Roche Alzheimer’s drug fails to meet primary endpoint in Phase 3 trial

By Rachel Arthur

- Last updated on GMT


Related tags Roche Alzheimer's disease Alzheimer

Phase 3 studies evaluating gantenerumab failed to meet the primary endpoint of slowing clinical decline.

The investigational anti-amyloid monoclonal antibody also showed a lower than expected level of beta-amyloid removal.

The disappointing results for Roche put increased focus on late-stage Alzheimer's drugs from Biogen/Eisai (lecanemab) and Eli Lilly (Donanemab).

Roche, meanwhile, says it remains committed to Alzheimer’s disease: highlighting its pipeline of investigational medicines for different targets, types and stages of the disease; and the potential learnings from its gantenreumab data.

Clinical decline was not statistically significant

Gantenerumab is a fully-human monoclonal IgG1 antibody designed to target and bind to aggregated forms of beta-amyloid, including oligomers, fibrils and plaques, and activate immune cells in the brain (microglia) to clear amyloid plaques and prevent further accumulation. Gantenerumab was discovered in collaboration with MorphoSys.

The Graduate I and Graduate II studies evaluated gantenerumab in a study group of 1,965 people with early Alzheimer’s disease over 27 months: with half receiving a subcutaneous injection titrated to reach a target dose of 510mg administered every two weeks and the other half receiving a placebo.

The CDR-SB measures cognitive & functional change across 6 areas: memory, orientation, judgement / problem solving, community affairs, home &  hobbies, and personal care.

Study participants showed a slowing of clinical decline of -0.31 (p=0.0954), and -0.19 (p=0.2998) respectively from baseline score on the Clinical Dementia Rating-Sum of Boxes (CDR-SB), however, neither was statistically significant.

This represents a relative reduction in clinical decline of 8% in Graduate I and 6% in Graduate II compared with placebo.

The level of beta-amyloid removal, the protein that builds up to make plaques in the brains of people with Alzheimer's disease, was lower than expected.

The incidence of ARIA-E (oedema or effusion) in the pooled gantenerumab arms was 25%, with the ‘vast majority being asymptomatic and very few leading to treatment discontinuation’. The incidence of isolated ARIA-H (haemosiderin) was balanced across the gantenerumab and placebo groups.

Roche will present topline findings of the trials at the Clinical Trials on Alzheimer’s Disease (CTAD) Conference on Wednesday, 30 November.

“So many of our families have been directly affected by Alzheimer’s, so this news is very disappointing to deliver,”​ said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development, commenting on the data.

“We are profoundly grateful to the study participants, their care partners and study sites for their contributions to this research.

"While the Graduate results are not what we hoped, we are proud to have delivered a high quality, clear and comprehensive Alzheimer’s dataset to the field, and we look forward to sharing our learnings with the community as we continue to search for new treatments for this complex disease.”

Potential insights towards accessible and affordable treatments

The Alzheimer’s Association notes several areas for such learnings which could inform future drug development.

“There were several innovative aspects of these gantenerumab trials," ​says the organization.

"For example, the treatment was delivered by injection under the skin rather than an infusion directly into a vein, and the drug was administered with half the dose delivered twice per month, rather than the whole monthly dose given at one time.

"These features could make it possible to have a more accessible and affordable treatment that can be administered in a doctor’s office and perhaps even at home.

"The hope is that this method, which is also being tested in other treatments, will be just as effective, more convenient and reduce potential travel-related hardships on people living with Alzheimer’s, their caregivers and family members.

“The global Graduate trials included local study sites in 32 countries, and we look forward to learning more about the representation in the trials in the coming weeks. It is imperative that clinical trials do more to reflect the global population and those most impacted by Alzheimer’s disease.”

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