Michael Cecere’s child, Weston, is five years old. He struggles with daily living. He cannot speak, usually move by stroller or wheelchair, and only just learned to drink from a straw. The reason: a genetic deletion on his 15th chromosome, causing a condition called Angelman Syndrome, discovered after his mother noticed that he was missing developmental milestones. Cecere has bought a bi-ski and an adaptive bicycle so he can take his son on outings with his other two children. “We’re trying to keep everything as typical and enjoyable as we can,” Cecere says.
This morning, Ovid Therapeutics, a small biotechnology company, is announcing data indicating that a drug, gaboxadol, may be of some help for patients like Weston as they grow to adulthood. Even in the wildest imaginings of the company and patients, gaboxadol, also known as OV101, will not be a cure, and the data so far leave several open questions that will have to be answered by further analysis. But it may help to ease the anxiety and sleep disturbances that patients suffer throughout their lives — although exactly what symptoms are helped is not clear from the data released this morning. The results will be presented by Ovid’s founder and president, Matthew During, at a scientific meeting dedicated to Angelman Syndrome that is being held in Chapel Hill, North Carolina today and tomorrow. The disorder occurs in one out of every 15,000 births.
“It’s pretty exciting,” says Jeremy Levin, Ovid’s chairman and chief executive officer. “We need to go and discuss with the [Food and Drug Administration] these results, which are striking.” Levin also said Ovid will explore making gaboxadol, also known as available to patients before approval, a policy known as expanded access.
The study randomized 88 patients with Angelman into three groups. One received placebo, a second gaboxadol once a day, and a third gaboxadol twice a day. In the once-a-day group, patients scored significantly better on the clinical global impressions of improvement (CGI-I), a scale physicians use to rate how well patients are doing. The main goal was safety, and the drug was similar to placebo.
The once-a-day group did better, scoring 3.00 on the CGI-I at 12 weeks, compared to 3.79 for placebo (lower is better). The result was highly statistically significant, with a p-value of 0.0006. (Anything lower than 0.05 is considered significant, meaning a result is not likely to have happened by chance). But with the twice-a-day group, patients scored 3.58 on the CGI-I, which was not significantly better than placebo. Levin says this was expected, because in animal models using a higher dose also resulted in less efficacy. At six weeks, the differences were not statistically significant in either group.
Ovid measured sixteen more measures of how patients were doing. In order to avoid reporting chance results, the original statistical analysis was stopped as soon as one of these failed. This is the right thing to do, but because the first of these measures failed, other measures that could shed light on whether or how gaboxadol is helping these patients will not be available until later.
“The data is convincing to me that it’s effective, the question is how is it effective compared to what’s out there,” says Ron Thibert, Director of the Angelman Clinic at Massachusetts General Hospital and head of the committee organizing Ovid’s Angelman trials. Says Levin: “Our goal is to find something significantly better.”
Gaboxadol is a more focused inhibitor of brain receptors called GABA, the same receptors hit by anti-anxiety drugs like Valium and Klonipin, known as benzodiazepenes. Angelman patients suffer from severe anxiety as they grow older, as well as seizures. Would patients have done just as well on the older drugs?
Levin points out that most patients were already on benzodiazepenes. Eighteen, or 62%, were taking the drugs in the placebo and twice-a-day groups; 21, or 72%, were taking benzodiazepenes in the once-a-day group. (That leads to another question: is it worrisome that more patients got benzodiazepenes in the dose that seems to have proved effective than in the placebo group? Ovid says no. All patients were on stable medication, so they were on these medications before the trial started. Also, the imbalance in benzodiazepenes was not statistically significant.)
Gaboxadol was originally invented in 1977, and Lundbeck and Merck tested it in various neurological disorders without success before licensing it to Ovid. Additional data from this study will clarify whether this experimental medicine has finally found a use and whether another study will be needed before Ovid asks regulators to approve this drug. Expecting approval on these data seems optimistic.
Levin would not comment on what the drug would cost if it reaches the market. But he notes that many patients have probably been misdiagnosed with cerebral palsy or other disorders, and the existence of an effective treatment could change that.
“It is our goal to get every single patient treated,” Levin says. “Every single one. We have a great opportunity with a great medicine and the patient population is one that is substantial and we look at this as an opportunity to get the medicine.”
This story has been updated with additional comment from Ovid Therapeutics and some additional detail.
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