Mere hours after reporting the failure of aducanumab in Alzheimer’s disease, Eisai has cued up a phase 3 trial of BAN2401, another amyloid-targeted drug.
The move surprised investors who had already started reducing or removing BAN2401 from their future sales predictions for Eisai and partner Biogen, on the grounds that aducanumab’s failure was likely one of the final throws of the dice for the much-discredited amyloid hypothesis of AD.
The idea that blocking the formation of the amyloid plaques that are seen in the brains of people with AD has dominated drug development of the disease for years – but has seen dozens of anti-amyloid candidates fail in clinical testing.
Despite those failures, there had been hope that aducanumab was one of the best chances of showing an impact after mid-stage trials showed evidence that it could stabilise cognitive decline.
BAN2401 has been seen as something of an also-ran in the Biogen/Eisai pipeline, particularly after reporting confusing results in a phase 2b trial last year. While it was shown to reduce disease progression by a third at the highest dose, there was concern that patients on lower doses seemed to decline more quickly than those on placebo.
Biogen and Eisai said this was due to an imbalance between the groups at enrolment in patients with a genetic predisposition for rapid progression (APOE4+), caused by regulatory demands to stop recruiting APOE4 carriers into the study because of a fear of side effects.
That didn’t convince everyone, and led to suggestions that the benefit of the drug may have been overestimated. Meanwhile, questions were also raised about disparities between the results on different AD symptoms scales used in the study.
Analysts at Jefferies described the data as “all over the place” but said a phase 3 programme was justified, although those comments came ahead of the aducanumab failure.
The new phase 3 trial of BAN2401 – called Clarity AD/Study 301 – will enrol 1,566 patients with early AD, in other words with mild cognitive impairment (MCI) due to AD or mild AD with confirmed amyloid pathology in the brain
Discussion about the amyloid hypothesis continues to evolve. While there have been arguments for years to push treatment earlier in the curse of the disease to try to prevent cognitive declines, there is now a shift towards thinking about the different forms of amyloid in the brain, which will give Biogen, Eisai and BAN2401’s originator BioArctic some hope for success.
Aducanumab was targeted at soluble beta amyloid, and some researchers now think that neurotoxic amyloid beta aggregates – which are the target for BAN2401 – are in fact the key driver of AD pathogenesis.
Time will tell if that is in fact the case. According to Eisai, the final readout of the primary endpoint in Clarity AD is slated for 2022.