Expectations of a treatment for Alzheimer’s disease have been dealt another blow by the failure of an experimental drug to slow the progression of the condition in global clinical trials by Swiss pharmaceutical giant Roche, which carried out two identical phase three trials of gantenerumab, with about 1 000 volunteers in each.
Roche said gantenerumab showed no clear benefit in twin trials, which explored its impact on memory, problem solving and other cognitive skills in people with early stage Alzheimer’s.
Experts had hoped for positive news from Roche’s Graduate 1 and 2 clinical trials after a US-Japanese collaboration between Biogen and Eisai reported in September that a similar drug, lecanemab, slowed cognitive decline in patients, making it the first proven to do so.
“This news is very disappointing to deliver,” said Levi Garraway, Roche’s chief medical officer.
Gantenerumab is an antibody therapy designed to bind to clumps of amyloid beta proteins and remove the plaques from the brain. The abnormal protein aggregates are believed to play a major role in Alzheimer’s, though many patients are likely to have multiple disease processes at work in their brains.
The Guardian reports that Roche conducted two identical phase three trials of gantenerumab, with about 1 000 volunteers in each receiving an injection of the drug or a placebo every two weeks. The participants took part in tests to monitor their cognitive decline for more than two years.
While those given the drug showed a relative reduction in clinical decline of 8% and 6% on the Graduate 1 and 2 trials respectively, the results were not statistically reliable, the company said. Roche released the main outcomes of the trials on 14 November and will give more details at the Clinical Trials on Alzheimer’s Disease conference in San Francisco on 30 November.
Rachelle Doody, Roche’s head of neurodegeneration, said the drug was less effective at removing amyloid than expected. “We will be showing that there is a relationship between the lowering of amyloid and the clinical outcomes. It’s just that when you don’t get the amyloid lowering that you expected you won’t get the clinical outcome that you expected.”
“Any large scale clinical trial of an Alzheimer’s drug that fails is a massive disappointment to patients,” said Professor Jonathan Schott, a neurologist at UCL’s Dementia Research Centre and chief medical officer at Alzheimer’s Research UK. “This is a particular disappointment because gantenerumab is given as a subcutaneous injection, which would have made it easier to administer than the infusions needed for most other anti-amyloid drugs.”
Dr Richard Oakley, associate director of research at Alzheimer’s Society, said: “These results today are disappointing, as we don’t currently have a drug for Alzheimer’s disease in the UK which slows down its progression. However, this is still an exciting time for dementia research, with promising early results from a similar Alzheimer’s drug, lecanemab, and 143 other drugs currently in clinical trials aiming to slow down the disease or help with symptoms.”
“Alzheimer’s Society research more than 30 years ago was pivotal in highlighting the importance of amyloid protein in the development of the disease – laying the basis for these drugs being tested today. But it’s so important to remember we need research into other types of dementia as these drugs are only for Alzheimer’s disease.”
Roche study details
Study participants treated with gantenerumab showed a slowing of clinical decline in GRADUATE I and GRADUATE II 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 CDR-SB measures cognitive and functional change across six areas including memory, orientation, judgement and problem solving, community affairs, home and hobbies, and personal care.
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. Roche will present topline findings of the GRADUATE I and II studies at the upcoming Clinical Trials on Alzheimer’s Disease (CTAD) Conference on Wednesday, 30 November, 2022.
Amyloid related imaging abnormalities (ARIA) are a common radiological finding associated with amyloid-targeting therapies. 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.
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