When Lori Weiss was diagnosed with mild cognitive impairment because of Alzheimer’s disease she thought it was a death sentence, given there were no approved treatments that could slow progress of the debilitating disease.
But after enrolling in a trial of an experimental therapy developed by Eli Lilly, the 65-year-old former teacher says her memory has improved and she is able to do things she previously found difficult.
“I’m able to drive again. I have freedom,” said Weiss, who was one of more than 1,700 participants in the late-stage trial of a drug called donanemab.
This week US drugmaker Lilly published positive results from the trial, raising hopes among patients and doctors for a new class of drugs being developed to treat Alzheimer’s. It also generated excitement across the pharmaceutical industry, which is enticed by the prospect of selling medicines to the more than 50mn people worldwide who suffer from the disease.
The trial showed donanemab slowed progression of the disease by 35 per cent compared with a placebo over an 18-month period. Although there is no evidence that the drug can reverse the symptoms of Alzheimer’s, the trial showed the decline in patients’ ability to perform daily tasks was 40 per cent lower for those on donanemab.
Lilly said it anticipates US regulators will approve the drug later this year based on the successful trial results.
The results mark the second significant breakthrough in a year for a class of drugs targeting a disease that is the most common cause of dementia and for which there is no cure. It comes as a new generation of blood tests for Alzheimer’s are being developed which offer the tantalising prospect of early detection and treatment of the condition for the first time.
In January the US Food and Drug Administration approved lecanemab, a drug co-developed by Japanese drugmaker Eisai and US biotech Biogen, under an accelerated process. In a late-stage trial the drug slowed the rate of cognitive decline in patients by 27 per cent when compared to placebo.
Both drugs work by reducing the build-up of sticky amyloid plaques in the brain known as beta-amyloid, which are at the centre of an acrimonious scientific debate about what causes Alzheimer’s.
Almost two dozen clinical trials on drugs seeking to treat Alzheimer’s by reducing these plaques have failed since 2003, prompting scepticism among some experts that removing amyloid can slow progression of the disease.
The controversial approval by the FDA of another amyloid reducing drug called aducanumab in 2021, despite conflicting evidence that it slowed the rate of cognitive decline, further inflamed the debate.
Lilly told the Financial Times the results of the donanemab and lecanemab trials together prove the “amyloid hypothesis”, the theory holding that sticky amyloid plaques are the main cause of Alzheimer’s disease.
“As you look across the class you should be reassured about the ‘amyloid hypothesis’ because you can see in medicines, not just ours but in others that robustly remove plaque, you see clinical benefit,” said Anne White, president of Lilly Neuroscience.
Donanemab showed strong efficacy in removing the plaques in the trial, with just over half of trial participants able to complete their course of treatment within a year as they achieved the target for amyloid clearance.
The Alzheimer’s Association, an advocacy group, said the trial results were the “strongest” released to date for an amyloid-reducing drug and suggested an “inflection point” for treatment of the disease. Many experts welcomed the Lilly data as an important step forward but cautioned that donanemab was not a cure and the full results of the trial have not yet been published and need to be closely studied.
“While this result is greatly encouraging, it is clear we still have a lot more work to do,” said Dr Ian Musgrave, senior lecturer in pharmacology at University of Adelaide, Australia. “Despite near total removal of amyloid plaque, the disease still did progress, although at a much slower rate than without treatment.”
Scientists are pursuing other targets beyond sticky plaques in their pursuit of Alzheimer’s therapies, including inflammation in the brain. But none of these are as advanced as lecanemab and donanemab.
However, there are concerns over whether the slowdown in cognitive decline achieved by both drugs is clinically meaningful and worth the risks posed by potentially dangerous side effects.
Rob Howard, a professor of old-age psychiatry at University College London, said slowing the progression of the disease by 35 per cent sounded superficially impressive. However, the absolute differences between donanemab and placebo in cognition and function, apparent from the trial, were so tiny that they would be unnoticed by patients and their families.
“This raises the question of whether taking the drug is worth the risks, given that three people died during the trials from side effects,” he said.
Both lecanemab and donanemab can cause severe side effects such as brain swelling and bleeding, which can be fatal. This will place a heavy burden on doctors when they recommend treatment, although the lack of alternatives suggests high patient demand for the drugs.
The high price of the drugs — lecanemab is priced at $26,500 per year — and tough restrictions imposed by the US government on reimbursement by publicly funded health schemes for amyloid-reducing treatments are other hurdles.
In the wake of the controversy over the FDA approval of Biogen’s aducanumab, the US Centers for Medicare and Medicaid Services said only patients taking part in a clinical trial would benefit from reimbursement. It was the first time CMS had imposed such restrictions on a drug approved by the FDA and it limits the number of patients on amyloid drugs to a few thousand, rather than the 6mn Alzheimer’s sufferers in the US.
“Unfortunately we are in uncharted territory,” said Robert Egge, chief public policy officer at the Alzheimer’s Association.
He said every day that reimbursement is denied about 2,000 Alzheimer’s sufferers in the US move past the window of eligibility for amyloid-reducing drugs, as they are only targeting early-stage patients.
Eisai said it is encouraged by “ongoing productive discussions” with CMS about lifting the restrictions. This could happen in July when lecanemab, which has been approved under an accelerated process, is expected to be granted full approval by the FDA.
For Alzheimer’s patients such as Weiss, a change of policy cannot come quick enough, even if concerns still exist about the safety and efficacy of the new drugs.
“These drugs give people a chance to get more years of their life back and live normal lives without having to face being in a nursing home,” said Weiss. “I’m still painting and going to parties with friends.”
