E2082 Discontinuation May Hit Eisai's Epilepsy Succession
Executive Summary
Fatality of healthy volunteer in early clinical trial prompts halt of all clinical work for candidate anti-epileptic, potentially hitting Eisai's product succession strategy in a core therapeutic area.
All clinical trials for Eisai Co. Ltd.'s E2082 have been discontinued following the death in June of a participant in a Phase I study with the investigational neurology drug.
The Japanese company said the fatality occurred after the completion of dosing in the trial, conducted in Japan in 118 healthy adult volunteers of both Japanese and Caucasian ethnicity.
E2082, a next-generation AMPA antagonist, was being progressed as a candidate for epilepsy and epileptogenesis in the placebo-controlled study, at ascending single and multiple oral doses using formulations ranging from 0.2mg to 5mg.
While extending "sincere condolences to the family of the subject," the company noted that exact causality and the link between the drug and the death remained unknown at this point; no other serious adverse reactions had been reported in the study.
Development Rationale
Reflecting its strategic interest in both dementia and epilepsy, Eisai is investigating as part of its R&D strategy the high incidence of epilepsy observed in Alzheimer's disease patients, which in a company scientific meeting this April it noted is around seven times normal. Epilepsy patients also show significantly higher amounts of brain senile plaques with age, and epileptiform (epilepsy-like abnormal brain) activity may be involved at the earlier stages of Alzheimer's.
E2082 was being developed on the hypothesis that an observed increase in calcium-permeable AMPA receptors, and accelerated expression of the AMPA receptor GluR1 subunit, contributes to hyper-excitation in Alzheimer's patients.
Along with the synapse function modulator E2730 (which remains in development), the molecule was being investigated as a potential preventative treatment for epilepsy, given that it had shown highly selective, non-competitive inhibition of the AMPA-type glutamate receptors linked to seizures.
It had also shown a higher affinity for activated synapses than Eisai's already marketed first-in-class, once-daily oral AMPA antagonist epilepsy drug perampanel (marketed as Fycompa), and the hope was to establish clinical proof-of-concept "at an early stage," the company said in April.
Besides the Phase I Japanese trial, E2082 was in Phase II development in the US in photosensitive epilepsy.
Fycompa, approved in various indications including partial-onset and primary generalized tonic-clonic seizures, is the main member of the AMPA antagonist class, where Biomedtracker lists the only other molecule in clinical development (Phase I) as Takeda's TAK-653, although this is for major depressive disorder.
Elsewhere in the novel epilepsy space, SK Biopharmaceuticals Co. Ltd.'s cenobamate - which acts on GABA and sodium channels - was accepted for review in the US in February, with a decision date of November. (Also see "New Option For Uncontrolled Epilepsy On Horizon As US Accepts Cenobamate NDA" - Scrip, 12 Feb, 2019.)
Eisai has a long-standing strategic interest in Alzheimer's through its now genericized former blockbuster Aricept (donepezil) and a development alliance with Biogen Inc., which includes the BACE inhibitor elenbecestat.
Age A Possible Factor?
In a comment on the trial death in Biomedtracker, analysts at Sagient Research noted that the approved doses of Fycompa are actually higher than those in the Phase I study with E2082, which "raises more questions and uncertainty over how the fatality arose."
Earlier Phase I clinical studies in healthy Asian patients also found the investigational molecule to be well tolerated, but the participant age range in these was 18-54, unlike the wider 20-85 years in the E2082 study, they observed.
More broadly, "This [development discontinuation] will be a great disappointment to the company" given that Fycompa's patent is set to expire in the next few years, Sagient noted; Orange Book data show this will be in June 2021 in the US. E2082 therefore appears likely to have been part of a strategy to protect Eisai's position in epilepsy, where besides Fycompa it has other drugs including Banzel (rufinamide) in the US.
Global Fycompa sales in the current fiscal year ending next 31 March are expected by the company to be JPY25bn ($235m), and Datamonitor Healthcare sees these peaking at a substantial $723m in 2022, helped by broadened indications.
The E2082 trial death has been reported to regulators and in Japan the ministry of health, labour and welfare has launched an investigation.