By Makoto Ishii, MD, PhD
Assistant Professor of Neuroscience and Neurology, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medical College
Dr. Ishii reports no financial relationships relevant to this field of study.
Despite the disappointing results in EXPEDITION 3, modifications of clinical trials for Alzheimer’s disease (AD) should be undertaken and trials targeting preclinical or early AD should continue with anti-amyloid agents.
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.
Alzheimer’s disease (AD) remains an incurable dementia without any disease-modifying therapy and no new FDA-approved drug since memantine in 2003. EXPEDITION 3 is the third Phase III clinical trial using solanezumab, a humanized monoclonal antibody designed to increase clearance from the brain of soluble amyloid-beta. Soluble amyloid-beta was targeted, as it was believed to be the most toxic form of amyloid-beta leading to synaptic dysfunction and preceding the deposition of insoluble fibrillary amyloid. In the earlier Phase III trials, EXPEDITION 1 and 2, solanezumab did not lead to significant reduction in the decline in cognition or function in those with mild-to-moderate AD. However, prespecified secondary analyses found that mild AD subjects receiving solanezumab had 34% less cognitive decline and 18% less functional decline compared to those receiving placebo. Therefore, EXPEDITION 3 was conducted to investigate the effects of solanezumab, specifically in mild AD.
EXPEDITION3 was designed as a double-blind, placebo-controlled, Phase III trial in mild AD, defined as Mini-Mental State Examination (MMSE) score of 20 to 26. Male and female subjects from 55 to 90 years of age who met the clinical diagnostic criteria and had biomarker evidence of cerebral amyloid-beta deposition by either cerebrospinal fluid (CSF) or florbetapir PET scans were enrolled in the study. Subjects received intravenous infusions of either 400 mg of solanezumab or placebo every four weeks for 76 weeks, with an optional 24-month, open-label period after completion of the double-blind period. Concomitant drug therapy with acetylcholinesterase inhibitors and memantine was allowed.
Between 2013 and 2016, 2,129 subjects underwent randomization, with 1,822 (85%) subjects completing the trial in equal numbers between the solanezumab and placebo groups. The primary outcome measure of change from baseline to week 80 on the 14-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog14) was not statistically different between the groups (change, 6.65 in solanezumab group and 7.44 in placebo group; difference, -0.80; P = 0.10). Because of the failure regarding the primary outcome, secondary outcomes, which included additional cognitive and functional scores such as the MMSE and Clinical Dementia Rating Scale-Sum of Boxes, were reported in descriptive fashion. Overall, there appears to be a trend in the secondary outcome measures toward modest benefit in the solanezumab compared to the placebo groups. Although detailed analyses of biomarkers were not provided, compared to placebo group, the solanezumab group had increased plasma and CSF levels of total amyloid-beta(1-40) and (1-42) levels, decreased CSF-free amyloid-beta(1-42) levels, and unchanged CSF-free amyloid-beta(1-40) levels. Amyloid deposition by florbetapir PET, tau pathology by CSF and flortaucipir PET, and MRI measures of whole brain or ventricular size were not different between the groups.
Adverse events were similar between the groups, with approximately 4% in each group discontinuing the trial because of an adverse event. Presence of antidrug and neutralizing antibodies, an important consideration in immunotherapy trials, similarly was low in both groups after exposure to the study drug. Amyloid-related abnormality of edema or effusions was seen in one case in the solanezumab group and two cases in the placebo group, which all were asymptomatic.
The disappointing results from EXPEDITION 3 undoubtedly led to gloomy headlines about another failed AD trial and provided further fuel to critics of the amyloid hypothesis. Failures from earlier trials could be attributed to the inclusion of non-AD dementia subjects, which was as high as 25% in the EXPEDITION 1 and 2 trials, and the lack of drug efficacy, once significant neurodegeneration occurs, as with moderate AD. However, both possibilities were taken into account for
EXPEDITION 3 and the results were negative. Does this mean that amyloid-beta was the wrong target and the amyloid hypothesis was disproved?
EXPEDITION 3 does not prove or disprove amyloid-beta as a drug target, especially early in AD, or the amyloid hypothesis. One criticism is that the solanezumab dose was too low. There were consistent trends toward the solanezumab group having better outcomes compared to the placebo group, but the effect size was low. Coupled with low adverse events reported with the dose used, higher doses of solanezumab potentially could lead to larger effect size and statistically meaningful outcomes without increasing adverse events. Also, it is possible that the treatment still was initiated too late. In response to these criticisms, current trials using solanezumab in cognitively normal subjects with biomarker evidence of AD (A4 trial) have increased the dosage and length of treatment with solanezumab. The A4 trial and the DIAN-TU trial, investigating solanezumab on subjects with familial AD mutations, will be critical in determining whether solanezumab becomes a viable therapy.
Despite the negative results, there are important lessons learned from EXPEDITION 3. It has paved the way for better trial design, including the use of amyloid-beta and tau biomarkers as both study inclusion criteria and outcome measures. Additionally, failure of one anti-amyloid therapy does not mean that all anti-amyloid therapies are destined to fail, such as the ongoing aducanumab trial, as they target different forms of amyloid-beta and hence different aspects of amyloid pathology. Therefore, the journey continues to find the first new AD drug since 2003.