November 14, 2022

expert reaction to top line results of a Phase 3 trial of gantenerumab for Alzheimer’s disease

Roche have announced that the results of their phase 3 trial evaluating gantenerumab in people with early Alzheimer’s disease did not meet their primary endpoint of slowing clinical decline.

Prof Bart De Strooper, Director of the UK Dementia Research Institute, said:

“The ganteneurumab results released today by Roche, are disappointing after the positive headlines from another Alzheimer’s drug, lecanemab, in September.

“There are currently four immunotherapy drugs in clinical trials that remove amyloid plaques, which all function differently. We had predicted before that ganteneurumab would likely be the least effective so it’s not surprising that the outcomes have not been positive.

“In order to see clinical benefits from amyloid treatments we must rely on how efficiently and quickly that drug can reduce amyloid plaques in the brain. If it takes more than half of the time of the trial to get the amyloid plaque levels below a threshold, then there is little chance for benefits in the short time that remains. It takes years for the symptoms of dementia to develop, it is unlikely that real positive clinical outcomes related to cognition will arise immediately. This also implies that the earlier in the disease trajectory you treat, the more chance one has to see real clinical benefits. 

“Although today’s news isn’t what we, and the millions of people affected by Alzheimer’s, would have hoped for, the Lecanemab data gives hope and we look forward to seeing the full data including the side effects. Every trial teaches us more about what the ‘right drug, right patient and right time’ looks like, and how we should test this. I remain hopeful of more positive news for the field in the near future and would like to recall that other fields of medicine also see more failures than successes. Trials are the way to find out what the best drugs are.”

For further information, see Karran & De Strooper (2022).”

Prof John Hardy, Professor of Neuroscience, UCL, said:

“Any drug trial failing to show efficacy against Alzheimer’s disease is a disappointment.  However, with the recent success of lecanemab and the possibly partial success of aducanumab we are beginning to understand what new agents need to do in terms of amyloid removal to have a clinical effect.  We will get more details about the effects of all these drugs in three weeks at the major Alzheimer meeting (CTAD).  I am optimistic that we are now on the road to effective therapies.”

Dr Francesco Tamagnini, Neurophysiologist at the Reading School of Pharmacy, University of Reading, said:

“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.

“Amyloid beta plaques are one of the most obvious physical changes that occur in the brains of people with Alzheimer’s disease, but it is increasingly becoming obvious that amyloid beta may not be the only fundamental cause of the disease. We know that there are a number of other mechanisms and processes going on in the brains of people with Alzheimer’s, many of which we don’t yet understand well, and we also suspect there are things going on that we don’t know about at all within different types of brain cells.

“This disappointing news is the latest in a long series of failures of therapies targeting amyloid beta. 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. New understanding about the disease would also help to find better and affordable ways to screen people for Alzheimer’s disease and other forms of dementia.”

Dr Susan Kohlhaas, Director of Research at Alzheimer’s Research UK, said:

“People with Alzheimer’s disease desperately need better treatment options, so it’s extremely disappointing when a potential drug doesn’t produce the benefits we were hoping to see.

“The drug’s manufacturer, Roche will soon be presenting the results from this trial, and this will allow the research community to learn from them, to help inform future Alzheimer’s drug development.

“Gantenerumab is one of several drugs that has been designed to remove the hallmark Alzheimer’s protein, amyloid, from the brains of people in the very early stages of the disease.

“Earlier this year a final stage trial of a different anti-amyloid drug, called lecanemab, successfully cleared amyloid from the brain and slowed the decline in participants’ memory and thinking skills.

“Looked at together, data from the lecanemab and gantenerumab trials will yield important insights as to why one anti-amyloid drug worked better than the other, and this will help further refine this approach to treating people with Alzheimer’s disease.

“Alzheimer’s disease is complex, and potential drugs that target other aspects of the disease are also making their way through clinical trials. There are over 140 potential Alzheimer’s drugs in clinical trials – the majority of which target proteins or processes other than amyloid. While anti-amyloid drugs are perhaps the closest to making it to patients, they are not the only hope for effective new treatments.

“It is now absolutely critical that the UK government delivers on its promise to double dementia research funding to £160m a year by 2024. This will help to put UK dementia research at the forefront of the global search for life-changing treatments, and pave the way for more breakthroughs that will transform the lives of people with dementia and their families across the UK.”

Dr Richard Oakley, Associate Director of Research at Alzheimer’s Society, said: 

“These results today are disappointing for the thousands of people living with Alzheimer’s disease, as we don’t currently have any drugs in the UK which slow down the progression of Alzheimer’s. Despite the negative findings, there are still so many lessons we can learn from this trial and the generosity of the people living with Alzheimer’s disease who have taken part will play a crucial role in driving future breakthroughs. This is still an exciting time for dementia research, with promising early results from a similar Alzheimer’s drug, lecanemab, and 142 other drugs currently in clinical trials aiming to slow down the disease or help with symptoms.

“Alzheimer’s Society research over thirty years ago was pivotal in highlighting the importance of amyloid protein in the development of Alzheimer’s disease – laying the basis for many 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.  

“We need to see the Government’s promised National Dementia Mission – to double dementia research funding – delivered urgently. It must drive early diagnosis, through improved access to PET brain scans and research to bring blood tests into the clinic, so people can get access to drugs which slow down or stop the progression of the diseases that cause dementia when they become available. With 900,000 people in the UK currently living with dementia, we need continued, unwavering investment into research for all types of dementia so no one living with dementia is forgotten.” 

https://www.roche.com/media/releases/med-cor-2022-11-14

Declared interests

Prof John Hardy: “I have consulted for Roche, Eli Lilly and Eisai on their Alzheimer programmes.”

For all other experts, no reply to our request for DOIs was received.