A small Phase 1 pilot study found improved physical function in idiopathic pulmonary fibrosis (IPF) patients treated with senolytic therapies. The trial was conducted by researchers at University of Texas Health San Antonio, in collaboration with the Mayo Clinic and the Wake Forest School of Medicine.
The findings were published in the journal EBioMedicine in an article titled “Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study.”
Senolytics are small molecules that can induce cell death in senescent cells, which are damaged cells that stop to divide but don’t die, also known as “zombie-like” cells. Senescent cells can release senescence-associated molecules that create a toxic environment to nearby cells, which in turn can lead to inflammation, tissue remodeling, and fibrosis (scarring).
Previous studies have shown a link between cellular senescence (which is associated with aging) and IPF. One study in particular showed that senescence markers are more abundant in IPF patients compared with healthy controls, as well as in a mouse model of IPF. In addition, a separate study showed that senolytic treatment could clear senescent cells in IPF mouse models.
Based on these observations, researchers tested the effects of senolytic treatment in IPF patients in a Phase 1 trial (NCT02874989). The study enrolled 14 adults, who were at least 50 years old, with stable mild-to-moderate IPF. Participants received a combination of 2 oral senolytic drugs — dasatinib (100 mg/day, also sold under the brand name Sprycel by Bristol-Myers Squibb for leukemia treatment), and quercetin (1,250 mg/day) — for 3 consecutive days per week, for 3 weeks (nine doses in total).
Researchers assessed the general health of participants (cognitive and physical weaknesses, lung function, laboratory tests), quality of life, and drug side-effects to test the safety and tolerability of the treatment. They also measured the patient’s physical function — through the six-minute walk distance, four-meter gait speed, and sitting-to-standing repetitions tests — and analyzed senescence-associated proteins.
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Results showed physical function gains greater than 5 percent in the majority of the participants after they completed the senolytic treatment. In particular, they found a significant improvement in participant’s mobility — the average increase of 21.5 meters (70.5 ft) observed in the six-meter walk test is considered a clinically significant improvement.
“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,” Anoop M. Nambiar, MD, associate professor of medicine at UT Health San Antonio and co-author of the study, said in a university news release written by Will Sansom.
“But in this pilot study of DQ [dasatinib/quercetin], participants’ six-minute walk distance improved an average of 21.5 meters,” Nambiar added.
However, other physical function markers such as grip strength and lung function, as well as self-reported health, were unchanged. Also, no significant change was seen in senescence-associated molecules.
“We should be cautious about whether this finding is true based upon this small study without a blinded placebo control group,” Nambiar said. “However, this and other results warrant further study in larger randomized, controlled trials.”
In terms of safety, side effects were mild to moderate in severity, and were reversible, according to questionnaires. The most common side effects were respiratory issues, skin irritation and bruising, and gastrointestinal discomfort or heartburn.
“Though small, this pilot study marks a major breakthrough in how we treat age-related diseases such as IPF,” said Jamie Justice, PhD, assistant professor at Wake Forest medical school, and the study’s co-lead investigator and corresponding author. “We’ve therapeutically targeted a fundamental biological hallmark of aging that is implicated in IPF, and we show early but promising results for the first time in human patients.”
Nicolas Musi, MD, professor of medicine at UT Health San Antonio, director of the university’s Sam and Ann Barshop Institute for Longevity and Aging Studies, and the study’s co-author, added: “Cellular senescence is clearly emerging as a main player in aging. 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,” Musi concluded.
IPF patients are currently being recruited at UT Health San Antonio and the South Texas Veterans Health Care System for a larger randomized, placebo-controlled study of DQ safety and effectiveness. Potential study subjects may call (210) 949-3898 to ask about their eligibility.