Senolytic Drugs for IPF: First-In-Human Trial Delivers Promising Preliminary Results

Senolytic Drugs for IPF: First-In-Human Trial Delivers Promising Preliminary Results

In a pilot study, two drugs that target senescent cells appear to be effective for some people with idiopathic pulmonary fibrosis (IPF). A larger trial is underway to explore the safety and efficacy of senolytic drugs for the treatment of IPF.

After cellular senescence was first described in 1965, there has been growing interest in the role of this non-proliferative cellular state in all aspects of human biology, from disease processes to aging.

In a Nature Medicine article published in 2018, Dr. James Kirkland and his team from the Mayo Clinic demonstrated the effectiveness of senolytic drugs (drugs that target senescent cells) in slowing physical dysfunction in mice.

“Current and future preclinical studies may show that senolytics could be used to enhance lifespan not only in older people, but also in cancer survivors treated with senescence-inducing radiation or chemotherapy and people with a range of senescence-associated chronic diseases,” said the researchers.

In collaboration with researchers from UT Health San Antonio and Wake Forest School of Medicine, Dr. Kirkland published new research in Ebiosciences: the first-in-human pilot study of senolytic drugs for the treatment of idiopathic pulmonary fibrosis (IPF).

IPF is a complex degenerative disease characterized by progressive worsening of lung function and tissue scarring. Because IPF mostly affects the elderly and senescent cells accumulate with increasing age, it is possible that IPF can be treated with senolytic drugs.

“Cellular senescence is clearly emerging as a main player in aging,” said manuscript co-author Dr. Nicolas Musi, Professor of Medicine at UT Health San Antonio. “Previously, no published data existed to demonstrate that drugs targeting cellular senescence could be safely given to older patients, or that they might be used to treat diseases of aging such as IPF. The pilot research we’ve reported is preliminary but encouraging.”

In this new study, 14 participants over the age of 50 with mild-to-moderate IPF were given nine doses of Dasatnib and Quercetin (DQ), two senloytic drugs. Dasatnib has US Food and Drug Administration (FDA) approval for the treatment of leukemia and Quercetin is a plant pigment.

The researchers measured senescent biomarkers through assays, quality of life and presence of side effects through questionnaires and physical mobility through standard tests.

Despite having a very small sample size and no placebo-controlled group, the researchers found their preliminary results promising.

“No drug therapies, including the available anti-fibrotic drugs, have ever shown to stop the decline in, let alone improve, an IPF patient’s six-minute walk distance,” said Dr. Anoop Nambiar, manuscript co-first author. “But in this pilot study of DQ, participants’ six-minute walk distance improved an average of 21.5 meters.”

Although IPF is considerably rare in North America, there are few effective treatments available to slow disease progression. Pirfenidone and nintedanib are two drugs that have been approved for the treatment of IPF, but they are not effective for all patients.

“This was a short safety trial to determine if we should move ahead with actual large-scale human trials,” said Dr. Kirkland. “It’s important to emphasize that, while some measurable improvement was noted in all the participants, this is simply the start of human studies. We don’t know what lies ahead.”

Dr. Nambiar and his team are now enrolling patients at UT Health San Antonio and South Texas Veterans Health Care System for a more robust clinical trial.

For people with IPF, alternative treatment strategies are desperately needed. With growing evidence supporting the role of cellular senescence in age-related, degenerative diseases, there may be new hope for people with IPF.