ICAD: Monoclonal Antibody that Binds to Amyloid Found Safe in Alzheimer's

By Todd Neale
CHICAGO,01 aug 2008-- An investigational monoclonal antibody that binds to beta-amyloid was well tolerated by Alzheimer's patients in a 12-week phase II study that was too short to establish meaningful clinical efficacy endpoints.
With a goal of enabling the body to more easily clear beta-amyloid42, from which plaques are predominantly made, LY2062430 was given IV to 52 Alzheimer's patients, said Eric Siemers, M.D., of Eli Lilly in Indianapolis, maker of the antibody, at the International Conference on Alzheimer's Disease here.
Dr. Siemers said the increased clearance of beta-amyloid could potentially slow the progression of Alzheimer's by preventing the build-up of plaques.
The antibody was well tolerated, he said, with no infusion reactions or evidence in the cerebrospinal fluid or on MRI scans of meningoencephalitis, microhemorrhage, or edema through 112 days of follow-up.
There was a slight immune response to the antibody in five patients, but it did not affect the pharmacokinetics or binding of beta-amyloid, Dr. Siemers said.
On the basis of the results, a phase III trial will be conducted starting in 2009.
Dr. Siemers and colleagues recruited patients diagnosed with mild-to- moderate Alzheimer's disease (mean age 71.2, mean baseline Mini-Mental State Examination score 20.2).
They were given infusions of the antibody for 12 weeks at one of four doses -- 100 mg per week (10), 100 mg every four weeks (11), 400 mg per week (11), or 400 mg every four weeks (10) -- or placebo (10).
All doses of antibody increased mean plasma concentrations of beta-amyloid to about 100,000 pg/mL for beta-amyloid40 and 10,000 pg/mL for beta-amyloid42.
About a 10th of a percent of the antibody entered the cerebrospinal fluid and similar increases in beta-amyloid concentration were found.
Surprisingly, as the dose increased, the amount of beta-amyloid42 -- the form of the protein found primarily in plaques -- that was not bound to the antibody also increased in the cerebrospinal fluid.
According to Dr. Siemers, that finding suggested that the antibody was not simply binding free beta-amyloid, which would cause the amount of the protein to decrease, but was also dissolving plaques in the brain.
Two other types of protein found primarily in plaques also increased in the plasma and cerebrospinal fluid with higher doses of the antibody, further strengthening the evidence that plaques were dissolving, he said.
However, MRI scans did not show any reduction in the amyloid plaque load in the brain through 12 weeks. The scans and the tracer used may not have been sensitive enough to detect the changes, Dr. Siemers said.
As expected, he said, there were no significant differences between the treatment groups or the placebo group in cognitive function measured using the Alzheimer's Disease Assessment Scale -- cognitive subscale.
The study was funded by Eli Lilly, maker of the antibody.
Dr. Siemers and four of his co-authors are employees of Eli Lilly. The other four co-authors have received grants or research support from the company.
Primary source: International Conference on Alzheimer's DiseaseSource reference:Siemers E, et al "Safety, tolerability, and biomarker effects of an Abeta monoclonal antibody administered to patients with Alzheimer's disease" ICAD 2008; Abstract P4-346.