Solanezumab fails to slow cognitive decline in preclinical Alzheimer's disease.

New research revealed that Solanezumab was not successful in delaying cognitive decline in patients with preclinical Alzheimer's disease when compared to placebo. The study was published in The New England Journal of Medicine. 

Alzheimer's disease (AD) is a multifactorial, progressive neurodegenerative disorder with a poor prognosis affecting the older population globally. Novel therapies for AD like disease-modifying therapies are currently in the pipeline in research as they are certainly needed in a growing population of who are at risk for AD. AD biomarkers like the amyloid-beta load in the brain, precede the onset of the disease, by approximately 20 years. Recent research has also shown that solanezumab, a humanized monoclonal antibody has shown beneficial cognitive effects in mild AD patients. As there were mixed results on the efficacy of solanezumab, researchers conducted a trial to evaluate the effect of solanezumab which targets the monomeric amyloid, on cognition in patients with AD. 

A phase 3 trial was carried out in patients aged 65 to 85 years with preclinical Alzheimer’s disease. Patients with a global Clinical Dementia Rating score of 0 (range, 0 to 3, with 0 indicating no cognitive impairment and 3 severe dementia), a score on the Mini–Mental State Examination of 25 or more (range, 0 to 30, with lower scores indicating poorer cognition), and elevated brain amyloid levels on 18F-florbetapir positron-emission tomography (PET) were enrolled. Participants were randomized in a 1:1 ratio to receive solanezumab at a dose of up to 1600 mg intravenously every 4 weeks or placebo. The primary endpoint was the change in the Preclinical Alzheimer's Cognitive Composite (PACC) score over a period of 240 weeks. PACC score was calculated as the sum of four z scores, with higher scores indicating better cognitive performance. 

Key findings: 

• Out of 1169 persons who underwent randomization, there were 578 assigned to the solanezumab group and 591 to the placebo group.
• The mean age of the participants was 72 years, approximately 60% were women, and 75% had a family history of dementia.
• At 240 weeks, the mean change in PACC score was −1.43 in the solanezumab group and −1.13 in the placebo group. 
• Amyloid levels on brain PET increased by a mean of 11.6 centiloids in the solanezumab group and 19.3 centiloids in the placebo group.
• In less than 1% of the participants in each group, Amyloid-related imaging abnormalities (ARIA) with edema occurred.
• ARIA with microhemorrhage or hemosiderosis occurred in 29.2% of the participants in the solanezumab group and 32.8% of those in the placebo group.

Thus, Solanezumab did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer’s disease. 

Further reading: Trial of Solanezumab in Preclinical Alzheimer’s Disease.  10.1056/NEJMoa2305032