Eli Lilly and Company presented detailed results of its phase 3 EXPEDITION3 trial at the 9th Clinical Trials on Alzheimer's Disease (CTAD) meeting. As previously disclosed, solanezumab did not meet the primary endpoint in the EXPEDITION3 clinical trial, a study of solanezumab initiated in people with mild dementia due to Alzheimer's disease (AD), and Lilly will not pursue regulatory submissions for solanezumab for the treatment of mild dementia due to AD.
"The results of EXPEDTION3 are without question disappointing," said Eric Siemers, M.D., distinguished medical fellow at Lilly. "However, Lilly remains committed to finding solutions for this devastating disease. We will continue to analyze study results and work with the external scientific community in the hopes of uncovering findings that will help shape and advance future Alzheimer's disease research."
Lawrence S. Honig, M.D., Ph.D., professor of neurology at Columbia University Medical Center and principal investigator of the EXPEDITION3 study, presented the data at the meeting.
"Alzheimer's is a challenging disease that researchers have been committed to studying for some years," Dr. Honig said. "Now is not the time to give up. While the outcome of this study is not what we had hoped for, it is reasonable to believe that disease modifying therapies to slow down the progression of Alzheimer's disease will be discovered."
While the study results, including many secondary clinical endpoints, directionally favoured solanezumab, the magnitudes of treatment differences were small.
Primary endpoint: Patients treated with solanezumab did not experience a statistically significant slowing in cognitive decline compared to patients treated with placebo. This finding represented an 11 per cent reduction in decline (p=.095), as measured by the Alzheimer's Disease Assessment Scale-Cognitive (ADAS-Cog14) subscale. The ADAS-Cog14 measures a person's cognitive functions, including memory, attention and language abilities.
Key secondary clinical endpoints: As the primary endpoint was not met in this study, the p-values for the efficacy secondary statistical analyses were not adjusted for multiple comparisons.
Patients treated with solanezumab had a 13 per cent slowing of cognitive decline (p=0.014) compared to patients treated with placebo as measured by the Mini-Mental State Examination (MMSE). The MMSE is the most commonly used test for complaints of problems with memory or other mental abilities and can be used by clinicians to help diagnose dementia and to help assess its progression and severity. It consists of a series of questions and tests, each of which scores points if answered correctly. The MMSE tests a number of different mental abilities, including a person's memory, attention and language.2
The Clinical Dementia Rating-Sum of Boxes (CDR-SB) scale showed a 15 per cent slowing in decline (p=0.004) between patients treated with solanezumab and patients treated with placebo. The CDR-SB scale measures cognitive and functional performance — in areas such as memory, orientation and personal care — through semi-structured interviews of patients and their family members or other reliable informants.
Patients treated with solanezumab had a slowing of decline in complex activities of daily living compared to patients treated with placebo. This finding represented a 14 per cent slowing of decline (p=.019) as measured by the Alzheimer's Disease Cooperative Study-Instrumental Activities of Daily Living (ADCS-iADL). The ADCS-iADL scale measures a person's independent performance in complex activities of daily living such as participating in a conversation, preparing a meal or shopping.
A different functional measure, the FAQ (Functional Activities Questionnaire), did not show a statistically significant difference between patients treated with solanezumab and patients treated with placebo (7 per cent reduction in decline, p=0.140). The FAQ scale is a different informant-based measure of functional abilities. Informants provide performance ratings of the patient on ten complex higher-order activities.
Changes in plasma a-beta were similar to those seen in previous studies, and the differences between treatment and placebo groups were statistically significant. Changes in amyloid deposition as measured by positron emission tomography (PET) imaging did not reach statistical significance between treatment and placebo groups.
Adverse events: Events more frequent in the solanezumab treatment group that were statistically significant include: spinal osteoarthritis (1.1 per cent in the solanezumab group, 0.4 per cent in the placebo group), dysuria (0.9 per cent in the solanezumab group, 0.2 per cent in the placebo group), vitamin D deficiency (1.4 per cent in the solanezumab group, 0.6 per cent in the placebo group), and nasal congestion (1.2 per cent in the solanezumab group, 0.4 per cent in the placebo group).
The incidence of vasogenic edema (ARIA-E or amyloid-related imaging abnormality-edema/effusions) was approximately 0.1 per cent of patients treated with solanezumab and 0.3 per cent of patients on placebo.
Solanezumab is Lilly's phase 3 monoclonal antibody being studied as a potential therapy for people with mild cognitive impairment due to Alzheimer's disease (EXPEDITION-PRO), preclinical Alzheimer's disease (Anti-Amyloid Treatment in Asymptomatic Alzheimer's "A4"), and Dominantly Inherited Alzheimer's Disease ("DIAN").
EXPEDITION3 is a multinational, phase 3 trial of solanezumab in more than 2,100 patients diagnosed with mild dementia due to Alzheimer's disease. The study includes an 18-month placebo-controlled period followed by an open label extension. Enrollment was completed in 2015 and the last patient visit for the placebo-controlled period occurred in October 2016. EXPEDITION3 is the first phase 3 trial to evaluate only people with mild dementia due to Alzheimer's disease.