Neurodegeneration — 8

The graveyard of putative Alzheimer’s disease treatments aimed at β-amyloid and other pathways is replete with hundreds of failed attempts over the past three decades. That appeared to change in 2016, when a paper claimed that aducanumab, a monoclonal antibody, reduced brain Aβ plaque after one year of monthly infusions; it claimed “compelling support for the amyloid hypothesis” if confirmed in ongoing phase 3 randomized clinical trials. Two phase 3 trials followed but were stopped early in 2019 because the treatment showed no clinical benefit to participants with mild cognitive impairment or mild Alzheimer’s. The trials were later restarted by the biotech company Biogen, who then claimed PET imaging showed that the high dose in one trial effectively lowered β-amyloid levels. Defying all ten experts on the FDA Advisory Committee who recommended against approving the drug, the FDA went ahead and gave this antibody, with the trade name Aduhelm, a green light in 2021. Some members of the FDA Advisory Committee resigned in protest, one proclaiming it as “probably the worst drug approval decision in recent U.S. history.” Serious side effects such as brain swelling in 35 percent of participants and microhemorrhages in 20 percent had not swayed the decision. It was later learned by STAT news that the FDA was working hand in hand with the company to help resurrect the drug. After approval, with a list price of $56,000 per year, Aduhelm was scantly prescribed, it did not get Medicare reimbursement, and Biogen gave away its ownership of the drug to Neurimmune in 2024. All in all, not a good start for the first amyloid monoclonal antibody that seemed to reduce brain plaque.

The monoclonal antibody entry that next reported positive results was lecanemab (Leqembi), with a phase 3 trial published in 2023. Compared with placebo, intravenous antibody infusions every two weeks for eighteen months led to reduction of β-amyloid and “moderately less decline” of cognition. Amyloid-related imaging abnormalities, brain edema, and microhemorrhages occurred in 12.6 percent of the antibody group and 1.7 percent in the placebo group. In 3 percent of the antibody group, these three factors caused serious problems, requiring urgent evaluation and management, compared with none receiving placebo. In the treatment group, the three factors were proportionally worse for individuals with the APOE4 gene than noncarriers. There was also more brain shrinkage with the antibody and a 3 percent incidence of major bleeding in people taking blood thinners. Despite these bad results, Leqembi was approved by the FDA in 2023 with an annual cost of $26,500 per year, and the associated imaging and monitoring brings up the cost to over $75,000 a year.

The third antibody drug to come along with signs of efficacy in a phase 3 trial was donanemab. The researchers used the same enrollment criteria of mild cognitive impairment or early Alzheimer’s, but with a monthly rather than biweekly infusion over eighteen months and stopping the treatment at twenty-four or fifty-two weeks if the PET scan showed sufficient amyloid clearance. For analysis, the trial partitioned the participants by level of Tau accumulation. Donanemab achieved more reduction of amyloid than lecanemab but also induced almost twice as many bad effects. Along with more edema and microhemorrhages, three deaths in the trial were from donanemab treatment. These fatal events may be related to accumulation of amyloid around brain blood vessels. Treatment appeared to delay the deterioration of cognitive function for four months, more for the group of patients with low to medium Tau levels on PET imaging. One difference from the lecanemab trials is that donanemab treatment was stopped when the brain scan showed minimal to no amyloid. This occurred in two-thirds of participants after one year of treatment. In contrast to the treatment’s impact on amyloid by brain imaging, using standard cognitive ability criteria, the reduction was 0.7 points compared with 0.5 points with lecanemab, a modest indication of incremental benefit. However, a full one-point reduction has been deemed to signal a clinically meaningful outcome, so this is still somewhat short of that goal. Nevertheless, donanemab was approved by the FDA in 2024.