Phase 3 Trials of Solanezumab for Mild-to-Moderate Alzheimer's Disease

BACKGROUND

Alzheimer's disease is characterized by amyloid-beta plaques, neurofibrillary tangles, gliosis, and neuronal loss. Solanezumab, a humanized monoclonal antibody, preferentially binds soluble forms of amyloid and in preclinical studies promoted its clearance from the brain.

METHODS

In two phase 3, double-blind trials (EXPEDITION 1 and EXPEDITION 2), we randomly assigned 1012 and 1040 patients, respectively, with mild-to-moderate Alzheimer's disease to receive placebo or solanezumab (administered intravenously at a dose of 400 mg) every 4 weeks for 18 months. The primary outcomes were the changes from baseline to week 80 in scores on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog11; range, 0 to 70, with higher scores indicating greater cognitive impairment) and the Alzheimer's Disease Cooperative Study–Activities of Daily Living scale (ADCS-ADL; range, 0 to 78, with lower scores indicating worse functioning). After analysis of data from EXPEDITION 1, the primary outcome for EXPEDITION 2 was revised to the change in scores on the 14-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog14; range, 0 to 90, with higher scores indicating greater impairment), in patients with mild Alzheimer's disease.

RESULTS

Neither study showed significant improvement in the primary outcomes. The modeled difference between groups (solanezumab group minus placebo group) in the change from baseline was −0.8 points for the ADAS-cog11 score (95% confidence interval [CI], −2.1 to 0.5; P=0.24) and −0.4 points for the ADCS-ADL score (95% CI, −2.3 to 1.4; P=0.64) in EXPEDITION 1 and −1.3 points (95% CI, −2.5 to 0.3; P=0.06) and 1.6 points (95% CI, −0.2 to 3.3; P=0.08), respectively, in EXPEDITION 2. Between-group differences in the changes in the ADAS-cog14 score were −1.7 points in patients with mild Alzheimer's disease (95% CI, −3.5 to 0.1; P=0.06) and −1.5 in patients with moderate Alzheimer's disease (95% CI, −4.1 to 1.1; P=0.26). In the combined safety data set, the incidence of amyloid-related imaging abnormalities with edema or hemorrhage was 0.9% with solanezumab and 0.4% with placebo for edema (P=0.27) and 4.9% and 5.6%, respectively, for hemorrhage (P=0.49).

CONCLUSIONS

Solanezumab, a humanized monoclonal antibody that binds amyloid, failed to improve cognition or functional ability. (Funded by Eli Lilly; EXPEDITION 1 and 2 ClinicalTrials.gov numbers, NCT00905372 andNCT00904683.)

N Engl J Med 2014; 370:311-321January 23, 2014DOI: 10.1056/NEJMoa1312889

Disappointing Alzheimer’s trial yields new ideas

Dr. Stephen Salloway pulls no punches in describing the results of two clinical trials of the Alzheimer’s drug bapineuzumab that he helped to lead. The antibody failed to produce cognitive improvement for volunteers compared to a placebo, he and colleagues report Jan. 23 in the New England Journal of Medicine.

Looking for a breakthrough

“The biggest disappointment from this trial, was that if we had shown benefit with a drug like bapi, it would give people hope that Alzheimer’s is a treatable disease, that we can slow it down,” Salloway said.

That much needed breakthrough could come from new trials that apply the lessons researchers learned. It is likely that many of the participants, for example, had some form of dementia other than Alzheimer’s disease, Salloway said. A future trial should only include those with amyloid buildup confirmed by a PET scan and spinal fluid testing.

“We were surprised to find that overall 20 percent of participants in both the bapi and solanezumab trials did not meet the threshold for amyloid buildup,” Salloway said. “That proportion was higher for ApoE4 noncarriers.”

Also amyloid plays a more critical role early in the development of the disease, he said. Trials that administer the medication earlier could produce greater effects.

It would make sense, he said, to pair drugs like bapi with drugs such as a beta secretase inhibitor that maximize amyloid lowering. The safety of such a combination, or combination with drugs that address the tangles of tau proteins also found in Alzheimer’s, is not known, Salloway said, but needs to be carefully tested.

“Without taking strategic risks, we aren’t going to make the progress we need to move forward,” he said.

Testing drug combinations, however, may require pharmaceutical companies to pool resources and share data. He acknowledged that’s something competitors are usually reluctant to do. These partnerships are forming in the pre-competitive arena, he said, but need to be expanded into clinical trials.

“For the level of suffering with this disease and for our economy, we have to break down some barriers and come up with innovative approaches.”

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