Solanezumab Shows No Significant Impact on Preclinical Alzheimer Disease

Reisa Sperling, MD

After topline data were announced earlier this year, investigators have published full findings from the phase 3 Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study (NCT02008357) in the New England Journal of Medicine. All told, treatment with solanezumab (Eli Lilly), an investigational antiamyloid agent, failed to slow cognitive decline as compared with placebo over a period of 240 weeks in patients with preclinical Alzheimer disease (AD).

The trial featured 1169 patients aged 65 to 85 years of age with a global Clinical Dementia Rating score of 0, indicating no cognitive impairment, and elevated brain amyloid levels on 18F-florbetapir PET. At the conclusion of a 240-week treatment period, findings showed a mean change in Preclinical Alzheimer Cognitive Composite (PACC) score of –1.43 in the solanezumab group and –1.13 in the placebo group (difference, –0.30; 95% CI, –0.82 to 0.22; P = .26), indicating no significant differences with active treatment.

Led by Reisa Sperling, MD, a neurologist at Brigham and Women’s Hospital, Harvard Medical School, the study’s goal was to assess whether solanezumab, an immunoglobulin G1 monoclonal antibody that binds to the mid-domain of the amyloid-ß monomer, could impact disease progression in patients with preclinical AD. Patients came into the study with a Mini-Mental State Examination score of 25 or more and a Wechsler Memory Scale Logical Memory Delayed Recall (LMDR) score of 6 to 18. Patients with LMDR scores greater than 18 were excluded to enhance the likelihood of enrolling persons with elevated brain amyloid levels.

Randomization was stratified according to apolipoprotein E (APOE) ε4 carrier status, years of education (≤12 or >12), and trial site. The dose was initially 400 mg intravenously every 4 weeks, but results from a previous trial indicated that this might not be the optimal dose, and thus the protocol was changed to adjust the dose to 1600 mg intravenously every 4 weeks, when approximately 970 participants had already been enrolled. At the same time, the double-blind phase of the trial was extended to 240 weeks to ensure substantial exposure to the higher dose and sufficient time to evaluate efficacy.

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Across both groups, 33.4% of participants had progression of the global CDR score at 240 weeks. Amyloid continued to accumulate above baseline levels in both groups throughout the trial; however, this increases was numerically larger in the placebo group (19.3 centiloids vs 11.6 centiloids; mean difference in change, 7.7 centiloids; 95% CI, 5.1-10.4). Among 114 participants in each group with available data on tau PET, increases in neocortical and medial temporal tau were similar between the groups. Additionally, changes in volumetric MRI measures in the hippocampus and total gray matter were similar as well.

"Solanezumab was selected for this trial on the basis of its safety profile and cognitive benefits in a meta-analysis involving persons with mild Alzheimer’s disease," Sperling et al wrote. "Because solanezumab does not bind to fibrillar deposits, the imaging results accorded with the expectation that it would not reduce amyloid plaque load on follow-up PET imaging below baseline levels. Solanezumab appeared to slow amyloid accumulation over the course of the trial, a finding consistent with target engagement."

In both groups combined, higher baseline amyloid levels were associated with faster cognitive and functional decline and a greater risk of progression to symptomatic AD, but no formal statistical conclusions were drawn from the analyses. Between the solanezumab and placebo groups, investigators found no differences in the frequency of adverse events (AEs; 97.9% vs 97.6%) and serious AEs (30.1% vs 26.7%). One case of amyloid-related imaging abnormalities (ARIA) with edema was reported in the solanezumab group and 2 cases were reported in the placebo group. ARIA with microhemorrhages or hemosiderosis were observed in 29.2% of solanezumab-treated patients and 32.8% of those on placebo.

REFERENCE
1. Sperling R, Donohue MC, Raman R, et al. Trial of solanezumab in preclinical Alzheimer’s disease. N Engl J Med. 2023;389:1096-1107. doi:10.1056/NEJMoa2305032