An experimental and closely followed drug for Alzheimer’s disease has failed a key clinical study, dealing yet another blow to the prevailing theory on how to treat a neurodegenerative illness that affects millions of people.
The drug’s developer, Roche, along with Banner Alzheimer’s Institute, the Phoenix-based organization helping lead the study, announced the negative results Thursday. After years following a family believed to be genetically predisposed to the disease, researchers found no significant difference in cognition or the ability to store and retrieve new memories between participants who received the drug and those who got a placebo.
The failure is an upset not only to Roche, which hopes to follow its rival Biogen in getting an Alzheimer’s therapy approved for market, but also to the wider Alzheimer’s research field. For years, a protein called beta amyloid has been at the center of efforts to treat the disease. But every drug designed to block this protein, including Biogen’s, has faced setbacks. Roche’s announcement may therefore add to concerns that this protein isn’t the best research target.
“We’re disappointed that the treatment did not demonstrate a statistically significant clinical benefit,” Eric Reiman, the executive director at Banner and one of the study’s leaders, said in a statement.
“This trial, the data, samples, and findings that we’ll share with the research community, and the related work that we and others are doing promise to further accelerate the evaluation and approval of future prevention therapies,” Reiman added.
Uniquely, this trial focused on an extended Colombian family whose genetic makeup puts them at a much higher risk of developing the disease. A total of 252 family members participated in the study, with two-thirds carrying a gene that, according to Banner, makes them “virtually certain” to develop early-onset Alzheimer's — usually by their mid-40s.
The trial officially began in late 2013. Over the course of five to eight years, participants were given either a placebo or Roche’s drug, which is known as crenezumab and works by binding to and clearing early forms of the beta amyloid protein before it aggregates into sticky, toxic plaques.
Throughout that time, other studies raised doubts about crenezumab’s ability to treat Alzheimer’s. Shortly after the Colombian trial kicked off, the drug missed the main goal of one so-called biomarker trial, plus another one that took place in Europe and North American and tested it in about 450 people whose disease was deemed mild to moderate.
Even so, Roche, through its Genentech subsidiary, continued to invest in crenezumab. The company tested different, higher doses of the drug, and by 2016 had pushed it into a large trial of people who had mild cognitive impairment or very early Alzheimer’s and evidence of amyloid beta. A second late-stage study kicked off the next year.
Negative results, though, led Roche to terminate both trials in 2019.
The Colombian trial has since become somewhat of a last chance at proving crenezumab’s merit as an Alzheimer’s treatment. Thursday’s readout, then, puts the drug’s future in doubt. Roche said analyses are ongoing, and that initial data will be presented at the Alzheimer's Association International Conference on Aug. 2.
But already, some don’t see much hope for crenezumab. “While management believes that the favorable safety and the numerical improvements observed across multiple endpoints warrant further analyses, it's likely that the clinical development of crenezumab will come to a halt given its” past failures, wrote Marc Goodman, an analyst at the investment firm SVB Securities, in a note to clients.
Analysts have argued the success or failure of drugs like crenezumab could also affect the prospects for Biogen’s marketed therapy, called Aduhelm, which works in a similar way. Despite receiving a landmark approval last year, Aduhelm has struggled on the market due to persistent questions about its effectiveness and the unusual path it took while being developed.
Roche is testing another amyloid-targeting drug called gantenerumab, for which hopes of success are higher. Results from two late-stage studies are expected in the fourth quarter. Biogen, too, has a different amyloid drug in development together with partner Eisai, which recently finished submitting the treatment for accelerated Food and Drug Administration approval. Phase 3 study data for that drug are anticipated this fall.