Results of phase 3 trials testing gantenerumab are latest blow to amyloid hypothesis
The second (and third) time was not the charm for Roche’s experimental antibody drug for Alzheimer’s disease. The company last night announced gantenerumab had failed to show a statistically significant benefit in two large, late-stage clinical trials that tested its ability to slow patients’ cognitive decline—echoing a previous failure in another so-called phase 3 trial.
“This news is very disappointing to deliver,” Levi Garraway, Roche’s chief medical officer, said in the company’s statement.
The setback comes amid new hints that antibodies targeting beta amyloid, a protein that builds up in the brains of Alzheimer’s patients, could finally break through as treatments for the memory-robbing neurodegenerative disorder. Earlier this year, Biogen and Eisai announced their jointly developed antiamyloid antibody lecanemab had scored an apparent win in a major clinical trial, although many questions remain about it. And Biogen in 2021 won U.S. approval for another antiamyloid antibody, aducanumab, although its effectiveness is modest at best and few patients are receiving the drug, as the U.S. Medicare system has so far declined to pay for it.
Roche launched its first phase 3 trial of gantenerumab in early 2014 but halted it early, at the end of that year, when an interim analysis showed the intervention wasn’t working. Many researchers were surprised by the company’s decision to try again, with higher doses of the antibody, in two more trials, which enrolled nearly 2000 people with mild cognitive impairment or mild dementia due to Alzheimer’s across 30 countries.
In those trials, subcutaneous injections of gantenerumab, which targets a different part of the amyloid protein than other antibodies, only slowed cognitive decline by 6% or 8% compared with placebo—a result Roche acknowledged was not statistically significant. The company added that the amount of beta amyloid removed by the treatment was “lower than expected.” That may cloud any attempt to discern whether the studies support or challenge the idea that beta amyloid directly harms neurons, the dominant but increasingly challenged hypothesis about what causes Alzheimer’s disease.
Roche said more information would be provided later this month at the Clinical Trials on Alzheimer’s Disease conference. The company did note that the incidence of amyloid-related imaging abnormalities (ARIA), the brain swelling and fluid buildup often seen with this class of antibodies, was 25% in the pooled gantenerumab-treated arms of the two trials, significantly more than the reported amount for lecanemab. Most ARIA cases were mild, the company said, and did not force doctors to discontinue treatment. Roche did not report how many were the more severe “hemorrhagic” form that involves bleeding in the brain, although it stated the number of those cases was “balanced across the gantenerumab and placebo groups.”
Based on past studies of gantenerumab, many scientists and biotech analysts had given it a poor chance of succeeding in the two trials. Even advocates of the amyloid hypothesis had low expectations. “Gantenerumab was the weakest candidate in the series [of antibodies], so I am not surprised that this antibody did not work,” Bart De Strooper, director of the UK Dementia Research Institute, told Science in an email. “The whole thing boils down to what is needed to get positive results in a trial. There is a lag phase during which amyloid plaque load is decreased [and] you will only see clinical gain once this lowering has happened below a threshold. Thus, if you have an antibody that takes too long to remove the plaques, your trial will be finished before you see benefits.
Still, David Holtzman, an Alzheimer’s disease researcher at the Washington University School of Medicine in St. Louis, noted the company did see “a subtle trend for less cognitive slowing.” The less-than-anticipated drop in amyloid levels “could be a major reason that the clinical results were not as robust as expected,” he said.
The Alzheimer’s Association, too, sought some positive news in the drug’s failure, saying in a statement, “The trials further illustrate the relationship between removal of amyloid-beta and reduction of clinical decline. We are seeing great progress and innovation in this class of treatment, and we learn from each trial.”
Many in the field will now hope for better results from another antiamyloid antibody, Eli Lilly and Company’s donanemab, which is nearing the end of its own phase 3 trial. But some see the Roche results as more reason to be wary of the one apparent success in the field, Biogen and Eisai’s lecanemab.
“This is another blow to the approach of attacking amyloid beta in the brain to slow down the progression or delay the onset of Alzheimer’s disease,” said University of Reading neurophysiologist Francesco Tamagnini in comments to the Science Media Centre. “Now more than ever, it is important to promote more basic research to understand the different ways the disease develops and identify new targets for treatment.”
Link: https://www.science.org/content/article/roche-alzheimer-s-antibody-fails-slow-cognitive-decline-major-test
Author: BYJOHN TRAVIS
Date: 14 NOV 20221:40 PM
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