Our Year in Review series highlights the major medical news stories of 2012. One of the most talked-about was the disappointing results in late-stage trials with a biologic drug targeting beta-amyloid protein plaques in Alzheimer’s disease. Here is the original article on the drug, published on Aug. 24. In a companion article, you’ll find out what has happened with it since.

Another once-promising drug for Alzheimer’s disease, designed to scavenge plaque-forming amyloid proteins, has failed to meet its endpoints in two phase III trials, the manufacturer announced Friday.

No significant benefit in either cognition or functional impairment was seen with solanezumab, a monoclonal antibody targeting beta-amyloid protein, in either EXPEDITION1 or in the similarly designed EXPEDITION2 trials, according to Eli Lilly.

Both trials enrolled patients with mild to moderate Alzheimer’s disease. More than 2,050 patients participated in the studies.

The failure essentially duplicated that of bapineuzumab, another anti-amyloid monoclonal antibody, which had most development work stopped earlier this month in the wake of similar clinical trial results.

Two trials of bapineuzumab, sponsored by co-developers Pfizer and Janssen, both failed to demonstrate clinical benefit in patients with mild to moderate disease. The companies said they were halting ongoing trials and other development work for that indication, but held the door open for trials in asymptomatic patients at high risk for Alzheimer’s.

Lilly, however, indicated that it isn’t ready to throw in the towel on solanezumab for established, symptomatic disease.

“A prespecified secondary analysis of pooled data across both trials showed statistically significant slowing of cognitive decline in the overall study population of patients with mild-to-moderate Alzheimer’s disease,” the company said in a statement.

“In addition, prespecified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer’s disease, but not in patients with moderate Alzheimer’s disease.”

The company said these data “support the amyloid hypothesis” of Alzheimer’s disease, which holds that beta-amyloid plaques are a direct cause of neurodegeneration and functional decline.

Many in the research community have begun to doubt the hypothesis, given the clinical failures of direct anti-amyloid drugs as well as those involving agents that inhibit enzymes responsible for producing beta-amyloid protein in the body.

No drug intended to reduce beta-amyloid accumulation has shown a significant clinical benefit in a phase III trial involving patients with established Alzheimer’s disease.

In the face of this record, and with negative findings in hand from EXPEDITION1, Lilly said it had tried to salvage a positive result in EXPEDITION2 by changing its primary endpoint, but to no avail.

EXPEDITION1, which finished first, had two primary endpoints—measures of cognitive ability and functional impairment—both of which were not met, Lilly explained.

“Based on those results, Lilly modified the statistical analysis plan for EXPEDITION2 prior to database lock to specify a single primary endpoint of cognition in the mild patient population,” the company said.

“This revised primary endpoint did not achieve statistical significance.”

Lilly’s chief executive, John Lechleiter, PhD, said in the statement that the company would discuss “potential next steps” with regulatory authorities. Those steps had not yet been decided, the company indicated.

Fuller results of the trials will be presented at two scientific meetings in October, Lilly said.

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By John Gever, Senior Editor, MedPage Today