Health & Wellbeing

The amyloid rollercoaster continues as another big Alzheimer's trial fails

The amyloid rollercoaster continues as another big Alzheimer's trial fails
Are researchers wrong to keep working on anti-amyloid treatments for Alzheimer's after years of clinical trial failures?
Are researchers wrong to keep working on anti-amyloid treatments for Alzheimer's after years of clinical trial failures?
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Are researchers wrong to keep working on anti-amyloid treatments for Alzheimer's after years of clinical trial failures?
Are researchers wrong to keep working on anti-amyloid treatments for Alzheimer's after years of clinical trial failures?

A new announcement from pharmaceutical company Roche has revealed the failure of a massive global Phase 3 trial testing its latest anti-amyloid Alzheimer's disease treatment. The failure marks another twist in the ongoing rollercoaster of research looking for drugs to reduce build-up of the protein commonly believed to be the primary pathological cause of Alzheimer's neurodegeneration.

The latest announcement from Roche covered the first results from a Phase 3 trial testing its anti-amyloid monoclonal antibody gantenerumab. The trial included nearly 2,000 participants in the early stages of Alzheimer's disease with mild cognitive impairment.

The huge placebo-controlled trial, spanning dozens of sites around the world, involved subcutaneous injections of the novel drug every fortnight for more than two years. At the end of the study period participants' cognitive functions were measured using a variety of tools. According to the preliminary data from Roche there was no significant slowing of cognitive decline in the gantenerumab group compared to placebo.

The results come just months after another similar trial testing lecanemab, a different anti-amyloid monoclonal antibody, reported positive results, slowing cognitive decline after a period of 18 months. That trial, from pharma companies Eisai and Biogen, was the first Phase 3 investigation to ever show an anti-amyloid drug reducing cognitive decline compared to placebo.

Amyloid what?

The "amyloid hypothesis" is the idea that a build-up of plaques, composed of a protein called beta-amyloid, contribute to the fundamental degenerative nature of Alzheimer's disease. The association goes back a century, to German scientist Aloysius Alzheimer who first noted the correlation between amyloid plaques in the brain and dementia.

In the 1980s the hypothesis became the dominant force for most Alzheimer's research. Scientists focused on developing treatments to reduce or remove amyloid accumulations in the brain with a hope that it would be an effective way to cure/prevent Alzheimer's disease.

Over the last decade, following a constant parade of failed anti-amyloid clinical trials, many researchers have started to question the prevailing hypothesis. Has the near-absolute focus on amyloid-reducing therapies been a research dead-end? How many treatments targeting amyloid need to fail before that hypothesis is abandoned?

In 2021 the world of anti-amyloid research was bolstered by the controversial FDA approval of a drug called Aduhelm (also known as aducanumab). The approval marked the very first anti-amyloid antibody therapy to ever be approved, but not everyone was convinced.

Some experts called it "the worst drug approval in recent US history" after an independent FDA advisory panel claimed there was no convincing evidence the drug actually worked. And the decision to approve the drug was so acrimonious it led to the resignation of several key FDA advisors.

The approval of Aduhlem was primarily based on clinical evidence showing the drug can reduce the build-up of amyloid plaques in Alzheimer's patient brains. However, the trial data couldn't point to this resulting in any significant reduction in signs of cognitive decline.

Then, in 2022, following the announcement that anti-amyloid antibody lecanemab both reduced amyloid plaque accumulations and slowed cognitive decline, all eyes turned back to the amyloid hypothesis. Maybe it was the correct target after all. Maybe researchers simply hadn't been delivering the treatment early enough? Maybe the amlyoid-targeting antibodies just needed optimizing?

It's not over for amyloid

The failure of gantenerumab, in a trial targeting very early-stage Alzheimer's patients, is a potent reminder that the vast majority of anti-amyloid Alzheimer's treatments have failed major clinical studies. Susan Kohlhaas, director of research at Alzheimer's Research UK, said these new findings are "extremely disappointing" but not necessarily the death-knell for amyloid treatments.

“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," said Kohlhaas. "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."

A statement from the US Alzheimer's Association also expressed disappointment in the gantenerumab results. However, echoing Kohlhaas's comments, the Association said lots will be learned from the gantenerumab study and anti-amyloid treatments may still offer benefits to certain patients.

"Each anti-amyloid treatment is being tested in a different way and may act differently on the protein that is one of the hallmarks of Alzheimer’s," the association said in a statement. "Research into their effectiveness and safety must continue."

Other researchers looking at the gantenerumab results are divided over what it means for the future of anti-amyloid therapies. John Hardy, a neuroscientist at University College London, is optimistic that comparing gantenerumab data with lecanemab will help offer novel understandings into, "what new agents need to do in terms of amyloid removal to have a clinical effect."

Francesco Tamagnini, a neurophysiologist from the University of Reading, is a little more skeptical. He calls the new findings a blow to approaches focusing on removing amyloid from the brain. He argues it is "obvious" there may be other fundamental mechanisms at play in Alzheimer's and researchers must shift their focus now.

"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," said Tamagnini. "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."

Chipping away further at the veracity of anti-amyloid research is a recently published commentary from an international team of radiologists and nuclear medicine researchers. The team questions the validity of the entire foundation of modern amyloid research – the amyloid PET scan.

The team claims current PET imaging techniques used to evaluate amyloid levels in the human brain are misleading and inaccurate. Abbas Alavi, from the University of Philadelphia and co-author on the paper, said it is possible these brain scans are mistaking treatment-induced brain damage for reductions in amyloid levels and the FDA should not be relying on the measure for drug approvals.

"We believe this kind of PET scanning is questionable and has misled the FDA into making a decision contrary to the agency's foremost mission to 'protect and promote the public health,'" said Alavi. "In addition to our concerns, we suspect that the amyloid PET scans performed are not reflecting amyloid removal, but rather are indicative of increased therapy-induced brain damage."

From the perspective of Roche pharmaceuticals this is not the end of their research into gantenerumab, or Alzheimer's disease in general. Other large Phase 3 trials are ongoing, testing the drug in different cohorts of patients, particularly those with early amyloid brain accumulations who are yet to show signs of cognitive decline.

Unlike companies like Pfizer, which completely got out the Alzheimer's research game back in 2018 after a several failed Phase 3 trials, Roche is placed alongside a few big pharma players still working on anti-amyloid therapies.

But amyloid certainly isn't the only game in town anymore.

A 2021 review looking at Alzheimer's drugs in the research pipeline cited over 100 clinical trials underway, and less than half are focused on amyloid. Compared to just a few years ago the world of Alzheimer's research has diversified and ongoing trials are testing everything from reducing brain inflammation to strengthening the blood-brain barrier.

Perhaps the biggest challenge Alzheimer's researchers face is dealing with a neurodegenerative disease that can progress slowly for decades before signs of cognitive decline appear. Some researchers argue the disease may only be effectively treated in its earliest stages, before dementia appears, presenting significant challenges for our current clinical trial model.

After all, it isn't feasible to run 20-year clinical trials just to test the possibility of a single intervention preventing dementia. And without a clear brain biomarker like amyloid offering a proxy for disease progression in Alzheimer's studies how are researchers to know a pre-symptomatic treatment is actually working?

Love this article!
They indeed seem to be barking up the wrong tree. I recall a study of the brains of nuns who bequeathed their brains for medical research which found that some nuns who died without signs of dementia had extensive amyloid plaques present in their autopsied brains.