By Michael T. Lin, MD, PhD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
SYNOPSIS: After a four-year, complex clinical trial of an anti-amyloid antibody, solanezumab, which acts via binding and elimination of monomeric soluble amyloid-beta, there was no benefit in reducing the likelihood of progression of cognitive impairment in patients with positive amyloid positron emission tomography scans who started the trial cognitively unimpaired, compared to placebo. Lessons learned from this trial may enable successful trials in the future, with other, more effective drugs.
SOURCE: Sperling RA, Donohue MC, Raman R, et al. Trial of solanezumab in preclinical Alzheimer’s disease. N Engl J Med 2023; Jul 17. doi: 10.1056/NEJMoa2305032. [Online ahead of print].
Alzheimer’s disease (AD) has a long preclinical course, more than a decade, in which amyloid plaques and neurofibrillary tangles accumulate without clinically evident cognitive impairment. The prevalence of preclinical AD increases exponentially with age, with approximately 20% to 40% of cognitively unimpaired older subjects having amyloid-positive positron emission tomography (PET) scans. These subjects are at an increased risk for cognitive decline. An intervention that could prevent or delay onset of cognitive decline would have enormous epidemiologic effect.
The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) trial was a double-blind, placebo-controlled, randomized clinical trial of the anti-amyloid monoclonal solanezumab in cognitively unimpaired subjects with positive amyloid PET scans. A total of 1,169 participants were randomized in a 1:1 ratio to receive placebo or solanezumab intravenously every four weeks for 240 weeks. The primary outcome was the change in Preclinical Alzheimer Cognitive Composite score, a composite of the Free and Cued Selective Reminding Task, the delayed paragraph recall on the Logical Memory test of the Wechsler Memory Scale, the Digit Symbol Substitution Test, and the Mini Mental State Exam.
It should be noted that the initial choice of solanezumab and dosage of 400 mg was made long before the recently reported successes of lecanemab and donanemab, based on a subgroup analysis of previous solanezumab trials in mild to moderate AD that suggested benefit in mild disease.1-3 However, in the middle of the A4 trial, a subsequent trial of solanezumab 400 mg in mild AD showed no benefit, so the dose in A4 was increased from 400 mg to 1,600 mg.4
Unfortunately, there was no significant difference between solanezumab and placebo in the primary outcome. In fact, there was a nonsignificant trend for the placebo group to perform better than the solanezumab group at all time points past 48 weeks. Solanezumab resulted in smaller increases than placebo in amyloid levels on PET, indicating target engagement. There was no increase in amyloid-related imaging abnormalities (ARIA) from solanezumab treatment compared to placebo.
COMMENTARY
Although the outcome was negative, the A4 trial was a tour de force with multiple potential lessons. Many participants were screened, and approximately one-quarter of older subjects eligible for amyloid PET had positive scans, in accord with previous epidemiology. The trial was long (> 4 years/subject), as required for a prevention trial in a slowly progressive disease, but succeeded with a 70% completion rate. The trial also was paused because of the COVID-19 pandemic, requiring modifications to the statistical analysis plan. The dosing regimen was modified midway, as noted earlier, which demonstrated resilience and forethought in answering the potential question of whether a negative trial was the result of an inadequate dose.
The difference between solanezumab, which is directed against monomeric soluble amyloid-beta, and lecanemab and donanemab, which are directed against fibrillar amyloid-beta, suggests differences in pathogenetic importance of different amyloid-beta species, although much remains to be explained. For example, bapineuzumab, which also is directed against fibrillar amyloid-beta, showed no clinical benefit.5 Also, the nonsignificant trend for solanezumab to worsen performance resembles the outcomes in trials of beta- and gamma-secretase inhibitors, which decreased amyloid-beta production and worsened performance compared to placebo.6 One possible interpretation of these results is that monomeric amyloid-beta may play some as yet unknown physiologic function and that plaques/fibrillar amyloid-beta may be deleterious because they sequester the monomeric amyloid-beta. Finally, the A4 trial established a network and machinery for a similar trial, now recruiting, testing the newly successful lecanemab in cognitively unimpaired subjects with positive amyloid PET.7
REFERENCES
- van Dyck CH, Swanson CJ, Aisen P, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med 2023;388:9-21.
- Sims JR, Zimmer JA, Evans CD, et al. Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 2023;330:512-527.
- Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:311-321.
- Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. N Engl J Med 2018;378:321-330.
- Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med 2014;370:322-333.
- Imbimbo BP, Ippati S, Watling M, Imbimbo C. Role of monomeric amyloid-beta in cognitive performance in Alzheimer’s disease: Insights from clinical trials with secretase inhibitors and monoclonal antibodies. Pharmacol Res 2023;187:106631.
- ClinicalTrials.gov. AHEAD 3-45 Study: A study to evaluate efficacy and safety of treatment with lecanemab in participants with preclinical Alzheimer’s disease and elevated amyloid and also in participants with early preclinical Alzheimer’s disease and intermediate amyloid. Updated June 28, 2023. https://clinicaltrials.gov/study/NCT04468659
