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ALZHEIMER’S Solanezumab Preclinical Testing

Alzheimer’s Solanezumab testing forms of amyloid at different stages had mixed results.


Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer’s disease


Solanezumab Phase 3 trial targeting monomeric amyloid was tested for people 65 to 85 years of age with preclinical Alzheimer’s disease.


A total of 1169 persons underwent randomization: 578 were 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. They were living independently without a diagnosis of mild cognitive impairment or dementia.


The trials were conducted at 67 sites in Australia, Canada, Japan, and the United States; sites were selected on the basis of experience in performing Alzheimer’s disease–related clinical trials.


Conclusion


In a phase 3 trial, solanezumab did not slow the progression of cognitive and functional decline in persons with preclinical Alzheimer’s disease as compared with placebo over a period of 4.5 years.


The A4 trial results indicate that the anti–monomeric amyloid antibody solanezumab did not slow the progression of preclinical Alzheimer’s disease as compared with placebo on the basis of the primary or secondary cognitive and functional end points over a period of 4.5 years. 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.


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 the tau PET sub study, there were similar increases in neocortical and medial temporal tau in the two trial groups.


Candidates for participation in the trial were selected for screening primarily on the basis of age and unimpaired clinical cognitive status. The screening process showed that close to 30% of these persons had abnormal amyloid PET scans, a finding consistent with those of previous studies.1-5 Cognitive and clinical decline, with progression of the global CDR score to more than 0 in 36% of the participants, in conjunction with accumulation of tau pathologic features shown on flortaucipir PET, is consistent with the view that the accumulation of brain amyloid in an unimpaired population may represent a marker for early-stage Alzheimer’s disease.


Numerical worsening with respect to the primary and secondary end points in the solanezumab group as compared with the placebo group, although not significantly different between groups, was unexpected in view of the results of a meta-analysis of the EXPEDITION trials, in which treatment with solanezumab at a dose of 400 mg intravenously every 4 weeks was associated with modest cognitive benefit in participants with mild dementia due to Alzheimer’s disease, although none of the constituent trials gave positive results. One conjecture is that the increase in the dose by a factor of four (to 1600 mg every 4 weeks) during our trial may have severely depleted monomeric Aβ and yielded cognitive worsening, similar to that seen with inhibition of γ- or β-secretase. Further analyses will explore the effect of the dose increase on cognitive and clinical outcomes.


This trial has several important limitations. Participants were not representative of older persons at risk for cognitive decline, and there were few Black participants. Our trial was complicated by a midtrial dose increase. The trial had widespread disruption of activities at the sites due to the Covid-19 pandemic.


Several trials involving persons with early symptomatic Alzheimer’s disease have shown that substantial reduction in brain fibrillar amyloid toward normal levels, as measured by amyloid PET, is associated with slowing of clinical and cognitive progression. In contrast, lesser reductions in amyloid levels have yielded disappointing results in symptomatic Alzheimer’s disease. The A4 results, in a cognitively unimpaired population, are generally consistent with these results; slowing amyloid accumulation without reduction of fibrillar amyloid levels below baseline did not slow clinical progression.


Solanezumab, which targets monomeric amyloid in persons with elevated brain amyloid levels, did not slow cognitive decline as compared with placebo over a period of 240 weeks in persons with preclinical Alzheimer’s disease.


Because solanezumab cdoes 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 the tau PET sub study, there were similar increases in neocortical and medial temporal tau in the two trial groups.


This article was published on July 17, 2023, at NEJM.org. For entire article, click here



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