Allogeneic Mesenchymal Stem Cells Under Exploration for Alzheimer Disease, Aging Frailty

Anthony Oliva, PhD, senior scientist, Longeveron

Anthony Oliva, PhD

Treatment with mesenchymal stem cells (MSC) could play an important role for patients with mild Alzheimer disease or age-related frailty, as well as other neurodegenerative conditions, given the anti-inflammatory and pro-regenerative effects associated with these cells.

An update on allogeneic MSCs being developed by Longeveron for Alzheimer disease and aging frailty was presented at the 19th International Conference on Alzheimer's Drug Discovery. In aging frailty, the cells showed improvements across multiple measures of physical function and decreased inflammation in a phase I/II study. In Alzheimer disease, the cells are being tested in a phase I trial, with an initial run-in period already showing high safety and tolerability.

"What we hope and anticipate is that this will become a standard of care," Anthony Oliva, PhD, senior scientist, Longeveron, told NeurologyLive at the conference, which was organized by the Alzheimer's Drug Discovery Foundation. "One of the beauties of these cells is that you don't need to worry about patient compliance. We're finding that a single treatment lasts for the better part of the year, if not more. You can go in annually for a single infusion and then you're done."

The rationale for the phase I trial for Alzheimer disease was established during investigation into aging frailty, where improvements were seen in mini-mental state exam (MMSE) in patients treated with the allogeneic MSCs. In combined data from phase I and II studies in aging frailty, a single infusion of 100 million MSCs improved MMSE scores by approximately 0.7 from baseline, which was a statistically significant improvement. In those treated with placebo there was nearly a 0.5 decline.

In the phase II trial, known as CRATUS, a single infusion of 100 million allogeneic MSCs showed a statistically significant improvement in 6-minute walk test (6MWT) and forced expiratory volume in 1 second compared with baseline (P = .01). There were also improvements in serum B cell intracellular TNF-alpha with the 100 million cells dose compared with placebo (P = .039) and baseline (P <.0001).

The phase I study for Alzheimer disease consisted of an initial safety run-in period, in which 2 patients received placebo and 3 received a single infusion of 20 million MSCs. This run-in period was followed by the full phase of the study, which also included a 100-million-cell arm.

At 30-days post-infusion for the phase I study, a data monitoring committee recommended the full study should proceed without modifications. In the first 10 patients infused, there were no treatment-related adverse events with the allogeneic MSC. Of the first 10 patients, the median age was 67.5 years, with 80% being ≥65 years of age. The study was split evenly between males and females, and 80% of participants were white.

"We have safety data. We know there aren't any safety issues with the cells. We know there aren't any serious adverse events, or any events attributable to the stem cell product. This is consistent with all the other research being done," said Oliva. "It's a very safe product."

MSCs are immunoprivileged, allowing for allogeneic treatment without adverse events. The cells are multipotent and stimulate regeneration and repair by recruiting intrinsic stem cells. MSCs have anti-fibrotic effects, immunomodulatory properties, stimulate endogenous cell differentiations, and impact mitochondrial function.

"I firmly believe that in the bigger picture, you have to have some type of stem cell therapy," said Oliva. "You need these physiologically responsive cells—you can think of these as cellular factories&mdash;that are responding dynamically to the changing environment to help promote and repair the damage."

MSCs have been explored for several years, and have long been shown to be tolerable. Work completed at the University of Miami helped established the treatments for aging frailty, which led to research into Alzheimer disease, an area of high unmet need where several late-stage agents have failed to produce meaningful results.

"There have been decades of failures for drugs for Alzheimer disease, and all of the drugs available treat the symptoms and not the disease itself," noted Oliva. A few drugs currently in the pipeline are showing promise, specifically those geared toward beta amyloid and tau. If these agents are successful, Oliva believes a combination approach will be possible, with MSCs used in conjunction with the targeted therapies.

"Stem cell therapies really need to be part of the equation to treat Alzheimer disease," he said. "Just targeting one thing ignores the pathology within the brain. You need MSCs as a combinatorial therapy to support revascularization, stimulate intrinsic neuronal regeneration, help rebalance all the inflammation at the sites of damage, and promote neurogenesis. These are all things the MSCs can do."

In addition to potential combination strategies, MSCs could be explored in a multi-dosing strategy, for moderate to advanced Alzheimer disease, and for other forms of dementia or mild cognitive impairment.

A phase IIb study is currently ongoing to compare placebo with the allogeneic MSCs at 4 different doses ranging from 25 million to 200 million cells for aging frailty. The co-primary endpoints of the study are 6MWT and change in TNF-alpha, both measured at 180 days (NCT03169231).

If this study is successful, Longeveron plans to launch a pivotal study for aging frailty. The development program currently is being conducted under FDA oversight, Oliva noted, and the cell culture product is highly purified. The company plans to further work with the FDA to develop the phase III pivotal trial, he said.

Oliva A. Safety and Efficacy of Longeveron Mesenchymal Stem Cells (LMSCs) to Treat Patients with Mild Alzheimer's Disease. Presented at: 19th International Conference on Alzheimer's Drug Discovery. September 17-18, 2018, Jersey City, NJ.