Roche’s drug candidate for early Alzheimer’s disease, gantenerumab, has failed to achieve its primary endpoint in two phase III trials carried out by the Swiss big pharma.
There were slight relative reductions in cognitive decline (six to eight percent) seen in both of the studies versus placebo, but these were not statistically significant and neither study met its primary endpoint. The company also announced in a press statement that the level of beta-amyloid removal by gantenerumab was lower than expected.
The GRADUATE I and II studies were double-blind, randomized, placebo-controlled clinical trials carried out in 30 countries. They were designed to evaluating the safety and efficacy of the anti-amyloid monoclonal antibody gantenerumab in people with mild cognitive impairment (MCI) due to Alzheimer’s and mild Alzheimer’s dementia.
Overall, 1965 participants were randomly assigned (1:1) to receive a subcutaneous injection of placebo or gantenerumab (titrated dose of 510 mg), every two weeks. The participants were then followed up for 27 months to assess changes in the Clinical Dementia Rating-Sum of Boxes, as a primary endpoint.
There were also 17 secondary endpoints including change in disease severity assessed using various neuropsychological and functional assessment tools, incidence of adverse events, disease biomarkers and scans, among others.
Alzheimer’s disease has been a notoriously difficult therapeutic area for developing new therapies. The controversial drug Aduhelm, also developed by Biogen and Eisai, was the first Alzheimer’s drug approved by the FDA in almost 20 years, despite only showing mild improvements in symptoms in those with the condition. However, it is not as effective as lecanemab and its use was recently limited by Medicare to patients in clinical trials only.
The failure of the GRADUATE I and II studies follows on from earlier phase III problems in 2014, when Roche’s SCarlet RoAD trial of gantenerumab in early Alzheimer’s disease was halted due to an interim futility analysis. Similarly, the phase III Marguerite RoAD study in mild Alzheimer’s, which began in 2014, also failed an interim futility analysis.
Despite this, the company decided to continue developing the drug, suggesting the dosage in the original phase III studies may have been suboptimal. Unfortunately, this hope seems to have been misplaced.
This leaves lecanemab, Biogen and Eisai’s mild Alzheimer’s drug that succeeded at phase III earlier this year, as a prime option for early or mild Alzheimer’s treatment with limited competition assuming approval goes as planned. Lecanemab is currently being reviewed by the FDA under their accelerated approval pathway and a decision is expected in January 2023. Eisai is also planning to submit for full approval in the U.S., Europe, and Japan before the end of March next year.
Roche has not announced the definitive fate of gantenerumab yet, but says it will present the study findings in more detail at the upcoming Clinical Trials on Alzheimer’s Disease Conference on Wednesday, 30 November, 2022.