Roche has announced that it has terminated two phase III trials of crenezumab, a monoclonal antibody targeting beta-amyloid. The trials, CREAD 1 and CREAD 2, were evaluating the agent in prodromal to mild Alzheimer’s disease.

In the phase II ABBY trial, crenezumab failed to meet its primary endpoints of change from baseline in ADAS-cog12 and Clinical Dementia Rating-Sum of Boxes (CDR-SB) scores (Cummings et al. Neurology 2018;90:e1889-e1897). BLAZE, a second phase II neuroimaging study, also failed to meet its endpoint of change from baseline in amyloid burden (Salloway et al. Alzheimers Res Ther 2018;10:96). However, in ABBY, there was a trend to improvement in a milder subgroup and Roche wagered that a higher dose might be effective.

In the preplanned analysis of the phase III studies, the data monitoring committee found that treatment was unlikely to improve CDR-SB scores despite dosing that was four times higher than what was used in the phase II study. Crenezumab was discovered by Immune SA, which licensed it to Genentech; the U.S. biotech was subsequently acquired by Roche.

Two other MAbs targeting beta-amyloid have met a similar fate. Elan terminated the clinical development program for bapineuzumab in 2012, and Lilly abandoned solanezumab in 2016. These failures have dimmed expectations for aducanumab, an anti-amyloid MAb in phase III testing by Biogen and Eisai. Aducanumab works somewhat differently than other MAbs, targeting beta-amyloid oligomers and insoluble fibrils.

Roche/Genentech plans to continue research with other AD agents. Also in development is gantenerumab, despite a failed phase III trial in prodromal AD (Ostrowitzki et al. Alzheimers Res Ther 2017;9:95). The GRADUATE 1 and 2 trials of gantenerumab plan to enrol over 1,500 patients at 350 centres, with results expected in 2022. Roche/Genentech will also continue its phase II TAURIEL trial evaluating RG6100, an antibody that targets extracellular tau, in patients with prodromal or probable AD. The trial is using GTP1, a PET tracer developed by Genentech, to evaluate treatment response. Results are expected next year.