Solanezumab Shows No Efficacy in Improving Cognition or Functional Ability for Mild-to-Moderate AD

Results of two phase 2, randomized, double-blind trials showed that solanezumab does not improve cognition or functional ability in patients with mild-to-moderate Alzheimer’s disease (AD) [N Engl J Med. 2014;370:311-321].

The study included the EXPEDITION 1 and EXPEDITION 2 trials in which patients with mild-to-moderate AD were randomized to receive solanezumab (400 mg administered intravenously in approximately 70 mL over a period of 30 minutes) or placebo once every 4 weeks for 18 months. In the EXPEDITION 1 trial, 1012 patients were randomized to receive solanezumab (n=506) or placebo (n=506). In the EXPEDITION 2 trial, 1040 patients were randomized to receive solanezumab (n=521) or placebo (n=519).

Patients in both trials were ≥55 years of age, healthy other then mild-to-moderate AD, and without depression.

No significant differences in baseline characteristics were seen between the placebo and solanezumab groups in terms of age, sex, or educational level. The majority of patients in both trials were white (76.6% in EXPEDITION 1 and 84.4% in EXPEDITION 2), and most were being treated at baseline with cholinesterase inhibitors, memantine, or both (88% and 91%, respectively).

The primary outcomes were effect on cognition and functional ability of solanezumab as measured by the change in baseline scores to week 80. The 11-item cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-Cog11) was used to assess cognition, and the Alzheimer’s Disease Cooperative Study – Activities of Daily Living Scale (ADCS-ADL) was used to assess functional ability.

Mixed-model repeated-measures analyses were used to assess between-group differences in the change in scores from baseline to week 80.

Based on the intention-to-treat populations, the study found no significant improvement in the primary outcomes in either randomized trial. In the EXPEDITION 1 trial, the modeled difference between groups (solanezumab minus placebo) in the change from baseline was -0.8 points (95% confidence interval [CI], -2.1-0.5, P=.24) for the ADAS-Cog11 score and -0.4 points (95% CI, -2.3-1.4; P=.64) for the ADCS-ADL score. For EXPEDITION 2, the same scores were -1.3 points (95% CI, -2.5-0.3; P=.06) and 1.6 points (95% CI, -0.2-3.3; P=.08), respectively.

After analyzing the data, the investigators changed the primary outcome of the EXPEDITION 2 trial to change in scores on the 14-item cognitive subscale of the ADAS (ADAS-Cog14) in patients with mild AD.

Results of this analysis showed that the modeled between-group difference in the change in the ADAS-Cog14 score from baseline to week 80 in the patients with mild AD was -1.7 points (95% CI, -3.5-0.1; P=.06). At week 64, a significant difference was seen in favor of the patients treated with solanezumab. In patients with moderate AD, the between-group difference in the change in the ADAS-Cog14 score from baseline to week 80 was -1.5 (95% CI, -4.1-1.1; P=.26).

According to lead author of the study, Rachelle S. Doody, MD, PhD, Effie Marie Cain Chair, Alzheimer’s Disease Research and Director of Alzheimer’s Disease and Memory Disorders Center, Baylor College of Medicine-Department of Neurology, Houston, Texas, extensive studies were completed.

“While [the study results] are not definitive,” she said in an interview with First Report Managed Care, “they suggest that the drug should be tested in milder patients with AD or in patients with pre-clinical AD who do not yet have symptoms.”

The study also looked at the combined safety data from both trials and found no differences between solanezumab and placebo in terms of the incidence of amyloid-related imaging abnormalities with edema (0.9% vs 0.4%, respectively; P=.27) or hemorrhage (4.9% vs 5.6%, respectively; P=.49).