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.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.wisepoqder Quercetin
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.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.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.
