The failure of a test medicine to reduce the Alzheimer’s course in international clinical trials has dealt another blow to hopes for a cure for the disease. The possible drug gantenerumab by Roche failed to slow clinical decline in patients with early Alzheimer’s in two phase-III trials.
On November 14th, 2022, the Swiss pharmaceutical company Roche stated that the twin trials that examined the effect of the drug gantenerumab on memory, problem-solving, and other cognitive skills in persons with early-stage Alzheimer’s exhibited no obvious advantage.
The disappointment came amid emerging indications that antibodies directed against beta-amyloid may one day successfully treat this memory-robbing neurodegenerative illness. After a US-Japanese partnership between Biogen and Eisai disclosed in September that a comparable medicine, lecanemab, reduced cognitive decline in patients, making it the first shown to do so, experts had hoped for encouraging results from Roche’s Graduate I and II clinical trials.
The Gantenerumab Trial
Gantenerumab is an antibody treatment that binds to clumps of amyloid beta proteins in the brain and removes the plaques. Although aberrant protein aggregates might play a significant part in Alzheimer’s, many patients are likely to have various disease processes at work in their brains.
About 1,000 volunteers in each of Roche’s two similar phase-3 studies of gantenerumab received an injection of the medication or a placebo every two weeks. For more than two years, the subjects underwent tests to track their deterioration in cognitive function.
Although individuals who received the medication experienced a relative fall in the clinical decline of 8% in the Graduate 1 and 6% in the Graduate 2 trials, the company stated the results were not statistically significant.
Early in 2014, Roche began their first phase 3 trial of gantenerumab. However, it was discontinued early at the end of the year when an interim analysis revealed the intervention was ineffective. Many researchers were shocked by the company’s decision to try again with greater doses of the antibody in two further trials that enrolled approximately 2000 individuals with moderate cognitive impairment or mild dementia attributable to Alzheimer’s across 30 nations.
What were the results of the trial?
In those studies, gantenerumab injections, which target a different portion of the amyloid protein than other antibodies, only slightly reduced cognitive decline compared to placebo. Roche admitted that this difference was not statistically significant. The company also stated that the treatment’s removal of beta-amyloid was lower than predicted. That may make it difficult to determine whether the research supports or refutes the widely held but increasingly challenged theory that beta-amyloid directly damages neurons, causing Alzheimer’s.
The company also pointed out that in the pooled gantenerumab-treated arms of the two trials, the prevalence rate of amyloid-related imaging abnormalities (ARIA), brain swelling, and fluid buildup frequently seen with this class of antibodies was 25%. This figure was significantly higher than the reported incidence for lecanemab.
According to the firm, most ARIA cases were minor and did not require doctors to stop treating patients. The number of cases of the more serious “hemorrhagic” variant, which involves bleeding in the brain, was not disclosed by Roche. However, it claimed they were balanced across the placebo and gantenerumab groups.
Based on earlier results, many scientists and biotech analysts thought that gantenerumab had little chance of being effective in the two trials. Even proponents of the amyloid theory had little hope.
Roche shutters most Alzheimer’s drug trials after failure
After disclosing the primary results on November 14th, Roche was to give more details on the clinical trial at an Alzheimer’s meeting in San Francisco on November 30th.
The company revealed on November 30th that it is ending most of its clinical trials for gantenerumab, an experimental treatment for Alzheimer’s, because, in two sizable, late-stage studies, it did not stop the spread of the debilitating condition.
According to a presentation, gantenerumab, administered by injection, only demonstrated amyloid clearance in 28% of patients in the Graduate I trial and 25% in the Graduate II trial after two years, which is half of what the firm predicted. In comparison, lecanemab eliminated amyloid in 68% of trial participants after 18 months.
There are a variety of potential reasons why Roche’s medicine may have failed, including variations in chemistry, dose, and the method it was provided by injection as opposed to infusion, according to the chief science officer at the Alzheimer’s Drug Discovery Foundation, Dr. Howard Fillit. However, it is evident that the drug’s apparent inability to eliminate amyloid deposits from the brain played a part.
To deliver more medication to the brain, Roche is still testing trontinemab (a different form of gantenerumab), which can transport the drug across the blood-brain barrier. This barrier is a set of protective blood vessels that blocks the entry of chemicals from the bloodstream into the brain.
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- Roche Alzheimer’s antibody fails to slow cognitive decline in major test. Science. https://www.science.org/content/article/roche-alzheimer-s-antibody-fails-slow-cognitive-decline-major-test?cookieSet=1. Accessed: 6.12.2022.
- Roche’s Alzheimer’s drug fails to meet goal in long awaited trial. Reuters. https://www.reuters.com/business/healthcare-pharmaceuticals/roche-says-phase-iii-trial-alzheimers-trial-drug-fails-2022-11-14/. Accessed: 6.12.2022.
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