Journey of a rare disease drug: Ovid’s OV101 for Angelman syndrome

Jeremy Levin - Credit: Kelly Boothe, agent of Ovid Therapeutics - Own work - CC BY-SA 4.0
Ovid will start the phase 3 study of its Angelman drug, OV101, in the third quarter and expects topline data in mid-2020. (Kelly Boothe, agent of Ovid Therapeutics - Own work - CC BY-SA 4.0)

Companies working to treat rare diseases don't have a roadmap to approval. They can’t rely on a well-trod path of validated endpoints and tried-and-true study designs and instead have to figure it all out for the first time. That's what Ovid Therapeutics is trying to do with the rare genetic disorder Angelman syndrome. 

As expected, there have been hiccups along the way. Last August, the New York-based biotech announced topline data from a phase 2 study of OV101, its Angelman program. The data came from 88 patients after 12 weeks of treatment and showed that OV101 beat placebo on one measure but failed to do so on 16 other metrics. Ovid’s stock price dipped more than 30% that day and has trended downward ever since. 

Ovid CEO Jeremy Levin, D.Phil, MB BChir., puts it down to misunderstanding. The endpoint that OV101 did meet, the clinical global impressions of movement, or CGI-I, is a way to measure general improvement but is not a well-known metric in drug development. That was coupled with a rare disorder that investors and analysts weren’t as familiar with as, say, immuno-oncology.

“We were very disappointed by the investor reaction, but I think, in large measure, it was unfair at that stage of our company’s life to have expected them to really, fully understand,” he told FierceBiotech. 

RELATED: Ovid posts results from midstage rare disease test, plots registrational path

While Wall Street saw 16 missed endpoints, Ovid saw a trove of learnings. Children with Angelman syndrome may have any number and combination of neurological symptoms that vary in severity. These may include seizures, trouble sleeping, problems with movement and balance, the inability or limited ability to speak, and ataxia, or the inability to coordinate voluntary movements. Ovid had to figure out how to show its drug could improve the lives of patients who experienced the same disease in different ways. 

“We had discovered the chemical, the safety database and the pharmacology. We had everything we needed to start the trial except for the right endpoints,” Levin said. “So we went out and met with patients and families and met with thought leaders. We compared to other trials and assessed over 200 different tools to measure symptoms.” 

The company divided those symptoms into four main buckets: general improvement, sleep, movement and behavior. It narrowed more than 200 tools down to just 17. And the study taught Ovid which of the 17 tools were best for measuring symptoms in kids with Angelman syndrome. 

For example, Ovid learned that using a sleep diary—which is usually self-reported—did not work with Angelman patients. Actigraphy, which uses a medical device to record movement or activity, proved a better way to track sleep. 

RELATED: New data back Ovid’s Angelman drug, say analysts

“The phase 2 was highly informative in telling us what we needed to measure, what physicians wanted and what the FDA would require for a sole endpoint,” Levin said. 

Ovid announced Thursday that the FDA has signed off on CGI-I as the sole primary endpoint for the phase 3 study of OV101, which is slated to start in the third quarter. CGI-I is a seven-point scale that allows doctors to rate whether a patient’s symptoms have improved or worsened compared to baseline. Ovid has tweaked it, renaming it CGI-I-AS, having refined the anchors for scoring and clinician training materials to be more specific to Angelman syndrome. 

“I think it reflects the FDA’s desire to help companies think through how best to measure diseases where there’s never been a measure of success. … The FDA wants to respond to patient need, but needs to do so in a very rigorous fashion,” Levin said. “There was a clear agreement to CGI-I as the sole endpoint and a lot of investors didn’t anticipate this would be the case.” 

Ovid expects to report topline data from the phase 3 Neptune study in mid-2020. 

Despite having “enormous scientific and clinical validity,” the first phase 2 readout for OV101 was “very complex for the investor base to understand,” Levin said. But Ovid followed up in October with more data, leading to the study being featured at the annual meeting of the American Academy of Neurology last month. The hope is, investors have caught on to how a rare disease drug is made. 

“The breadcrumbs have now been laid in the sand. We will now lay out the design for Neptune, which highlights the fact that the FDA agreed on the sole endpoint, which is the same endpoint scale we used in phase 2," Levin said. " ... Hopefully, they understand it better.”