Call it Leukine. Call it sargramostim. Call it, if you dare, granulocyte-macrophage colony stimulating factor (GM-CSF).
Whatever you call it, the little-prescribed drug approved 30 years ago to boost white blood cell production among bone-marrow transplant patients shows increasing promise as a therapy with the potential to not only stop – but perhaps even reverse – the ravages of Alzheimer’s disease.
That’s what the latest work of a University of Colorado School of Medicine team that has been testing the drug (let’s call it Leukine) for more than a decade has found. The team, led by neuroscientist Huntington Potter, the director of the University of Colorado Alzheimer’s and Cognition Center, reported evidence that Leukine helps the body clear out protein tangles and other hallmarks of Alzheimer’s disease and improves brain function among those given the drug. Patients from UCHealth Neurology Clinic – Central Park were central to the study’s success, and they will also be indispensable to a longer-term follow-up study that’s about to launch.
More than plaques
Alzheimer’s afflicts more than 6 million people in the United States alone, including some 76,000 people in Colorado, where the cost to the state’s Medicaid program tops $630 million annually. That doesn’t count the costs to private insurers, much less the burden on families which amounts to an estimated $3.7 billion a year in unpaid care.
Given the immense personal, societal, and financial impacts of Alzheimer’s disease – and the potentially massive market for an effective Alzheimer’s drug – the pharmaceutical industry has spent years trying to develop them. Many have focused on clearing out the beta-amyloid protein plaques that collect in the brains of Alzheimer’s patients. But those efforts have largely failed despite their effectiveness in eliminating the Alzheimer’s-associated plaques.
Potter says that, while it’s not clear why removing those plaques hasn’t proven pivotal in reversing the course of disease, there are a couple of possible explanations. One is that the damage was already done, so the best-case scenario was to limit the disease’s progression, “and that’s basically what they got.” The other theory is that the drugs have possible side effects that counterbalance the positives of plaque removal, he says.
Although, Leukine also removes amyloid in mouse models of Alzheimer’s disease, its mechanism of action is more complex than the current approaches of simply using an antibody designed to stick to amyloid to help the body remove it. Leukine may also help the brain heal itself, Potter adds.
The recently reported CU study was a randomized, placebo-controlled, double-blind (meaning neither those administering the drug nor the patient knew if they were getting the drug or the placebo) phase 2 trial. It involved 40 patients, half of whom got a Leukine injection five days a week for three weeks, half of whom got placebo saline injections instead. The team followed up at 45 days and again at 90 days with neurological, neuropsychological, blood-biomarker and imaging assessments.
Potter and colleagues found that this short-term Leukine treatment boosted numbers of innate and other immune cells and was safe and well-tolerated by participants. Measures of blood biomarkers of Alzheimer’s disease – brain amyloid, tau-protein tangles, and neurodegeneration – all improved. Perhaps most strikingly, the team also found that cognition and memory improved by about two points in the 30-point Mini-Mental State Exam.
“Quite frankly, why Leukine has shown an improvement in at least one measure of memory and cognition is unclear,” Potter said. “It’s a very complex molecule that has lots of benefits in animal models – not only with Alzheimer’s disease, but also with stroke, Parkinson’s disease, and aging. It may mean it has many benefits.”
Long time coming
The study represents an important milestone in work Potter has been dedicated to since the late 1980s. His efforts to show the link between Alzheimer’s disease and Down syndrome brought him from the University of South Florida to the CU School of Medicine’s Linda Crnic Institute for Down Syndrome in 2012. (The neurons of many patients with Alzheimer’s disease have three copies of chromosome 21 rather than two – the same trisomy 21 as those born with Down syndrome. All of those with Down syndrome develop Alzheimer’s disease brain pathology, and more than half develop dementia by age 50-60.) The institute as well as the Global Down Syndrome Foundation, among others, have long supported his work.
Along the way, Tim Boyd, who earned his PhD under Potter’s supervision, led work to test Leukine on mice. Potter suspected that the drug might fight Alzheimer’s disease. Why? Those with rheumatoid arthritis are protected from Alzheimer’s disease, and rheumatoid arthritis patients happen to produce more natural GM-CSF (Leukine’s active ingredient) than usual. Indeed, Boyd found that mice engineered for Alzheimer’s that got a three-week course of Leukine cleared 55% of their amyloid plaques – and that their cognition returned to normal.
Leukine works by stoking the innate immune system and cooling off inflammation. The combination appears not only to clear plaque, but also rebuild lost and damaged tissue. In mice, Leukine stimulates the development of new neural stem cells and new nerve cell connections to fill the voids the plaque had left behind. Leukine has also been shown to help regrow blood vessels. That combination could help patients who take Leukine avoid the problems of drugs that just clear out plaques leave voids that can induce brain swelling and microhemorrhaging known as ARIA (amyloid related imaging abnormalities).
The team’s prior Leukine research also extended to humans. They studied the cognition of bone marrow transplant patients who had taken Leukine for the standard three-week course of injections. They found that, six months later, such patients showed improved cognition and function as compared to those treated only with a different immune-system booster. More recently, Potter, Boyd, and others in the CU School of Medicine’s Neurology Department suggested early in the COVID-19 pandemic that Leukine could help repair the lungs of those with severe cases – an insight that appears to be bearing out in practice.
Follow-on study launching soon
The recent study’s promising results are leading to a longer-term follow-on trial at UCHealth Neurology Clinic – Central Park. Neurologist Dr. Peter Pressman will lead the clinical trial with Potter. It’s tentatively set for launch in May. Of the 42 participants with Alzheimer’s disease, 28 will receive Leukine injections five days a week for six months and 14 will receive placebo saline injections.
The study – also a randomized, placebo-controlled, double-blind phase 2 trial – has two main goals, Pressman says. First, it will assess the safety of Leukine when taken over a period of months rather than weeks.
“You don’t usually need to take sargramostim over this really extended period of time, and especially among people with Alzheimer’s disease,” he said. “We want to make sure we can give it to people safely.”
The second goal is to see if the cognitive improvement measured in the most recent study manifests among those who take the drug for 24 weeks. That improvement will be measured through both standard tests and reports from patients and families on how they’re faring in their day-to-day lives, Pressman says.
‘We know so much more’
If these Leukine injections prove to be safe and to help Alzheimer’s patients, the next step would be a major, phase 3 trial involving multiple medical centers and thousands of patients.
Pressman says the demand is certainly there: He and colleagues at UCHealth Neurology Clinic – Central Park see more than 2,500 Alzheimer’s patients a year and have a six-month waiting list. (The clinic is expanding capacity, he says, but it still won’t be able to keep up with a disease that afflicts one in nine people over age 65). With Alzheimer’s drugs such as cholinesterase inhibitors and memantine providing little relief, lifestyle changes related to diet and exercise are common prescriptions today, he says.
It’s still early days, and hundreds of experimental Alzheimer’s drugs have failed. Leukine, even if effective, could prove inferior to one or more of the roughly 100 drugs currently in clinical trials for the disease. Potter will let the scientific process play out as he always has, he says.
“I’m very optimistic, not only for the potential for Leukine, but I’m also optimistic that academic and industry scientists are working together on other approaches,” he said.
“We know so much more about the disease than we did even five years ago.”