P4‐203: INTERIM BIOMARKER ANALYSES OF PHASE II STUDY DATA ON SAFETY AND EFFICACY OF GM‐CSF/LEUKINE ^® IN MILD‐TO‐MODERATE AD

Epidemiological studies have shown that most rheumatoid arthritis (RA) patients do not develop Alzheimer's disease (AD), which was not due to their use of non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized that intrinsic factors associated with RA pathogenesis itself may underlie the protective effects against AD. We focused on increased myeloid lineage phagocytes in RA and found that 20 daily subcutaneous (SC) injections of granulocyte-macrophage colony-stimulating factor (GM-CSF) in transgenic AD mice reduced cerebral amyloid by greater than 50% and completely reversed their cognitive impairment. We subsequently found that Leukine® (recombinant human GM-CSF) treatment of leukopenia in bone marrow transplant patients was associated with a significant improvement in cognitive functioning. We are conducting a randomized placebo-controlled double-blind Phase II safety and efficacy trial of Leukine® in mild-to-moderate AD subjects at 250 mg/m2/day SC for 5 days/week for three consecutive weeks with 45- and 90-day follow-up visits. Neurological and neuropsychological assessments, MRI and amyloid-PET neuroimaging, and blood biomarker electrochemiluminescence (ECL) analyses are performed to assess treatment effects. Interim analyses of 15 Leukine®-treated and 15 placebo-treated subjects showed no drug-related serious adverse events, including no amyloid-related imaging abnormalities (ARIAs). When comparing measures at the end of treatment to baseline, the mean changes of the MMSE score showed improvement in the Leukine® group relative to baseline (p=0.0029) and to the placebo group (p=0.0175) by repeated measures mixed model analysis. Differences were not significant by the follow-up visits. Interim ECL analyses of blood biomarkers for 64 analytes suggest that the levels of several cytokines and chemokines change significantly from baseline to end of treatment, correlating with Leukine® treatment and neuropsychological score changes. The safety and neuropsychological results, although preliminary and based on a small number of subjects, indicate that completing this three-week trial and continuing our Alzheimer's Association “Part the Cloud”-funded 24-week trial of GM-CSF/Leukine® in subjects with mild-to-moderate AD are warranted. Furthermore, the observed blood biomarker changes support further analyses with additional subjects from this trial and from the 24-week trial, as well as investigation into whether the Leukine®-associated changes in biomarker levels also correlate with changes in AD pathophysiology.