Biogen, developer of the controversial but promising Alzheimer’s drug Aduhelm (aducanumab), has announced it will stop selling the drug and end further study of it that was needed for full approval by the Food and Drug Administration (FDA). A company spokesperson said there are about 2,500 people worldwide taking the drug through the commercial market, and they can continue doing so until November.
Aduhelm had been given an accelerated but provisional FDA approval in 2021 but required additional study to gain full approval. At the time it was one of the first drugs that appeared to slow progression of, but not cure, Alzheimer’s disease, and thus moderately slow cognitive decline. Aduhelm is a monoclonal antibody that targets beta amyloid plaques in the brain and reduces their buildup. The plaques are believed to be closely associated with Alzheimer’s. Aduhelm was initially priced at $56,000 a year, which triggered an increase in Medicare premiums in anticipation of what coverage might cost the program. Biogen later reduced the price by half, but doctors reportedly were hesitant to prescribe the intravenous drug due to weak evidence that it adequately improved the lives of Alzheimer’s patients. There was also controversy over whether the FDA had maintained strict objectivity in evaluating Aduhelm and had coordinated too closely with its developers. As a result of these multiple factors, the drug did not fulfill Biogen’s blockbuster financial expectations for Aduhelm.
Biogen is reportedly continuing to help Japanese drugmaker Eisai market the Alzheimer’s drug Leqembi (lecanemab), which did receive full FDA approval in 2023. This drug also targets beta amyloid plaques but has been shown more convincingly to slow cognitive decline, although only at a modest level.
(For more information on Aduhelm and Leqembi, see our AgeWise Colorado articles at https://agewisecolorado.org/blog/alzheimers-drugs-are-works-in-progress/ and https://agewisecolorado.org/blog/colorado-physicians-weigh-in-on-alzheimers-drug-leqembi/.)
Alzheimer’s Drug Donanemab Undergoing Trials
Meanwhile, drugmaker Eli Lilly has been studying and testing a drug called donanemab, which is also a monoclonal antibody that goes after beta amyloids, but with potentially greater risks, according to detailed clinical trial data as reported by the American Association for the Advancement of Science (AAAS).
At an Alzheimer’s Association International Conference in Amsterdam, Eli Lilly officials reported that regular infusions of donanemab slowed the rate of cognitive decline as much as 35% compared with a placebo. They described it as a “positive trial.” Results were published in the medical journal JAMA.
“But both donanemab and lecanemab [Leqembi] come with risks of serious and even fatal brain swelling and bleeding,” AAAS states. The Association notes that geriatrics specialists in a commentary to the JAMA paper pointed out that amyloid antibodies are not low-risk, inexpensive, or simple to administer, so caution has its place. Bottom of Form
Key Benefit Remains with Early-Stage Alzheimer’s Disease
AAAS explains that the donanemab trial enrolled 1736 patients across eight countries, who were randomized to get either the experimental antibody or a placebo. Both groups got intravenous infusions every 4 weeks for 18 months. (Only 1320 of the participants completed the trial, 622 of whom were on the treatment; dropouts were attributed to side effects, changes in caregiver circumstances, and other reasons.) More than 91% of the participants were white, which triggered criticism for lack of diversity.
All the participants had symptoms of early-stage Alzheimer’s disease, and brain imaging confirmed they had amyloid buildup in the brain. Eli Lilly divided them into two different groups based on measures of a second brain protein called tau. “Typically as the condition progresses, tau can malfunction inside neurons and form clumps,” AAAS noted. “In general, scientists believe that having more such tau ‘tangles’ indicates a more advanced stage of disease.” Almost one-third of the trial participants were considered to have “high” tau pathology, based on positron emission tomography (PET) scans, and the rest had “low/medium” tau pathology.
With key Alzheimer’s drugs so far, it is expected that anti-amyloid antibodies will work better in earlier stages of Alzheimer’s disease. The donanemab trials did show the drug’s power to slow cognitive decline was greater for participants with lower tau levels. Eli Lilly reported that the low/moderate tau participants took an extra 4.5 to 7.5 months to experience the same level of cognitive and functional decline as members of the placebo group. But in the high-tau group, the cognitive advantages for those on donanemab were comparable to those on placebo, or at least not statistically different. One researcher said this confirms that Alzheimer’s needs to be treated as early as possible.
Nonanemab Appears Riskier than Lecanemab in Treating Alzheimer’s
AAAS goes on to note that nonanemab appears to come with higher risks than lecanemab. “As a class, anti-amyloid antibodies carry a chance of brain swelling and bleeding,” AAAS says, “known collectively as amyloid-related imaging abnormalities (ARIA) — whose severity can range from asymptomatic to fatal. In the donanemab trial, almost 37% of people getting the antibody developed ARIA.” AAAS added that one-quarter of participants on donanemab had brain swelling, the more common form of ARIA, and about one-quarter of these patients had symptoms, which included headaches and confusion. Three people died from brain swelling or bleeding attributed to the treatment. “By contrast, 21% of those taking lecanemab in the phase 3 trial developed ARIA, and 12.6% had brain swelling; there were no deaths linked directly to the drug [lecanemab] in the main phase 3 trial.”
Can Drug Therapy Be Paused or Stopped?
One open question about anti-amyloid antibodies is whether people taking them must do so indefinitely, which has downsides because of cost, side effects, and the inconvenience and discomfort of infusions. Eli Lilly’s trial experimented with discontinuing donanemab if a PET scan 6 or 12 months into treatment showed overwhelming clearance of amyloid plaques. AAAS says about half of the participants in the low/medium tau group met this benchmark and were switched to infusions of a placebo (unbeknownst to them or the trial doctors caring for them). “Their cognition didn’t decline any faster over the remaining time of the 18-month trial than the group that stayed on donanemab,” AAAS says, “suggesting it may be possible to shorten time on treatment or at least interrupt it, though study of this group continues.” Brain scans for ARIA are recommended now for lecanemab and will likely be part of regular care if Eli Lilly’s drug gets the OK. AAAS says physicians suggest that patients can restart treatment after ARIA resolves, depending on its severity, but there remains uncertainty about when the risk has subsided.