With the elderly population growing — both in the United States and globally — there is mounting pressure to develop treatments that address unmet needs in geriatric populations. Regenerative medicines, including allogeneic stem cells, show promise in treating aging frailty in elderly populations, but the regulatory path forward presents challenges.
Aging Frailty is a Growing Concern
The U.S. Census Bureau predicts that 78 million people will be older than 65 by 2035; globally, the over-60 population will double by 2050 and triple by 2100, outpacing their younger counterparts.1 Yet, for a condition that plagues this population — aging frailty — there is no FDA-approved treatment, leaving them susceptible to poor clinical outcomes, such as institutionalization, falls, fractures, hospitalization and even death. Frailty is associated with sarcopenia, or loss of muscle mass and chemical markers in the blood that trigger inflammation are elevated in aging frailty and other conditions, including Alzheimer’s disease and metabolic syndrome.
Stem Cell Therapy for Aging Frailty
Longeveron has been studying the potential of stem cell therapy as a way of treating patients with aging frailty, exploring the immunomodulatory effects of mesenchymal stem cells (MSCs) in suppressing inflammation and reversing chronic aging-related disorders. As reported in 2017,2 the results of phase I and phase II clinical studies (sponsored by the University of Miami) were published in the Journals of Gerontology. These studies evaluated the safety and tolerability of intravenously infused allogeneic MSCs derived from the bone marrow of young healthy donors, in patients with aging frailty.3 Now, thanks in part to a two-year, $3.8 million grant from the National Institute of Aging, we are recruiting for an expanded phase IIb study in aging frailty. This marks the first multi-center, randomized, placebo-controlled trial using stem cells to treat aging frailty. The study’s aim is to demonstrate the efficacy of allogeneic MSC infusion in ameliorating the signs and symptoms of the condition in patients aged 70–85.
MSCs used in treatment are procured from the bone marrow of young, healthy donors. These specialized cells, once isolated from the bone marrow, are culture-expanded in vitro and then cryopreserved. Once ready for use, the stem cells are thawed, washed and tested for viability prior to infusion into clinical trial subjects. MSCs are multipotent, self-renewing cells that differentiate into bone, fat and cartilage tissue and are essential for self-repair. As these cells migrate within the body, MSCs are believed to secrete chemical signals that induce tissue repair, reduce inflammation, modulate the immune system and promote the formation of endothelial tissue. This mechanism of action is being tested in elderly patients to determine the biological effect and the ability to reverse or reduce the severity of frailty and to prevent or reduce adverse health outcomes.
Clinical Trials Exploring Efficacy
Our phase IIb trial was originally slated to include 120 subjects in four treatment arms, but the NIA grant award has allowed Longeveron to expand the study to 150 subjects and five treatment arms. Currently, two-thirds of subject enrollment is complete, and the final subject is expected to be enrolled this summer. The trial was designed to assess the effect on physical function and mobility, as limitations in these areas increase with advancing age. Many aging frailty patients experience difficulty in performing basic activities of daily living, such as navigating stairs, crossing the street or even rising from chairs without the risk of falling. Our society urgently needs new treatments that can prevent or reverse the physical deterioration that often leads to an individual becoming dependent on others for care. We are one of the few organizations conducting clinical studies in these areas, and we believe that a regenerative medicine approach holds great promise.
One of the main challenges from a drug development standpoint is that chronic conditions of “aging” do not necessarily fit well into the U.S Food and Drug Administration (FDA) criteria for a treatable indication or condition. Overcoming this challenge will require compelling data and frequent interaction with the FDA to agree on trial designs, patient definitions and appropriate endpoint selection.
The endpoints in the trial design include lower body strength, grip strength, mobility, endurance, balance, walking speed and fear and risk of falling. In addition, changes to pro- and anti-inflammatory molecules in the blood are being measured in the hope of identifying a potential biomarker. Assessing these endpoints helps determine whether the patient is experiencing deteriorating health. The effect of intervention on the long-term clinical outcomes will require a multi-year study, but the current phase IIb trial is focused on these more intermediate endpoints to determine efficacy over 6–12 months.
MSCs For Other Therapeutic Areas
After the phase IIb trial results are known, Longeveron will, in consultation with regulatory authorities and advisors, evaluate the next steps toward eventual commercialization. In addition, Longeveron is also recruiting patients for a phase I Alzheimer’s trial and a phase II trial to evaluate the safety and efficacy of its stem cells for improving flu vaccine immune response in aging frailty patients. Additionally, Longeveron has worked with the PMDA in Japan to successfully finalize a phase II trial design for treating aging frailty. The country’s aging population, along with a single-payer health system and progressive regulatory framework, supports the development of regenerative therapy and an expedited route to market. That trial is planned to commence this year.
Reference
- World Population Prospects, The 2017 Revision, Key Findings and Advance Tables. United Nations, Department of Economic and Social Affairs, Population Division. 2017. Web.
- Branch, Emilie. “Aging Frailty Stem Cell Therapy Advances.” Pharma’s Almanac. 19 Oct. 2017.
- Tompkins, Bryon A. et al. “Allogeneic Mesenchymal Stem Cells Ameliorate Aging Frailty: A Phase II Randomized, Double-Blind, Placebo-Controlled Clinical Trial.” J. Gerontol. A Biol. Sci. Med. Sci. 72: 1513–1522 (2017).