Takeda Takes Back Dravet, Lennox-Gastaut Candidate From Ovid
Executive Summary
Revising the two companies’ 2017 epilepsy collaboration, Takeda will take over Phase III development and commercialization of soticlestat. Ovid gets $196m up front, and it can shift focus.
Takeda Pharmaceutical Co. Ltd. and Ovid Therapeutics, Inc. said they are revising their 2017 partnership to address severe pediatric epilepsies on 3 March, with a new agreement that gives the Japanese pharma full development and commercial rights to Phase III-ready soticlestat, while Ovid avoids significant R&D spending commitments and monetizes its share of the drug candidate. Takeda plans to launch Phase III trials of soticlestat in Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS) during the second quarter of 2021.
On a same-day call, Ovid chairman and CEO Jeremy Levin said his company was obligated to make a $50m milestone payment to Takeda upon initiation of a Phase III pivotal study of soticlestat, a first- and only-in-class inhibitor of cholesterol 24-hydroxylase (CH24H). In total, the New York-based firm could have owed its partner $85m in milestones and been responsible for 50% of the development and commercialization costs for soticlestat.
Now, Ovid will instead get $196 up front from Takeda for surrendering rights to the candidate, with potential for an $85m milestone payment upon approval of soticlestat in any indication. In total, Ovid could realize up to $660m in milestones under the revised pact as well as worldwide sales royalties as high as 20% in some geographies, Levin said. The deal was reworked both with a goal to accelerate development of soticlestat in Takeda’s hands and relieve Ovid of its financial responsibilities under the 2017 agreement, the exec added, estimating $250m in savings to his company.
Levin predicted that with Takeda solely developing and commercializing soticlestat, the drug eventually could bring in multi-billion dollar revenues annually. “This provides meaningful long-term cash flow and value,” he said.
Takeda Plans Phase III Studies In Both Indications
Last August, the two companies revealed that soticlestat had met its primary endpoint in the Phase II ELEKTRA study, by reducing the number of seizures in patients with rare development and epileptic encephalopathies (DEEs) compared to placebo. (Also see "Takeda/Ovid Plan Phase III For Soticlestat In Dravet Syndrome, But Pull Back On LGS" - Scrip, 25 Aug, 2020.) However, when breaking down the trial data into DS and LGS patient groups, the companies found that soticlestat met statistical significance for reducing seizures in the DS patients while only showing a positive trend in LGS patients. At the time, the firms said they would advance soticlestat into Phase III in DS, but further analyze the results in LGS.
In an interview, Takeda’s neuroscience therapeutic area unit head Sarah Sheikh noted that the trial had not been powered to demonstrate efficacy on the primary endpoint in LGS patients. ELEKTRA had grouped patients from two developmental and epileptic encephalopathies (LGS and DS) primarily for operational efficiency purposes given that DS and LGS patients often receive treatment at the same facilities, many of which served as trial sites, she explained. [Editor's note: This article has been corrected; the grouping of LGS and DS patients in ELEKTRA was not done to help more stringently define drop seizures.]
For both diseases, the treatment challenge is that many patients still suffer refractory seizures despite being on one or more medications for their illness, Sheikh said. But DS differs as a homogeneous disorder caused by a mutation of the SCN1A gene, while heterogeneous LGS can have multiple root causes. In addition, DS patients mainly suffer convulsive seizures while LGS patients suffer harder-to-categorize drop seizures as well as other types, the exec noted.
“Both of these syndromes share a commonality and that is that seizures are highly refractory to treatment with anti-epileptic drugs, meaning that patients, young children, have seizures despite being on multiple different therapies,” Sheikh said. “That can lead to additive side effects of these different drugs and can lead to drug/drug interactions, so it’s very clear that there remains an unmet need here for an effective seizure-controlling agent that is also safe and tolerable and easy to use.”
The novel CH24h inhibition mechanism has shown a tolerability and safety profile in clinical trials to date that indicates it should prove optimal for add-on therapy in patients already on multiple therapies, she added. “The risk for drug/drug interactions and additive side effects is relatively low, which is a great value proposition if you’re developing a drug in a fragile patient population like this,” the exec noted.
Multiple drug therapies have gained approval to treat DS in recent years, including GW Pharmaceuticals plc’s Epidiolex (cannabidiol) and Biocodex’s Diacomit (stiripentol). (Also see "Dravet Syndrome: A Rare Epilepsy, Now With Two Approved Treatments" - Scrip, 24 Aug, 2018.) Takeda and Ovid decided to include DS as part of their partnership in 2018. (Also see "Takeda/Ovid Broaden Pioneering CH24H Inhibitor To Rare Epilepsies" - Scrip, 19 Jul, 2018.)
Addressing The Different Seizure Types In DS, LGS
A key challenge in designing the Phase III studies in DS and LGS will be finding how best to address the varying symptomology of the two disorders, Sheikh said. While the convulsive seizures common in DS patients are easy to define, drop seizures common to LGS can be as a simple as a head nod or as severe and potentially dangerous as a fall to the ground, she added. LGS patients can suffer as many as 4,000-5,000 seizures per month. That variability compared to DS symptomology made it harder in Phase II to demonstrate efficacy for seizure reduction compared to placebo, Sheikh explained.
“If you can apply a more stringent definition of what a drop seizure is, you decrease the variability,” the exec said. “We have interacted with regulators to align on our Phase III plans moving forward in both conditions and identified a path forward that includes a more stringent definition of drop seizures, which increases our confidence in the path forward.”
Takeda plans to detail plans for the two trials during an investor presentation on 6 April, but she said endpoints for epilepsy trials are well defined and a 16-week duration of therapy is likely for both studies. Enrollment is not expected to be a challenge due to relationships developed with the trial sites during Phase II and with patient advocacy groups.
Takeda researchers in Shonan, Japan, initially discovered soticlestat, Sheikh pointed out, and the decision to bring the asset fully back in-house reflects an increased emphasis by the Osaka-headquartered firm on rare neurological and neuromuscular diseases of unmet medical need. Takeda has no plans to find an additional development or commercial partner for soticlestat, she said. It hopes to launch the drug in both indications in 2024.
JMP Securities analyst Jason Butler praised the revised agreement from Ovid’s standpoint in a 3 March note, saying it provides capital to fund development of Ovid’s preclinical pipeline – which became the biotech’s main focus after a disappointing Phase III trial failure with gaboxadol (OV101) in Angelman’s syndrome last December. (Also see "Ovid Shifts Focus After Angelman Syndrome Drug Disappoints In Phase III" - Scrip, 2 Dec, 2020.) Additionally, Ovid should benefit from “solid back-end economics” pegged to soticlestat’s commercial potential, the analyst said.
Ovid’s R&D goals moving forward are to file three investigational new drug (IND) applications over the next three years, led by OV329 for tuberous sclerosis complex and infantile spasms. It also has a small-interfering RNA (siRNA) candidate in preclinical development for Angelman’s, OV882.