Setbacks can lurk around any corner in neuroscience R&D — even when the path ahead looks clear. Ovid Therapeutics recently encountered a harsh reminder of that fact.
About three years ago, Ovid sold development and commercialization rights for an experimental drug soticlestat to Takeda after scoring positive mid-stage readouts for two rare forms of epilepsy. And if phase 3 studies confirmed the results, soticlestat was poised to become a “blockbuster of major proportions” for the complex condition with scores of ineffective or side effect-laden treatments, Ovid’s CEO, Jeremy Levin, told PharmaVoice last spring.
But it wasn’t quite meant to be.
In June, Takeda announced soticlestat missed primary endpoints in late-stage trials targeting Dravet syndrome and Lennox-Gastaut syndrome. Now the drug’s future, and Ovid’s potential $660 million in milestone payments, hang in the balance as Takeda works with regulators to determine if positive outcomes on secondary endpoints for certain patients is enough to move forward.
Despite the results and the layoffs it triggered, Ovid is charging confidently ahead with new leadership at the helm. Dr. Amanda Banks came on board as the new chief development officer in August, bringing a deep background in biotech drug development and neuroscience. And earlier this month, Meg Alexander was promoted to president and chief operating officer after serving in other executive positions since 2020.
The C-suite shakeup comes as Ovid embarks on a transformation from a core focus on epilepsy to restoring “balance and homeostasis in the brain,” Alexander said.
“Under the hood of our company we have exciting programs,” Alexander said.
Pipeline hopefuls
The company’s lead asset is a novel ROCK2 inhibitor in early-stage trials for brainstem cavernous malformations. But because the ROCK2 signaling pathway “may be hyperactive in multiple neurological diseases,” the company sees broader potential.
Alexander said Ovid could also have a “potential franchise” on its hands with a preclinical KCC2 platform that could deliver multiple first-in-class compounds for epilepsy and other CNS disorders.
“Each program is allowing us to broaden into more therapeutic areas by addressing the cause of pathology of disease,” Alexander said.
“Endpoints tend to be exquisitely dependent on the patients."
Dr. Amanda Banks
Chief development officer, Ovid Therapeutics
Ovid isn’t abandoning its roots, however, and is also advancing a GABA-AT inhibitor that could deliver better efficacy and safety for rare and treatment-resistant forms of epilepsy.
Despite recent obstacles, Bank said lessons from soticlestat’s shortcomings along with bigger-picture advances in neuroscience have become “fertile ground” for an eventual win.
Lessons learned
When asked what went wrong with the phase 3 trials for soticlestat, Alexander pointed to the inherent complexities of the disease.
“Lennox-Gastaut in particular is an incredibly difficult indication to find a therapeutic for,” she said. “As we learn more about it, my strong suspicion is that we will actually not call it Lennox-Gastaut — it will likely be known as 10 to 20 different conditions.”
Trial design could have also come into play.
“Endpoints tend to be exquisitely dependent on the patients,” Banks said.
Going forward, specialized drug development and staffing expertise could help Ovid design fit-for-purpose trials targeting the appropriate patient population, Banks said.
“In neurodegenerative diseases, there are a couple of areas of variability we can control,” Banks said. “We have to work with people who have deep experience working with these conditions.”
Ovid is also banking on an increased use of biomarkers, which Banks said could minimize the variability that “plagues” the industry in neuroscience. For example, Ovid can use transcranial magnetic stimulation to measure levels of GABA in the brain while testing its GABA-AT inhibitor, OV329.
“That gives us a good sense of [whether] we see signs of that mechanism of action in the works,” Alexander said. “These are incredibly sensitive tools that don’t require taking spinal fluid from a patient or other invasive procedures … and it helps give us conviction that we have a medicine that works, which de-risks the trials.”
While the pursuit of experimental drugs may seem dicier, Alexander said it’s a lane Ovid is comfortable occupying.
“We’re doubling down on novel mechanisms,” she said, pointing out that if Ovid follows current trends in neurodegenerative drug development, it won’t be as well positioned in five to 10 years.
“One more small company going after the same target, and then you’re trying to win on the market with slightly better pharmacology or efficacy — that’s not good for patients or the company,” she said.
In the coming months, Alexander said some of the cards from its clinical programs will be “starting to turn over.”
Ovid plans to deliver new preclinical animal data on its GABA-AT program within the next few weeks along with a phase 1 readout before the year’s out. And while Ovid prepares for a phase 2 of its ROCK2 program, Banks is getting ready to file the first regulatory submission for its KCC2 platform. After that, Alexander predicts Ovid will be submitting an IND leveraging KCC2 annually for the next five years.
But Alexander admitted that “none of this is going to work” if Ovid goes it alone.
“We are focused on the right partnerships to bring it all forward,” she said. “This is the only company I know that has these programs and mechanisms, so it’s very exciting, and hopefully we’ll make a tremendous impact for patient communities.”
