Alzheimer’s research progresses: antibody drug donanemab shows efficacy

Study results, however, again reveal severe side effects

Following the controversial approval of aducanumab (Aduhelm™) two years ago and the approval of lecanemab (Leqembi™) earlier this year by the U.S. Food and Drug Administration (FDA), a third Alzheimer’s antibody is about to be launched: manufacturer Eli Lilly published preliminary results of its Phase III study with the anti-amyloid antibody donanemab in a press release on May 3, 2023. This humanized IgG1 antibody specifically targets a pyroglutamate epitope of beta-amyloid found exclusively in deposited plaques. These deposits in the brains of Alzheimer’s patients are a key indicator and, according to the amyloid hypothesis, the cause of the disease.

Donanemab uses body’s own immune system to remove amyloid plaques

Donanemab works by attacking a common hallmark of Alzheimer’s disease in the brain: amyloid plaques. Beta-amyloid is a protein that plays an important role in brain function in all people. But in patients:with Alzheimer’s, beta-amyloid becomes toxic – it clumps together and disrupts the connections between brain cells and their functions. This leads to cognitive problems such as memory loss.

Donanemab uses the body’s immune system to target and remove these amyloid plaques from the brain, and in the process also manages to stem the decline caused by the disease. The most important thing about this new drug, however, is that it binds only to harmful, established plaques, leaving other forms of beta-amyloid untouched.

Cognitive decline slowed by 35%

The study was conducted in 1,182 subjects who showed signs of early Alzheimer’s disease and were found to have plaques in their brains. Of the participants, half received intravenous doses of 700 mg of donanemab three times initially every four weeks, followed by 1400 mg every four weeks. The other half of the participants:in were treated with a placebo.

The duration of treatment of the participants:in was determined individually by measuring the plaques in the brain. Treatment was always completed only when the plaques in the brain were considered eliminated. Slightly more than half of the subjects completed their treatment after one year, and another 20% after 18 months.

Almost half of the participants who received donanemab showed no worsening of their disease after one year. In contrast, this was true for only 29% of the placebo group. Importantly, compared with the placebo group, donanemab slowed clinical and functional decline in memory function by 35% in all cases studied.

The researchers then focused their analyses on an additional 552 patient:ing who had high levels of tau in the brain (a small protein typically used as a marker of Alzheimer’s disease progression and severity). They found that cognitive decline was slowed by 22% relative to data from those study participants:in who had intermediate levels of tau.

Encouraging results, but even more severe side effects than with lecanemab and aducanumab

Although data published to date suggest that donanemab may be more effective than lecanemab in delaying cognitive decline, results from the phase 3 trial also show that the drug can have significant side effects. Brain swelling occurred in 24 percent of participants:and three study participants:died from brain swelling or bleeding.

Donanemab can neither cure nor stop Alzheimer’s disease

In scientific circles, there is encouragement on the one hand that after so many setbacks in Alzheimer’s drug development, research approaches using antibody drugs finally seem to be succeeding. But numerous critical voices are dampening exaggerated expectations.

For the individual patient, the positive effect will hardly be noticeable after 18 months,” says Prof. Stefan Teipel, head of the Clinical Dementia Research Group in Rostock, for example, regarding the study results. The hope is “that the effects last over longer periods of time, but this has not yet been shown”.

The study results on donanemab are a “real advance for patients,” said Frank Jessen, director of the Department of Psychiatry and Psychotherapy at the University Hospital of Cologne. In principle, he said, the effects of donanemab and lecanemab are comparable. “For an exact comparison, one needs to see the study data and hopefully also gain comparative experience with these substances in future care in Germany.

Donanemab is “unfortunately not a gamechanger, but possibly a next step in the right direction,” said Linda Thienpont, director of science at the Alzheimer’s Research Initiative. “It can neither cure nor stop Alzheimer’s disease, but also like lecanemab, it can at least slow cognitive decline.” However, Thienpont also reiterated the side effects, some of which are severe, and the effect is “dearly bought.

We are encouraged by the potential clinical benefits that donanemab may offer, although as with many effective treatments of debilitating and fatal diseases, there are associated risks that can be severe and life-threatening,” Mark Mintun, MD, group vice president of neuroscience research and development at Lilly and president of Avid Radiopharmaceuticals, accordingly acknowledged in the manufacturer’s press release.

Manufacturer seeks global approvals as soon as possible

It is not yet known which patient:s are at higher risk of developing dangerous side effects, nor whether the use of donanemab can be preventive in patient:s without symptoms but with established plaques. Finally, it is not yet known whether and when plaques may recur or whether the effects of donanemab are permanent. Further studies need to focus on investigating these unknowns.

Nonetheless, U.S. company Eli Lilly is seeking approval for its Alzheimer’s drug candidate donanemab. Approval applications are now to be submitted worldwide as soon as possible, in the U.S. still in the current second quarter.