these kids," he said.

Dose: Less Is More

OV101 is an extrasynaptic δ-selective GABAA receptor agonist. Animal studies suggest that the drug has the potential to normalize tonic inhibition that is decreased in AS.

To test the agent's safety and tolerability, investigators conducted a multicenter, 12-week, phase 2, randomized, double-blinded, placebo-controlled trial, known as the STARS study. Adult and adolescent AS patients aged 13 to 49 years were randomly assigned to receive OV101 once daily (n = 29), twice daily (n = 29), or placebo (n = 29).

Patients in the placebo group received placebo morning and night. Those in the once-daily group received a placebo pill in the morning and a 15-mg dose of the active drug at night. Participants in the twice-daily group received 10 mg of the active drug in the morning and 15 mg at night.

The study's primary endpoint was safety and tolerability, as assessed on the basis of the frequency and severity of adverse events (AEs) and serious adverse events (SAEs).

Results showed that side effects did not differ between study groups and were for the most part "nuisance" adverse events that were not serious, said Kolevzon. There were two SAEs that were seizure-related — one in the once-daily medication group that was deemed unrelated to the study medication, and one in the twice-daily group that was deemed possibly related to OV101.

Exploratory endpoints included efficacy, as measured by changes in sleep, motor, behavioral, and quality-of-life outcomes, and overall clinical scores on the CGI-I scale.

Results showed that at week 12, there was global improvement, as measured by the CGI-I. The improvement was associated with once-daily dosing with OV101 compared to placebo (P = .0006).

Kolevzon noted that the once-daily dose of OV101 appeared to be significantly more effective than the twice-daily dose compared to placebo. He said the reason for this is unclear, but he speculated that some tolerance may develop with the twice-daily dose.

Testing Earlier Intervention

Kolevzon addressed concerns about the use of the CGI-I as a clinical endpoint because of its subjective nature. These results from the phase 2 trial, he said, will help investigators hone the CGI-I in specific AS domains as they design a phase 3 study.

At this point, he added, there is no outcome measure specific to AS, "so we are anchoring our [CGI-I] in specific domains that we've seen improve, in the context of a phase 3 trial."

Dr Cesar Ochoa-Lubinoff

Study coinvestigator Cesar Ochoa-Lubinoff, MD, MPH, developmental behavioral pediatrics, Rush University Medical Center, Chicago, Illinois, told Medscape Medical News that an open-label study of 40 patients from the phase 2 STARS study is currently underway.

He also said the phase 3 study will include younger patients, which will allow them to examine whether earlier intervention with OV101 has a larger impact.

"The phase 3 trial will include children 4 to 12 years of age, and we expect we will see an even bigger effect size in these younger patients. This is a long-term condition, and these are very impaired individuals who require a lot of support. This drug may be able to alleviate a lot of their challenges and perhaps ease some of this burden," said Ochoa-Lubinoff.

First Hope

Commenting on the findings for Medscape Medical News, Natalia Rost, MD, MPH, scientific chair of the AAN Scientific Program Committee, said the study offers the first hope for a patient population that up until now has had no prospect of a disease-modifying treatment.

Dr Natalia Rost

Clinicians, she said, have been largely powerless to help these patients, and although OV101 is not curative, it is disease-modifying. By understanding the genetics of AS, the investigators "appear to have been able to affect the biology of the disease pathway."

Rost, who is director of the Acute Stroke Service at Massachusetts General Hospital and professor of neurology at Harvard Medical School, Boston, added that she is looking forward to the results of the phase 3 trial and the long-term outcomes data.

"I have hope," she said.

The study was supported by Ovid Therapeutics. Relevant financial relationships of the study investigators are listed in the study abstract.

American Academy of Neurology (AAN) 2019 Annual Meeting: Abstract P6-074. Presented May 7, 2019.

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