Solanezumab, a monoclonal antibody that binds to the monomeric or soluble form of amyloid-beta, is no better than placebo in slowing the progression of preclinical Alzheimer's disease (AD), results of a phase 3 trial show.
Although the study was negative, its design provides important clues for future trials, lead investigator Reisa Sperling, MD, Center for Alzheimer Research and Treatment, Brigham and Women's Hospital, Massachusetts General Hospital, Harvard Medical School, told Medscape Medical News.
"The results indicate that you really need to decrease (amyloid) plaque ― it's very clear now across studies that decreasing plaque is key."
The results of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study, which is the first trial of its kind to enroll patients who were asymptomatic, also underlines the importance of early intervention, she added.
"We can detect people who have amyloid in their brain with PET [positron-emission tomography], and now with blood tests, to the point where we can predict who will decline. Unfortunately, this trial did not bend that decline, but it says to me it's possible to detect amyloid early, and hopefully one day decrease it safely and prevent dementia," said Sperling.
The findings were presented at the Alzheimer's Association International Conference (AAIC) 2023 and were simultaneously published online July 17 in The New England Journal of Medicine.
No Impact on Amyloid Accumulation
The double-blind, multicenter trial included 1147 patients (mean age, 72 years; 94% White) who were not cognitively impaired at baseline but who had elevated amyloid levels on PET.
Participants were randomly assigned to receive placebo or solanezumab for 4.5 years. The initial drug dose was 400 mg administered intravenously every 4 weeks, but the dose was quadrupled ― to 1600 mg ― part way through the trial because another trial of the drug "suggested the researchers were underdosing," said Sperling.
The primary efficacy endpoint was change at 4.5 years in the Preclinical Alzheimer Cognitive Composite (PACC), a scale that measures amyloid-related cognitive decline in unimpaired populations in clinical trials.
The mean change from baseline in the PACC score among 824 patients was -1.43 (95% CI, -1.83 to -1.03) in the solanezumab group and -1.13 (95% CI, -1.45 to -0.81) in the placebo group (difference, -0.30; 95% CI, -0.82 to 0.22; P = .26).
This indicated that there was no significant between-group difference and that there was a numerically greater decline in the solanezumab group.
The lack of significant between-group difference precluded claims of significance for subsequent endpoints ― including changes on the Cognitive Function Index, the Alzheimer's Disease Cooperative Study Activities of Daily Living Prevention Questionnaire, and the CDR–Sum of Boxes score.
PET imaging showed that amyloid continued to accumulate in both trial groups. The increase was numerically greater in the placebo group (mean difference in change, 7.7 centiloids; 95% CI, 5.1 – 10.4), but the authors note limitations with regard to statistical inferences from these results.
"Unfortunately, the antibody did not reduce amyloid in anyone, really, below baseline, and I think it insufficiently slowed accumulations, because pretty much everyone accumulated more amyloid over time," said Sperling.
In a supplement to the article, researchers examined baseline tertile levels of amyloid that predicted decline. "People with the highest tertile had twice the rate of progression to mild cognitive impairment as those in the lowest tertile," said Sperling.
On tau PET, increases in neocortical and medial temporal tau were similar in the two groups. There were also similar changes in volumetric MRI measures in the hippocampus and total gray matter for the two groups.
Sperling believes the negative results are due to the type of monoclonal antibody used. Solanezumab doesn't bind to amyloid plaque; rather, it binds to a single amyloid protein. This is in contrast to other anti-amyloid therapies, including lecanemab, which binds to protofibrils or aggregated forms of amyloid and decreases plaque, and donanemab, which binds only to plaque.
Dose analyses carried out by the researchers were inconclusive. "There's some evidence that the higher dose was worse, not better, than the lower dose, but this was not significant," said Sperling.
"That's very interesting to me and suggests that maybe going after too much of the soluble form [of amyloid] is not good."
She noted that people who take other medications that reduce monomeric forms of amyloid, such as beta secretase and gamma secretase inhibitors, also experience transient cognitive worsening.
However, the drug appeared to be safe ― serious adverse events were similar in the two groups with respect to both type and incidence.
There was one case of amyloid-related imaging abnormalities (ARIAs) with edema in the solanezumab group; there were two cases in the placebo group. ARIAs with microhemorrhage or hemosiderosis occurred in 29.2% of those in the solanezumab group and in 32.8% of those in the placebo group.
Despite the antibody that was used, Sperling praised the study design. "It went as expected, and our power calculations were as expected. We learned from the study design, and now we need a good molecule," she said, adding that they believe they have one. The AHEAD study is investigating lacanemab in asymptomatic people, some as young as 55 years, who are at risk for AD. The study is being conducted at multiple centers.
Commenting for Medscape Medical News, Claire Sexton, DPhil, senior director of scientific programs and outreach, Alzheimer's Association, said even though the study was negative, the results "will contribute to our understanding of Alzheimer's and help us better conduct trials in people in the presymptomatic stages of the disease."
This "well-crafted and conducted secondary prevention study" implemented several important practices, including a focus on recruiting a diverse and representative population, noted Sexton.
The study was supported by a public-private philanthropic partnership and received funding from the National Institute on Aging, Eli Lilly, the Alzheimer's Association, the Accelerating Medicines Partnership Through the Foundation for the National Institutes of Health, the GHR Foundation, the Davis Alzheimer Prevention Program, and the Yugilbar Foundation, with in-kind support from Avid Radiopharmaceuticals, Cogstate, the Albert Einstein College of Medicine, and the Foundation for Neurologic Diseases. Sperling is a consultant to AC Immune, Acumen, Bristol-Myers Squibb, Genentech, Ionis, Janssen, Oligomerix, Prothena, Shionogi, and Vaccinity.
Alzheimer's Association International Conference (AAIC) 2023: Presented July 17, 2023
N Engl J Med. Published online July 17, 2023. Abstract
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Cite this: Solanezumab for Preclinical Alzheimer's: Phase 3 Data - Medscape - Jul 20, 2023.