Roche’s discontinued Alzheimer’s disease drug has shown signs that it could prevent onset of the disease.
The Phase II/III Knight Family Dominantly Inherited Alzheimer Network-Trials Unit (DIAN-TU) platform trial (NCT05552157), was conducted by researchers at the Washington University School of Medicine. The study evaluated Roche’s gantenerumab in 73 participants aged between 30 to 50 with rare, inherited genetic mutations that cause the overproduction of amyloid in the brain, which investigators say all but guarantees they will develop Alzheimer’s disease in middle age.
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The participants were dosed in the DIAN-TU-001 (NCT01760005) and the open-label extension (OLE) (NCT06424236) studies. Data from the DIAN-TU-001 trial showed that Roche’s gantenerumab, an amyloid beta peptide inhibitor, reduced amyloid levels in the brain and improved some measures of Alzheimer’s proteins, but did not meet the primary endpoint.
Now, new OLE study data published in The Lancet has shown the anti-amyloid drug cut the risk of developing symptoms by 50%.
For a subgroup of 22 participants who had no cognitive problems at the study’s start and who received the drug the longest – an average of eight years – the treatment cut the risk of developing symptoms, according to a primary analysis of the data and supported by multiple sensitivity analyses supporting the trend.
The investigator’s calculation not only considers how many people developed symptoms but also when symptoms emerged for each participant compared to his or her expected age of onset. That means the effect size could change as time goes on.
Investigators said that some participants in the study are at or just past their expected age of onset and if they continue to go without developing symptoms, the effect size will increase. However, if some who are healthy now develop symptoms in later years, this would reduce the effect size.
The Charles F and Joanne Knight Distinguished Professor of Neurology at Washington University School of Medicine, Dr Randall Bateman, said: “We don’t yet know how long they will remain symptom-free – maybe a few years or maybe decades.”
The DIAN-TU-001 study was launched in 2012, and all participants in the trial had no to very mild cognitive decline and were within the range of 15 years before to ten years after their expected age of Alzheimer’s onset, based on family history.
When the trial concluded in 2020, it was not clear whether Roche’s therapy would provide cognitive benefit to those without symptoms. This caused investigators to launch the OLE study to evaluate gantenerumab’s effects and determine whether higher doses or longer treatment could prevent or delay cognitive decline.
Investigators hope that this result could also translate to those at risk of late-onset Alzheimer’s disease.
“If late-onset Alzheimer’s prevention trials have similar results to the DIAN-TU trials, there soon could be Alzheimer’s preventions available for the general population,” Bateman added.
“I am highly optimistic now, as this could be the first clinical evidence of what will become preventions for people at risk for Alzheimer’s. One day soon, we may be delaying the onset of Alzheimer’s disease for millions.”
Patients switched to Leqembi
The therapy was discontinued after Roche’s Phase III programme as the GRADUATE I and II studies failed to meet their endpoints. As a result, participants receiving gantenerumab in DIAN-TU OLE were switched to Eisai and Biogen’s anti-amyloid therapy Leqembi (lecanemab).
Another study, the DIAN-TU-002 trial (NCT06647498), has been launched as part of the platform series, evaluating Eli Lilly’s remternetug in young adults to assess its efficacy as a preventative of the disease.
Eli Lilly is already a big name in the Alzheimer’s disease space after the launch of the anti-amyloid therapy Kinsula (donanemab).
An issue with anti-amyloid drugs such as Leqembi, Kinsula and gantenerumab is the adverse event (AE) amyloid-related imaging abnormalities (ARIA). In the OLE study of gantenerumab, ARIA rates were one-third higher than in the original clinical trial (30% versus 19%), which the researchers attribute to the higher doses used in the extension. Two participants developed such severe ARIA that they needed to be taken off the drug, at which point they recovered. There were no life-threatening AEs or deaths.
The global Alzheimer’s disease market across the eight major markets (8MM: US, France, Germany, Italy, Spain, UK, Japan, and China) is forecast to grow from $2.4bn in 2023 to $19.3bn by 2033, according to GlobalData.
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