16 November 2022

The ultimate failure

Antibodies against beta-amyloid from Roche failed in clinical trials

Irina Konova, PCR.news

On November 14, 2022, Roche announced the results of phase 3 KI gantenerumab, a human monoclonal antibody of the IgG1 class intended for subcutaneous administration and targeting beta—amyloid aggregates. Gantenerumab was positioned as a drug against cognitive decline in Alzheimer's disease, however, according to new data, it cannot fulfill its task.

Previously, the results of KI gantenerumab in comparison with solanezumab (Eli Lilly), conducted on a small sample, were published. None of the antibodies slowed the cognitive decline in the participants, however, gantenerumab, unlike solanezumab, reduced the formation of amyloid plaques in the brain and reduced the levels of Alzheimer's disease biomarkers in the cerebrospinal fluid. Then the scientists decided that it made sense to test gantenerumab further. The new results seem to put an end to the drug.

As he writes Science, Roche has launched the third phase of KI gantenerumab twice. The first attempt took place in 2014, but by the end of the year the project was suspended due to interim test results. Then the company decided to restart the CI using an antibody in a higher dosage.

An international project consisting of two double-blind randomized placebo—controlled CI — GRADUATE I and II - recruited 1,965 people. They received a subcutaneous injection of gantenerumab or placebo every two weeks, with the dose gradually increasing. The primary endpoint was the cognitive and functional statuses of patients determined by the CDR-SB scale at week 116 of treatment. Changes in the severity of the disease, side effects, biomarker levels, etc. were used as secondary points. As a result, the relative decrease in cognitive abilities in the gantenerumab groups compared to the placebo groups was only 8% and 6% for GRADUATE I and II, respectively, and was not statistically significant. The reduction of beta-amyloid plaques in the patients' brains was less intense than expected. Thus, the story of gantenerumab ended in failure. The main results of GRADUATE I and II will be presented on Wednesday, November 30, 2022, at the Clinical Trials on Alzheimer's Disease conference.

"Many of our families are directly affected by Alzheimer's disease, so this news is very disappointing," says Levi Garraway, Roche's chief medical officer. "We express our deep gratitude to the participants of the study, the people who take care of them, and the centers on the basis of which the study was conducted, for their contribution to the work." Garraway noted that in any case, the company has received a high-quality data set that will be useful to the entire scientific community. According to him, Roche will continue to search for therapy for Alzheimer's disease.

Other specialists not associated with Roche, whose comments are cited by The Guardian, also speak of great disappointment for patients. It is compounded by the fact that gantenerumab was intended for subcutaneous injections, whereas other drugs targeting amyloids involve intravenous administration.

Gantenerumab is not the first antibody against amyloid aggregates. The amyloid cascade is considered a promising target for the fight for cognitive functions in Alzheimer's disease, but there are no completely successful stories in this area yet. For example, around the 2021 approved adukanumab (Biogen) a scandal broke out. According to some experts, it is time to expand research on the pathogenesis of the disease and find other possible targets for therapy.

The message [Ad hoc announcement pursuant to Art. 53 LR] Roche provides update on Phase III GRADUATE program evaluating gantenerumab in early Alzheimer's disease is published on the Roche website.

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