Clinical trials of a drug aimed at reducing beta-amyloid plaque accumulation in Alzheimer’s disease have been stopped because of lack of efficacy, striking another blow against the amyloid theory of the disease.
Eli Lilly announced that it was halting development of a drug called semagacestat, an inhibitor of the gamma-secretase enzyme that produces beta-amyloid protein, after preliminary results from two large placebo-controlled trials indicated no benefit from the treatment.
“It did not slow disease progression and was associated with worsening of clinical measures of cognition and the ability to perform activities of daily living,” according to a Lilly press release.
The trials had a total of more than 2,600 participants with mild to moderate Alzheimer’s disease. Patients receiving the drug showed greater declines in these measures than did those in the placebo groups.
Lilly said it had instructed site investigators to stop dosing patients as soon as possible but to continue following participants for at least six months to collect cognitive function scores and safety data.
“These additional follow-up visits will help to answer a number of important questions, including whether the differences between patients who received semagacestat and those who received placebo will continue after semagacestat has been discontinued,” the company indicated.
The two trials began in 2008; one was scheduled to run until June 2011 and the other until March 2012.
Lilly is also halting other, smaller, short-term studies of semagacestat.
The drug is the latest anti-amyloid agent to fail in late-stage, placebo-controlled trials, casting more doubt on whether this approach can ever work in established Alzheimer’s disease.
Negative clinical results have also been found for tarenflurbil, latrepirdine (Dimebon), and bapineuzumab, which target beta-amyloid protein production or the sticky plaques that form when soluble beta-amyloid changes shape to become fibrous and insoluble.
But development of bapineuzumab is continuing, with preliminary PET scan data indicating that the drug successfully breaks up amyloid plaques in Alzheimer’s patients as intended. Clinical results from the phase III study are now eagerly awaited in the Alzheimer’s community.
The Lilly trials of semagacestat also included PET scans to measure effects on plaque burden. The company’s announcement did not include those results; a Lilly spokesman said the PET data were still blinded and would not be available for analysis for at least six months.
Those data could be critical in determining whether beta-amyloid is a worthwhile target for Alzheimer’s drugs, as well as what went wrong with semagacestat specifically.
A finding that semagacestat treatment did reduce plaque accumulation, yet failed to show clinical benefit, might suggest that this approach will not work in patients with established symptoms.
Lilly emphasized that it was not giving up yet on beta-amyloid as a target. The company is continuing development of an anti-amyloid monoclonal antibody, solanezumab, with two phase III trials now underway.
Source: MedPage Today