On 14 November, Roche announced that its anti-amyloid beta (Aβ) monoclonal antibody (mAb), gantenerumab, had failed to significantly slow clinical decline in patients with early Alzheimer’s disease (AD) in two Phase III clinical trials, GRADUATE I and II (NCT03443973 and NCT03444870). The primary endpoint, Clinical Dementia Rating-Sum of Boxes (CDR-SB), was not met, with gantenerumab treatment resulting in a relative reduction in clinical decline of 8% in GRADUATE I and 6% in GRADUATE II compared with placebo.
Gantenerumab’s failure comes as a significant blow to Roche, which had gambled on the continued development of the product despite a previous Phase III failure in 2014 (SCarlet RoAD; NCT01224106). In addition, the failure follows another for Roche in June this year, when the company announced that its anti-Aβ mAb, crenezumab, failed to slow or prevent AD in cognitively unimpaired people who carry a specific genetic mutation causing early-onset AD in a Phase II trial (NCT01998841).
In GRADUATE I and II, not only did gantenerumab fail to significantly slow clinical decline, but results showed less Aβ removal than expected. Roche announced it will present topline findings of the GRADUATE I and II studies at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) Conference at the end of this month. Although Roche is yet to announce future plans for gantenerumab, it has paused enrolment and dosing in another ongoing Phase III trial evaluating the drug in AD (SKYLINE; NCT05256134). Combined with previous failures, the latest results make it challenging to see a path forward for gantenerumab. It is possible that following the failures of gantenerumab and crenezumab, Roche may shift away from the amyloid hypothesis to focus on other mechanisms of action for AD. For example, Roche has three products targeting tau in Phase II development: semorinemab, bepranemab and REM-0046127.
While this has been a blow for Roche, the news will boost the prospects of Eisai and Biogen’s anti-Aβ mAb lecanemab, which in September demonstrated both a significant reduction in clinical decline and a reduction in Aβ in patients with early AD in the Phase III Clarity AD trial (NCT03887455). Lecanemab is an intravenously administered mAb, whereas gantenerumab would have become the first subcutaneously administered mAb for AD. This alternative route of administration would have been a key differentiator and potential competitive edge for gantenerumab, as subcutaneous administration could allow for at-home administration.
With gantenerumab no longer looking like a promising candidate, lecanemab could become the market-leading mAb for AD. The drug has shown superior safety and efficacy compared with Biogen’s Aduhelm (aducanumab), which is marketed in the US but faces highly restricted Medicare reimbursement. And although the verdict is still out on how lecanemab will compare with Eli Lilly’s donanemab (pivotal Phase III results are expected early next year), Phase II data suggests there may be a higher occurrence of safety issues such as amyloid-related imaging abnormalities with donanemab than with lecanemab.
Gantenerumab’s unexpected failure falls during Alzheimer’s Awareness Month and highlights the significant challenges in drug development for AD, as well as the ongoing unmet need for more effective disease-modifying therapies. Whether these future therapies will target amyloid plaques or another mechanism entirely, such as tau, remains to be seen.