R01AG071151

Phase II Trial of GM-CSF/Sargramostim in Alzheimer's Disease - 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).

The Regents Of The Univ. Of Colorado

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Colorado United States

State-Wide

Early Stage Clinical Trials for the Spectrum of Alzheimers Disease and Age-related Cognitive Decline (R01 Clinical Trial Optional) (PAR-18-877)

Amendment Since initial award the End Date has been extended from 11/30/24 to 11/30/26 and the total obligations have increased 368% from $1,340,244 to $6,265,868.