An experimental Alzheimer’s drug made by Eli Lilly slowed cognitive decline in early-stage patients, data confirmed on Monday, putting it on course to be the second treatment approved within months that alters the course of the disease.
AN EXPERIMENTAL Alzheimer’s drug made by Eli Lilly slowed cognitive decline in early-stage patients, data confirmed on Monday, putting it on course to be the second treatment approved within months that alters the course of the disease.
Donanemab, a once-a-month treatment administered intravenously, slowed cognitive and functional decline by about 35 percent, compared with a placebo, over 18 months, according to data published in JAMA, the peer-reviewed journal of the American Medical Association. Company officials said the results showed the benefits of treating Alzheimer’s as early as possible.
The late-phase clinical trial enrolled about 1,700 people with mild cognitive impairment or early dementia – the earliest stages of symptomatic disease – who had a build-up of the toxic protein amyloid beta in their brains.
The trial outcomes were “the most positive we have seen,” said Howard Fillit, co-founder and chief science officer of the Alzheimer’s Drug Discovery Foundation, a non-profit that promotes research on treatments for Alzheimer’s. He said therapies that target amyloid, as donanemab does, “will serve as the first line of defence in the arsenal of drugs needed to treat this disease,” and he predicted the Food and Drug Administration would approve the medication within months.
Other experts were not impressed. While donanemab was very effective at eliminating amyloid, “the clinical effect was comparatively weak,” Jennifer Manly, of Columbia University Irving Medical Center, and Kacie Deters, of the University of California at Los Angeles, wrote in an editorial accompanying the data in JAMA. In addition, they said, the drug, like others in its class, poses safety issues including brain swelling and bleeding.
The trial divided participants into two groups – those whose brains contained low-to-medium levels of a toxic form of tau, a marker for the progression of Alzheimer’s, and those with high tau levels. For the low-to-medium tau group, the medication slowed the disease by about 41/2 to 71/2 months.
When patients with high levels of tau – whose disease had progressed further – were included in the calculation, the drug slowed decline by 22 percent on one assessment tool and 29 percent on another, compared with a placebo. That represented a slowing of progression of 21/2 to almost 51/2 months.
The efficacy numbers were modest but slightly better than for Leqembi, the first disease-altering drug to receive full FDA approval. But Leqembi had fewer safety issues. Experts cautioned against comparing trials that are conducted differently.
Both drugs, by lowering amyloid, can slow the spread of tau, which is closely linked to the death of neurons.
“The earlier you get to patients . . . the better the results in efficacy you can see from this drug,” Mark A Mintun, Lilly’s vice president of pain and neurodegeneration research, said on Monday during a briefing with reporters.
He pointed to a subgroup analysis that showed the drug slowed decline in people with mild cognitive impairment, the earliest stage of participants included in the study, by up to 60 percent. But that analysis, and another showing that people younger than 75 benefited more from the drug, were not included in the JAMA article and should be viewed cautiously, some researchers said.
Mintun acknowledged that the number of patients in the trial with mild cognitive impairment was small but expressed confidence future data would support the value of early treatment.
Many of the top-line numbers in the study were included in a company news release in May but had not yet been reviewed by outside scientists. The JAMA article, and additional information from the company, was released simultaneously at the Alzheimer’s Association International Conference in Amsterdam.
Detractors say the anti-amyloid treatments have only limited effectiveness and pose potentially serious safety risks. Almost 37 percent of patients in the donanemab trial experienced brain swelling or bleeding – something called amyloid-related imaging abnormalities – a higher rate than with Leqembi. In most cases, the side effects were safely managed. But with each drug, there were three deaths in trials linked to the medications.
Lilly, which has already filed for full FDA approval of donanemab, said it expects a decision by the end of the year. The agency approved Leqembi based on data showing the drug slowed cognitive and functional decline by 27 percent over 18 months compared with a placebo. That represented a five-month slowdown in progression.
If donanemab is cleared, there would be two drugs on the market shown to affect the course of Alzheimer’s – a striking development considering decades of failure to develop disease-modifying treatments.
The Lilly trial showed that the benefit of donanemab compared with a placebo increased during the 18-month trial and reduced the risk of progressing to a more serious stage of illness.
Unlike in the Leqembi trial, patients in the donanemab trial were taken off the drug once most of the amyloid plaque in their brains was removed – which occurred within a year for many patients, Lilly said. Being able to stop the drug – instead of continuing on it indefinitely – could provide comfort to Medicare and other insurers who will foot the bill for the drug, and for patients who don’t relish the prospect of a lifetime of treatments.
Leqembi, which is made by the pharmaceutical firms Eisai in Tokyo and Biogen in Cambridge, Mass., and donanemab are monoclonal antibodies, or lab-made proteins that target a substance in the body – in this case, amyloid beta. The medications are not a cure and do not restore memories ravaged by the fatal neurodegenerative disease. Leqembi, an intravenous drug administered every other week, is priced at $26,500 a year.
Experts praised a novel part of the trial – Lilly’s use of tau as a biomarker – saying it could be an important indicator of which patients will benefit from the medication.
“The main message here is the need to biologically stage the illness,” just as oncologists determine the stage of cancer before deciding on treatment, said Gil Rabinovici, director of the Alzheimer’s Disease Research Center at the University of California at San Francisco. Rabinovici co-wrote one of several editorials in JAMA that accompanied the clinical trial results. He was not involved in the study.
Rabinovici said people with high levels of tau received “little to no benefit” from the drug and that donanemab should be limited to patients with low-to-intermediate levels of tau. But he acknowledged in the editorial that it would be difficult to follow that guideline because of limited access to special brain scans for tau. He said he hoped blood tests could soon be used as an alternative to those scans.
Lilly disagreed with Rabinovici’s assessments, saying donanemab helped the high tau patients given the drug, even though the benefit was smaller. Fillit of the Alzheimer’s Drug Discovery Foundation said he doubted that the FDA would require the scans as a requirement for starting treatment.
In a statement, the Alzheimer’s Association called the Lilly results “an important advancement,” and noted that nearly half of participants at the earlier stage of disease had no clinical progression at one year, compared with 29 percent on a placebo. But it also expressed disappointment at the low numbers of people of colour represented in the study.
“Dementia disproportionately affects Black and Hispanic Americans yet, too often, they are severely under-represented in treatment studies,” the organization said. Only about 2 to 3 percent of the participants in the trial were Black and less than 6 percent were Latino.
Soon, patients and doctors might face a difficult choice: whether to try donanemab, Leqembi – or neither.
James E Galvin, a neurologist at the University of Miami Health System, said that when more than one treatment is available, “each patient needs to be considered as an individual case,” depending on other medical conditions, the state of the disease and possibly the insurance company involved.
In some cases, he said, patients and their families might choose donanemab because of its amyloid-clearing ability, but others might prefer Leqembi, with its lower rate of side effects.
– THE WASHINGTON POST
