BOSTON—Data from two large phase III trials of solanezumab suggest that the drug may slow cognitive loss in patients with mild to moderate Alzheimer’s disease, according to a presentation by Rachelle S. Doody, MD, PhD, at the 2012 Annual Meeting of the American Neurological Association (ANA).
The trials, EXPEDITION 1 and EXPEDITION 2, were conducted by Eli Lilly to study the effects of solanezumab, a humanized anti–amyloid-beta monoclonal antibody that binds to soluble amyloid-beta. In August, Lilly reported that its early analysis of the data indicated that the studies were both negative by their prespecified criteria.
The solanezumab analysis presented at the ANA meeting was performed by the Data Analysis and Publications Committee of the Alzheimer’s Disease Cooperative Study (ADCS).
“As part of our contract with [Lilly], the ADCS receives the raw data from the company, which is really quite unusual, and there are no constraints on our analysis,” said Dr. Doody, Effie Marie Cain Chair in Alzheimer’s Disease Research at the Baylor College of Medicine in Houston.
The two trials involved patients with mild to moderate Alzheimer’s disease, which was defined as a Mini-Mental State Examination score ranging from 16 to 26. A total of 2,052 patients were randomized to receive either placebo or 400 mg of solanezumab every four months for 18 months.
The coprimary end points of EXPEDITION 1 were scores on the Alzheimer’s Disease Assessment Scale Cognition 11 (ADAS Cog 11) and the ADCS–ADL (Alzheimer’s Disease Cooperative Scale–Activities of Daily Living), and these end points were initially chosen as the end points for EXPEDITION 2. With the approval of the FDA, Eli Lilly modified the EXPEDITION 2 end points after the completion of EXPEDITION 1. The primary end point of EXPEDITION 2 was ADAS Cog 14 score in the milder subset of patients.
According to Dr. Doody, the ADCS analysis found similar results to those of Eli Lilly for the specified outcomes. However, the statistical analysis approach of the ADCS analyzed all the outcomes, not just those of the mild subset of patients.
In particular, when the researchers examined the combined outcomes of EXPEDITION 1 and 2 in the mild and moderate patients on the ADAS Cog 14, they found a statistically significant difference between the solanezumab and placebo groups, said Dr. Doody.
Overall, the data showed positive, yet modest results on cognitive measures in both studies, in prespecified subanalyses of mild patients, and in the pooled analyses of the two studies.
“I believe that these data, taken together, suggest that solanezumab slowed cognitive loss, compared to placebo, in mild to moderate patients, and that there was some evidence of a functional benefit in the mild subgroup,” said Dr. Doody.
She added that although the overall effect may be small, may take several months to become apparent, and may be limited to mild patients, “I think there is evidence that targeting amyloid-beta may benefit Alzheimer’s disease patients.”
The results of another phase III trial targeting amyloid-beta were also presented. The trial, which examined bapineuzumab, did not show significant clinical benefit in patients with mild to moderate Alzheimer’s disease, but did yield biomarker findings that will likely provide the foundation for future studies of antiamyloid therapies, according to lead researcher Reisa A. Sperling, MD.
“We saw evidence of amyloid lowering, or at least differences over the course of the trial, and also evidence that we hit a key marker in spinal fluid, which is phosphorylated tau,” Dr. Sperling, Director of the Center for Alzheimer’s Research and Treatment at Brigham and Women’s Hospital in Boston, told Neurology Reviews.
She added, “It was disappointing that we didn’t see a clinical signal, and this dissociation between having biologic activity without clinical benefit is really problematic for the field.”
Dr. Sperling noted that the data from the bapineuzumab studies have yielded a wealth of data to analyze.
“Hopefully, these new biomarker results from the bapineuzumab studies, together with the clinical results from the solanezumab studies, may provide a potential path forward for Alzheimer’s disease research.”