Biogen and Eisai spent the latter half of 2018 defending phase 2b results with their Alzheimer’s disease candidate BAN2401 against sceptics, and will start a phase 3 trial this month to try to resolve the debate.
The confirmatory trial in early AD patients will generate results in 2022 and run alongside an open-label extension of the phase 2b trial that will assess the highest dose of BAN2401 used in that study (10mg/kg twice a month).
Biogen and Eisai show no signs of reduced optimism about the high-risk project, despite the questions being raised about their mid-stage results and the poor track record of amyloid-targeting drugs like BAN2401 in AD to date.
The two partners say they are also considering another phase 3 trial in even earlier-stage subjects that they describe as having ”preclinical” AD – in other words some signs of the amyloid changes in the brain that characterise the disease but no overt cognitive symptoms.
The strategy adheres to the notion that the way to unlock the efficacy of amyloid-targeting drugs is to give them as early as possible in the course of the disease.
The additional study could also include an arm combining BAN2401 with Eisai’s BACE inhibitor elenbecestat, a drug class that has also seen a string of failures in late-stage testing including Merck & Co/MSD’s verubecestat and AstraZeneca’s lanabecestat.
BACE inhibitors are designed to an enzyme involved in the conversion of amyloid precursor protein (APP) into amyloid beta, which is deposited as plaques in the brains of patients with Alzheimer’s disease, while BAN2401 binds to and eliminates soluble, toxic amyloid beta aggregates.
The headline news from Biogen and Eisai’s phase 2b readout for BAN2401 was that the drug reduced disease progression by a third at the highest dose, hitting the mark on two efficacy endpoints but missing a third, while effectively clearing amyloid from the brain.
There was concern that patients on lower doses of the amyloid-targeting drug seemed to decline more quickly than those on placebo, which was ascribed to an imbalance in the proportion of patients in patients with an APOE4 phenotype, in other words a genetic predisposition for rapid progression.
The imbalance was caused by a regulatory directive to stop enrolling APOE4 carriers into the study because of a fear of side effects, but led to suggestions that the benefit of the drug may have been overestimated, although this is disputed by the drug’s developers.
BAN2401 stems from a strategic research alliance between Swedish biotech BioArctic and Eisai to identify a potential immunotherapy for AD, and is one of three amyloid-targeting drugs in the Japanese company’s pipeline along with elenbecestat and aducanumab.
Aducanumab is in two ongoing phase 3 trials as an AD treatment due to generate results in 2020, with a pair of elenbecestat studies due to read out the following year.
Meanwhile, Eisai says in an update published today that it is considering phase 3 studies of both aducanumab and elenbecestat monotherapy in preclinical AD.