NATIONAL HARBOR, Maryland—New York City-based Ovid Therapeutics, led by one of the world’s most respected biotech executives, had originally set its sights on Angelman syndrome—a rare genetic disease that causes severe physical and learning disabilities and has no approved treatments.

But after gaboxadol, Ovid’s investigational therapy for the disease, failed to meet its primary endpoint in a phase 3 trial in 2020, the company gave up on Angelman and refocused its attention on 2 extremely rare developmental epileptic encephalopathies: Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).

To that end, Ovid and Takeda Pharmaceuticals have codeveloped soticlestat (TAK-935/OV935), a twice-a-day pill that “has the potential to reduce seizure susceptibility and improve seizure control” in both types of epilepsies, said Jason Tardio, Ovid’s chief operating officer.

“I’ve always had a passion for rare disease,” Tardio said during an interview at the 2023 World Orphan Drug Congress (WODC) here. “I believe that attacking these disorders, many of which have no available treatments, is at the cornerstone of what the pharmaceutical industry is about.”

DS, which affects about 1 in 20,000 individuals worldwide, is named after French neurologist Charlotte Dravet, who first referred to the disease in 1978 as severe myoclonic epilepsy of infancy. Usually caused by mutations in the SCN1A gene, the disease is noted for prolonged focal seizures that can evolve into convulsive tonic‑clonic seizures.

Jason Tardio, chief operating officer of Ovid Therapeutics, speaks during the 2023 World Orphan Drug Congress. (Photo by Larry Luxner)

Developmental disabilities worsen in children with DS as their seizures increase, with 90% of patients unable to control symptoms with their current antiepileptic medicines. These patients also have difficulty walking. Some 20% of people with the disease die before adulthood.

LGS is slightly more common, occurring in about 1 in 11,000 people globally. A heterogeneous syndrome characterized mainly by atonic or drop seizures, this disease causes cognitive dysfunction as well as behavioral problems. A recent study of over 1300 caregivers of patients with LGS showed that 50% of their loved ones suffer at least 20 seizures a month, despite the availability of several therapies, Tardio said.

A Growing Number of Treatment Options

Fenfluramine (Fintepla®), which targets the serotonergic system, was approved by the US Food and Drug Administration (FDA) in 2020 to treat seizures associated with DS; in 2022, LGS was added as an indication. However, the use of fenfluramine requires periodic monitoring via echocardiogram due to the risk of valvular heart disease and pulmonary arterial hypertension.

The FDA has granted Orphan Drug designation for DS to 3 modulators of serotonin signaling: clemizole (EPX-100); lorcaserin, EPX-200 (Belviq®); and trazodone (EPX-300). Clemizole also has received the designation for LGS.

Other common antiseizure medications used in both diseases are cannabidiol (Epidiolex®), clobazam (Onfi®), stiripentol (Diacomit®), topiramate (Topamax®), and valproate (Depakote®).

Soticlestat is a selective inhibitor of cholesterol 24-hydroxylase (CH24H), an enzyme in the brain. According to Tardio, 2 recent phase 2 trials showed it slashed neuronal levels of 24S-hydroxycholesterol (24HC), which, in turn, reduces glutamatergic signaling and inflammation in the brain. Specifically, he said, the phase 2 ELEKTRA trial of soticlestat “demonstrated a statistically significant reduction of seizures from baseline compared to placebo” in the combined DS and LGS study population.

In March 2021, Ovid relinquished its rights to soticlestat to Takeda but “maintains a significant financial interest in soticlestat, including potential milestones payments and royalties, if soticlestat receives regulatory approval and is commercialized,” Tardio said.

Meanwhile, Takeda is currently overseeing a pair of pivotal, randomized phase 3 studies for both DS and LGS.

The first, known as SKYWAY, is a double-blind, placebo-controlled trial to evaluate its efficacy and safety as an adjunctive therapy in children and adults with LGS aged 2 through 55 years. The trial, which hopes to enroll 234 patients, is taking place at sites throughout the United States, Europe, and Asia.

The second, SKYLINE, is a multinational, randomized, double-blind, placebo-controlled study to evaluate the effects of soticlestat as adjunctive therapy in patients with DS aged 2 to 21 years. Results are expected sometime in 2024, Tardio said.

A New Focus on Rarer Epilepsies

Asked why Ovid decided to pursue therapies for these 2 very rare disorders, Tardio said it’s a reflection of a “shift in the epilepsy community” that has taken place in recent years.

“Previously, the focus was to go broad in large epilepsies such as focal, such as primary generalized tonic‑clonic, broad generalized epilepsies that affect countless number of patients,” he told Rare Disease Advisor.

“But these studies are long and expensive. They require thousands and thousands of patients to drive a powering and statistical significance. What you see more recently are companies focused more on rare epilepsies. By doing so, you can really provide an unmet need to communities that have been underserved, I believe, for many, many years.”

Tardio’s boss is Jeremy Levin, DPhil, MB BChir, chairman and CEO of Ovid. Before joining Ovid in 2015, he was president and CEO of Israel’s Teva Pharmaceutical Industries, the world’s largest generic drugmaker. And before that, the South African-born entrepreneur was on the executive committee of Bristol Myers-Squibb, where he had global responsibility for strategy, alliances, and transactions.

Jeremy Levin is CEO of Ovid Therapeutics. (Photo by Larry Luxner)

Among other honors, Dr. Levin is the immediate past chairman of the 1700-member Biotechnology Innovation Organization. Fierce Biotech named him among the 25 most influential biotech leaders, and in 2021, Endpoints selected him as one of the 60 living pioneers of the industry. He’s also the winner of the Albert Einstein Award for Leadership in Life Sciences.

Dr. Levin said the mechanism of soticlestat can also be useful in treating CDKL5, a rare epileptic encephalopathy which affects fewer than 50,000 Americans and causes seizures, developmental delay, and severe intellectual disability.

“This mechanism has potentially many other areas it could go into,” he said in an email. “Importantly, the tolerability of this drug during the many years that hundreds of people have been on it in open-label extension has demonstrated very favorable characteristics.”

Tardio previously worked at Novartis, where he headed that company’s neuroscience and multiple sclerosis business. Speaking at a WODC panel, he said Ovid employs fewer than 50 people and is uniquely positioned to come up with treatments for both DS and LGS.

“Large companies take a different approach to drug development than smaller ones do,” Tardio said. “They ask, for example, ‘does it align with our current portfolio of products?’ We start with the question of where’s the unmet need, where’s the science to meet that need, and how can we explore therapeutics when there’s nothing else currently available.”