Subcutaneous administration of sargramostim (recombinant granulocyte-macrophage colony-stimulating factor; GM-CSF) safely improved cognition, memory and blood biomarkers of Alzheimer's disease (AD) in a small phase-2, placebo-controlled trial. "GM-CSF is the first Alzheimer's drug to show patient improvement in a phase-2 clinical trial," Dr. Huntington Potter of the University of Colorado Anschutz Medical Campus told Reuters Health by email. "Looking ahead to strengthen the finding, we have received FDA approval, and funding from the NIH and the Alzheimer's Association, to carry out a longer, larger trial of GM-CSF in Alzheimer's patients. We expect to start recruitment in a month or two." As reported in Alzheimer's and Dementia: Translational Research and Clinical Interventions, the team's previous work found that short-term treatment of transgenic AD mice with GM-CSF led to an increase in activated microglia, a 50% reduction in amyloid load, an increase in synaptic area, and improvement in spatial memory. "These results called into question the consensus view that inflammation is solely detrimental in AD," Dr. Potter and colleagues write. In the current study, they tested their hypothesis that modulation of the innate immune system might similarly be used to treat AD in humans. They randomized 40 adults with mild-to-moderate AD (mean age, about 68; about 58% women; 90% White) to receive either sargramostim at the standard dosage of 250 mcg/m2/day via subcutaneous injection - or subcutaneous saline - five days a week for three weeks. As expected, sargramostim changed innate immune system markers, with no drug-related serious adverse events or amyloid-related imaging abnormalities. At the end of treatment (EOT), the Mini-Mental State Examination (MMSE) scores of the sargramostim group increased compared to baseline and compared to placebo, and the treatment effect persisted at first follow-up (FU1, 45 days). Specifically, improvement occurred in: 70% of sargramostim-treated participants compared to 35% of placebo-treated participants at EOT; 60% versus 20% at FU1; and 55% versus 25% at FU2 (90 days). Combining the results to identify an overall treatment effect, 80% of sargramostim-treated participants were "responders," according to the authors, in that they showed a higher MMSE score compared to baseline at either EOT or at FU1, versus 35% of those who received placebo. Further, in the treated group plasma markers of amyloid beta (normally decreased in AD), increased 10%, whereas plasma markers of neurodegeneration - total tau and UCH-L1 - decreased 24% and 42%, respectively, compared to placebo. Dr. Potter noted, "We also studied a quality-of-life measure, Alzheimer's Disease Cooperative Study Activities of Daily Living, which we found to improve in parallel with the improvement in memory, as determined by the MMSE." Dr. Noll Campbell of the Regenstrief Institute and Purdue University College of Pharmacy in Indianapolis, commented in an email to Reuters Health, "While the inflammatory mechanism is complex and worth pursuing, it is appropriate to consider these results cautiously until longer-term studies can provide more information on the sustainability of both pathologic and cognitive outcomes." "It is promising that rates of adverse events were lower than those seen in other populations in which sargramostim is used, such as acute myeloid leukemia," he noted, "though additional studies must also include a robust evaluation of long-term safety." "Furthermore," he added, "attention to cost and treatment duration will be relevant clinical considerations, given that a single course of the treatment used in this trial carries an average wholesale price of $5,000, which would equate to at least two years of treatment with acetylcholinesterase inhibitors, which are currently approved for those with mild-moderate Alzheimer's dementia." —Marilynn Larkin Source
