Ovid Shifts Focus After Angelman Syndrome Drug Disappoints In Phase III
Company Pauses OV101 Program Based On NEPTUNE Results
Executive Summary
The Phase III clinical trial showed a noticeable placebo effect compared with OV101.
Ovid Therapeutics, Inc. is hitting the pause button on its program to develop OV101 (gaboxadol) for Angelman syndrome following the failure of the Phase III NEPTUNE trial. The company plans a full analysis of trial data and further discussions with the US Food and Drug Administration.
OV101 was Ovid's lead asset, but now the company will turn its attention to OV935 (soticlestat) in Dravet syndrome and Lennox-Gastaut syndrome. Developing the first drug to treat AS, a rare neuro-genetic disorder, was a tall order. Now, there could be an opportunity for another company that has ventured into the space to advance a treatment for AS, potentially using an endpoint pioneered by Ovid for its study.
“By pioneering the endpoint, we’ve also reached a moment in opening up how you actually test new medicines on brain disorders that could never before be assessed,” Ovid CEO Jeremy Levin said in an interview ahead of the data release. “If you think about it that way, it’s not just a commercial event for Ovid or for Angelman syndrome, it’s a field event for all of neurodevelopment."
Ovid announced the top-line results of NEPTUNE on 1 December, showing the study did not meet its primary endpoint of change in overall score on the Clinical Global Impression-Improvement-Angelman syndrome (CGI-I-AS) scale. Among patients who received gaboxadol, there was a 0.7-point improvement on the scale, while those in the placebo arm showed a 0.8-point improvement. Although secondary endpoints are being evaluated, they are initially showing no difference between the two arms, the company said. No significant safety issues were observed, and the drug was described as well-tolerated.
The company will continue offering OV101 to AS patients in the Phase II open-label ELARA study, data from which it expects to report in the first quarter of 2021.
Shares of Ovid opened 2 December at $3.01, down 54.7% from their 1 December closing price.
NEPTUNE Results Negative
Cantor Fitzgerald analyst Charles Duncan, in a 2 December note, said that despite the limited data provided, the large placebo effect seen in the study is a “conundrum” because it does not correlate with the natural history of AS. He further pointed to NEPTUNE’s short duration of 12 weeks as perhaps being insufficient for any clinical benefit in the treatment arm to separate from the placebo arm. In addition, he noted that NEPTUNE enrolled patients aged 4-12, compared with the Phase II STARS study, which enrolled patients aged 13-49 and speculated that it may have been a confounding factor in terms of the prior data’s predictive value.
Although the company has paused gaboxadol’s development for AS – apart from continuing to allow patients into the ELARA study – it remains in Phase II development for Fragile X syndrome, a genetic disorder that causes intellectual disability. Angelini Labopharm LLC obtained rights to the drug in AS for the EU, UK and Russia, along with options rights for Fragile X syndrome, earlier this year. (Also see "Ovid De-Risks Its Phase III Angelman Program With EU Angelini Partnership" - Scrip, 13 Jul, 2020.)
“NEPTUNE is our first study focused on the pediatric and adolescent population in Angelman syndrome, and we will fully assess all the data from this trial to understand this outcome and determine next steps, if any, for OV101 in this and other conditions, including Fragile X syndrome,” Ovid president Amit Rakhit said.
Other Drugs Nip At OV101’s Heels
Notably, NEPTUNE was the only study to use CGI-I-AS as its sole primary endpoint.
“It’s never been used as the sole primary endpoint of any trial, and we were given the right to use it by the FDA because of the rigor in which we had established the objectivity of it,” Levin told Scrip.
While CGI-based endpoints have been used in a number of trials in patients with mental disorders, this marked the first time such an endpoint had been specifically defined for AS, the CEO said.
Among other drugs in development for AS, at least one – GeneTx Biotherapeutics LLC and Ultragenyx Pharmaceutical Inc.'s GTX-102 – also has CGI-I-AS as an exploratory secondary endpoint in its Phase I/II trial. The study was launched in February 2020, five months after Ovid initiated NEPTUNE, according to ClinicalTrials.gov.
On 26 October, the companies announced positive interim data from their Phase I/II study of the drug in patients aged 4-17. (Also see "Pipeline Watch: Phase III Starts In Huntington's Disease, COVID-19, Head And Neck Cancer" - Scrip, 3 Nov, 2020.) In five of the patients, there was a two- to three-point improvement in the overall CGI-I-AS score, while patients either did not improve or experienced improvements between one and three points in the scale’s sleep, behavior, communication, gross motor and fine motor domains. On the other hand, four patients experienced Grade 1-2 lower extremity weakness – considered a serious adverse event – that was regarded as significant but reversible.
Another drug in development for AS by Roche Holding AG, RO7248824, was in Phase I as of August, according to ClinicalTrials.gov, though it does not list CGI-I-AS among its endpoints.
Attention Shifts To Epilepsy Asset
Ovid’s other late-stage drug candidate is soticlestat, and it is turning its attention to that asset and its development for severe forms of epilepsy, for which it is partnered with Takeda Pharmaceutical Co. Ltd.. The company plans to start registration-directed trials of the drug in the first half of 2021. Based on Phase II data, the companies said 25 August that they would pursue soticlestat in a Phase III trial in Dravet syndrome, but a lack of statistical significance prompted further analysis on Lennox-Gastaut syndrome. (Also see "Takeda/Ovid Plan Phase III For Soticlestat In Dravet Syndrome, But Pull Back On LGS" - Scrip, 25 Aug, 2020.)
Analysts have likewise shifted their focus in light of the gaboxadol results, with Ladenburg Thalmann’s Higgins calling it the “sole value driver” for the company. Cantor Fitzgerald’s Duncan pointed to “provocative” Phase II data not only for Dravet and Lennox-Gastaut syndromes, but also for Dup15q syndrome and CDKL5 deficiency disorder, two other rare forms of epilepsy.
Data from the Phase II ARCADE and ENDYMION studies announced on 30 September showed that 12 patients with CDKL5 deficiency disorder experienced a 24% reduction in median motor seizure frequency in ARCADE and a 50% reduction in ENDYMION, a long-term extension study. For Dup15q syndrome, there were median increases in median motor seizure frequencies among eight patients during the 20-week study and 12-week maintenance periods. However, ENDYMION showed a 74% reduction.