Phase II trial of GM-CSF/sargramostim in Alzheimer's Disease

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PROJECT ABSTRACT Alzheimer’s disease (AD) treatments designed to target the amyloid-beta peptide have shown encouraging results in transgenic animal models but less encouraging results in human trials, which have also been plagued with serious adverse events (SAEs), including amyloid-related imaging abnormalities (ARIAs). Our proposed innovative therapeutic approach is based on epidemiological evidence that patients with the inflammatory disease rheumatoid arthritis (RA) have a reduced risk of developing AD, unrelated to their use of non-steroidal anti-inflammatory drugs (NSAIDs). We identified the innate immune system stimulant Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) as a hematopoietic factor upregulated in RA, which we found reduced brain amyloidosis and reversed cognitive impairment in transgenic AD mice. Other studies have shown GM-CSF to be neuroprotective, anti-apoptotic, and neurogenic in several models of neurological diseases and injuries. We also found that recombinant human GM-CSF(sargramostim/Leukine) treatment is associated with cognitive improvements in leukemia patients after bone marrow chemo-ablation and hematopoietic cell transplant therapy. Notably, sargramostim is an FDA-approved drug for increasing the production and differentiation of white blood cells with an excellent safety record over 30 years. Most importantly, we recently completed a Phase I/II safety and efficacy trial (NCT01409915) in which mild-to-moderate AD participants were treated with sargramostim (250 mcg/m2/day SC) or placebo five days/week for three weeks (20:20 participants per group) with neurological, neuropsychological, neuroimaging, and blood biomarker assessments. Sargramostim treatment was safe (Primary Endpoint) with no drug-related SAEs and no ARIAs. Furthermore, the Mini-Mental State Exam (MMSE) showed cognitive improvement in the sargramostim group at the end of treatment (EOT) compared to baseline (p=0.0074) and in the sargramostim group compared to the placebo group at the EOT (p=0.037) and at 45 days after the EOT (p=0.0281). Other assessments showed no treatment benefits, but there was a trend negative correlation between changes in MMSE versus amyloid-PET. We now propose to carry out a randomized, double- blind, placebo-controlled trial in 42 mild-to-moderate AD participants, 28 of whom will receive sargramostim (250 mcg/m2/day SC) and 14 of whom will receive placebo, five days/week for 24 weeks with a 45-day follow-up visit. We have received both an IND exemption (134291) and IRB approval (17-0215) but will submit improved versions in the coming months. Our Specific Aims are: 1) Assess the long-term safety and tolerability of sargramostim in mild-to-moderate AD participants (Primary Endpoint). 2) Assess the effects of sargramostim treatment on cognition and activities of daily living in mild-to-moderate AD participants (Secondary and Exploratory Endpoints). 3) Assess changes in biomarkers associated with sargramostim treatment in mild-to- moderate AD participants (Exploratory Endpoints).