Double‐blind placebo‐controlled trial of the safety and efficacy of GM‐CSF/sargramostim in subjects with mild‐to‐moderate Alzheimer’s disease: Human/Human trials: Cognitive enhancement

Background Rheumatoid arthritis (RA) patients have a reduced risk of developing Alzheimer’s disease (AD), originally hypothesized to be attributable to their use of non‐steroidal anti‐inflammatory drugs (NSAIDs). However, clinical trials with NSAIDs were unsuccessful in both AD and Mild Cognitive Impairment (MCI) subjects. We hypothesized that intrinsic innate immune system factors associated with RA itself may underlie the AD protective effect(s). We tested several cytokines upregulated in RA blood and found that 20 daily injections of 5 μg granulocyte‐macrophage colony stimulating factor (GM‐CSF) reduced cerebral amyloidosis by greater than 50% and completely reversed the cognitive impairment of transgenic AD mice. In a retrospective study, we found that short‐term treatment with sargramostim/Leukine ® (recombinant human GM‐CSF) plus G‐CSF improved cognition of leukemia patients following bone marrow chemoablation/hematopoietic cell transplant compared to patients who received G‐CSF alone. Method A double blind Phase II safety and efficacy trial of sargramostim in 40 mild‐to‐moderate AD subjects, half receiving placebo and half receiving 250 μg/m 2 /day sargramostim by subcutaneous injection five days/week for three weeks with follow‐up visits at 45 and 90 days post‐treatment is complete (NCT01409915). Neurological and neuropsychological assessments and MRI and amyloid‐PET scans were performed to assess the safety and efficacy of treatment. Result Clinical and imaging analyses showed no drug‐related serious adverse events, including no amyloid‐related imaging abnormalities (ARIAs; micro‐hemorrhage or vasogenic edema). At the end of treatment, the mean Mini‐Mental State Examination (MMSE) score in the sargramostim group was improved relative to baseline (p=0.0074) and to the placebo group (p=0.037) by repeated measures mixed model analysis. The beneficial effect of sargramostim on MMSE, compared to placebo, was retained at the first follow‐up visit at 45 days after the end of treatment (p=0.0272). In contrast, there was a single poorer ADAS‐Cog‐13 (Alzheimer’s Disease Assessment Scale‐Cognitive Subscale‐13) mean score in the sargramostim group compared to placebo–at the first follow‐up visit 45 days after the end of treatment. Amyloid and volumetric brain scans are being analyzed. Conclusion These results indicate that GM‐CSF/sargramostim shows promise as a potential treatment for AD and that our Alzheimer’s Association “Part the Cloud”‐funded 24‐week treatment trial is warranted.