A Phase 1 trial shows that combining Sprycel (dasatinib) with the plant-based flavonoid quercetin improved the physical function of people with idiopathic pulmonary fibrosis (IPF). However, patients’ pulmonary function remained unchanged.
The study, “Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study” was published in EBioMedicine.
Numerous biological changes go along with aging, among them senescence — a process where cells stop dividing and enter a “zombie-like” state, where they evade cell death and promote a pro-inflammatory environment.
Many age-related diseases are a consequence of the deregulation of this cellular mechanism. IPF is an example of a cellular senescence-associated disease.
Previously, a plant pigment (flavonoid) called quercetin administered together with the chemotherapy dasatinib (sold under the brand name Sprycel by Bristol-Myers Squibb), used in chronic myeloid leukemia treatment, was shown to decrease senescence and lessen the fibrotic burden in the lungs of the bleomycin-induced pulmonary fibrosis mouse model.
Now, researchers explored the feasibility of using the combo therapy in people with mild to severe IPF.
The open-label, Phase 1 study (NCT02874989) enrolled 14 patients over age 50 with a confirmed diagnosis of IPF.
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The combo was administered orally — dasatinib at 100 mg/day, and quercetin at 1,250 mg/day — on an intermittent schedule as three doses given on three consecutive days followed by four days without treatment. This dosing schedule was repeated over three weeks, for a total of nine doses.
Results showed that the combo was well-tolerated in IPF patients, with minor side effects including cough, shortness of breath, skin irritation and bruising, and gastrointestinal discomfort or heartburn.
Pulmonary function and overall health did not change during the study.
Nonetheless, clinically meaningful improvements were seen in physical function tests — the 6-minute walk distance (6MWD), 4-meter gait speed, and five-repetition chair-stand times tests — for all 14 patients one week after completion of the treatment.
In the 6MWD, which measures the maximum distance a person is able to walk over six minutes on a hard, flat surface, participants showed a 21.5-meter increase.
“The 21.5-m increase in 6MWD is consistent with a clinically important improvement in IPF,” researchers said, adding that “the majority of participants exhibited physical function gains equal or higher than 5%.”
Patients also showed improvements in short physical performance battery (SPPB), which measures functional status and physical performance by evaluating walking speed, standing balance, and sit-to-stand performance.
“This was a short safety trial to determine if we should move ahead with actual large-scale human trials,” James Kirkland, MD, PhD, head of the Mayo Clinic’s Robert and Arlene Kogod Center on Aging, and the study’s lead author, said in a press release.
“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,” Kirkland said.
Despite these encouraging first results, researchers emphasize that work still needs to be done until this therapy becomes a reality in the clinic.
“We are studying the effectiveness of this and other [drugs that induce the death of senescent cells], but that does not mean that these should be used by patients or prescribed by physicians for any off-label conditions,” Kirkland said. “I want to emphasize that no one should take these drugs. This research is only beginning.”
One of the major limitations of the study is the absence of a standard-of-care or placebo group (control group).
Nonetheless, the team believes that the study “provides initial evidence that senolytics may alleviate physical dysfunction in IPF, warranting evaluation of [dasatinib plus quercetin] in larger randomized controlled trials for senescence-related diseases.”
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