Following the news that Roche’s anti-amyloid beta (Aβ) monoclonal antibody (mAb), gantenerumab 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);

Pippa Salter, Senior Neurology Analyst at GlobalData, a leading data and analytics company, offers her view:

“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. Its failure will be a significant blow to Roche, which had gambled on continued development of the product despite a previous Phase III failure in 2014 (NCT01224106). Roche’s anti-Aβ mAb, crenezumab, also 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 earlier this year.

“In GRADUATE I and II, not only did gantenerumab fail to significantly slow clinical decline but results showed less Aβ removal than expected. Although Roche is yet to announce future plans for gantenerumab, these results, combined with previous failures, make it challenging to see a path forward for the product. It’s possible that Roche may shift away from the amyloid-hypothesis to focus on other mechanisms of action for AD.

“This negative data will boost the prospects of Eisai and Biogen’s anti-Aβ mAb lecanemab, which demonstrated both a significant reduction in clinical decline in early AD and a reduction in Aβ levels in its Phase III Clarity AD trial (NCT03887455) in September 2022. 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. It has shown superior safety and efficacy compared to Biogen’s Aduhelm (aducanumab), which is marketed in the US but faces highly restricted Medicare reimbursement. Furthermore, although the verdict is still out on how lecanemab will compare with Eli Lilly’s donanemab, Phase II data suggests there may be higher occurrence of safety issues, such as amyloid-related imaging abnormalities, with donanemab than with lecanemab.”