What did a placebo comparison reveal about taking dasatinib and quercetin for lung scarring?

A treatment can be feasible to deliver without being easy to tolerate, and neither fact tells us whether it preserves lung function. That tension sits at the center of a small randomized trial of dasatinib and quercetin, a drug combination being studied as a way to target senescent cells in idiopathic pulmonary fibrosis, or IPF.

Published on February 28, 2023, the report describes 12 people with IPF who were randomly assigned to the combination or placebo. All completed the planned regimen. The active-treatment group reported many more non-serious adverse events, however, while the study did not show a meaningful difference between groups in its exploratory breathing and physical-function measurements.

The result is useful for understanding what it is like to run this treatment regimen in a selected group of patients. It is not evidence that dasatinib and quercetin improve breathing, reduce lung scarring, extend survival or are ready for routine use.

A completed regimen answered only one part of the question

The investigators designed this phase I pilot primarily around feasibility and tolerability, not treatment effectiveness. They wanted to know whether participants could take intermittent dasatinib and quercetin as planned, complete the assessments and avoid serious problems clearly linked to dosing. The placebo comparison made it easier to interpret the treatment experience than an uncontrolled study would have.

Every randomized participant completed the study regimen and all 108 scheduled doses were taken across the two groups. Planned clinical assessments were also completed. That is a concrete advance for trial planning: the schedule could be delivered in this setting, with weekly monitoring and follow-up after treatment.

Completion still has a narrower meaning than clinical success. A person may finish a short course even while experiencing unpleasant symptoms, and a small study can miss uncommon harms or effects that appear only after longer exposure. The trial therefore answered whether this particular research process was workable more clearly than it answered whether the drugs help people live better with IPF.

Why researchers are targeting senescent cells

IPF is a chronic, progressive form of lung scarring. The paper describes cellular senescence as one feature of the aging-related biology seen in lung tissue. Senescent cells stop dividing but can resist normal removal and release signaling molecules associated with inflammation and fibrotic activity. In the proposed model, those cells may help maintain an environment that damages tissue and promotes scarring.

Senolytics are drugs intended to remove senescent cells by disrupting the survival pathways that help them persist. Dasatinib affects multiple tyrosine kinases, while quercetin affects several signaling pathways. The combination is intended to make senescent cells more vulnerable to elimination. That mechanism is a biological rationale for testing the drugs, not proof that senescent cells were cleared from the lungs of participants in this trial.

The current paper gives brief context about an earlier uncontrolled pilot by the same investigators. Its main contribution here was the addition of a randomized placebo group and a direct look at whether intermittent dosing could be carried out with careful monitoring.

The experiment took place in a tightly defined setting

Participants were recruited at one center and had confirmed IPF and clinical stability during the prior year; those taking antifibrotic medication were required to have stable therapy for the preceding three months. The group was small and selected, with mild to moderate disease and controlled enough health conditions to meet the study’s exclusion criteria. Participants were masked to their treatment assignment, but the design was single-center and single-blind rather than a large, broadly representative efficacy trial.

The active regimen lasted three weeks. Participants took 100 milligrams of dasatinib and 1,250 milligrams of quercetin on three consecutive days during each of three consecutive weeks, for nine dosing days in total. The medication context mattered: nintedanib was withheld on dosing days, while pirfenidone was continued. The treatment experience was therefore part of a supervised protocol with medication adjustments, rather than a simple test of two drugs detached from ordinary IPF care.

Participants were followed for complications, and laboratory checks were performed around treatment. These safeguards help explain why the study could document feasibility, but they also mean that the findings should not be generalized automatically to people with different disease severity, other medications or health conditions.

More reported events did not automatically mean more serious harm

The active-treatment group had 65 reported non-serious adverse events, compared with 22 in the placebo group. Those are event totals, not counts of people and not a calculation that each participant faced a threefold personal risk. One participant can report more than one event. Many of the symptoms reported with dasatinib and quercetin, including fatigue, nausea, headache, weakness and feeling unwell, are also familiar in IPF or were anticipated from dasatinib’s known effects.

Sleep disturbance and anxiety stood out as more prominent in the active-treatment group. The authors identified these symptoms as concerns to monitor in future studies. With only six participants receiving the combination, the trial cannot determine how often those symptoms would occur in a larger population or whether every difference was caused by the treatment. It does show that tolerability includes more than avoiding hospitalization or stopping a regimen.

A serious event occurred after dosing had ended in a participant assigned to dasatinib and quercetin. The event involved infectious and postoperative complications and ultimately ended in death. The paper reports that the University of Texas Health San Antonio institutional review board adjudicated it as unrelated to dasatinib and quercetin, citing the participant’s known health risks, the clinical circumstances and the drugs’ short elimination half-lives.

That reported attribution matters, but it should be read precisely. The event was categorized separately from the mild, moderate and severe symptoms recorded during treatment, and the investigators reported no serious adverse event judged related to the combination. Neither point establishes long-term safety or excludes rare harms. The study was too small and too brief to do that.

Breathing and mobility remained open questions

The researchers also measured pulmonary function, walking performance, frailty and related symptoms before and after the three-week regimen. Changes in measures such as forced vital capacity, forced expiratory volume, six-minute walk distance and physical-function tests did not appear meaningfully different between the treatment groups.

That observation is not a finding of equivalence. The sample size was chosen for feasibility and tolerability, with only six participants per arm. The groups also differed in some baseline features, including the proportion taking antifibrotic medicines. Three weeks is a short period in which to detect a clinically meaningful change in lung scarring or everyday function, and several of the measurements can vary with effort, repeated testing and the combined effects of heart, lung and muscle performance.

For patients hoping to preserve their breathing or mobility, the practical message is therefore limited. The study did not reveal a measurable functional advantage, but it also was not designed to settle whether a larger, longer efficacy trial would find one. It established a treatment experience that could be studied further while leaving the central benefit question unanswered.

A biological target needs a way to be measured

There is another unresolved problem besides showing patient benefit. Researchers need to know whether the treatment is affecting the biological target it was intended to affect. In this study, GPNMB was explored as a possible biomarker signal. GPNMB is a protein associated with inflammation and cellular senescence.

A change in such a protein could help researchers design future studies around biological response, but this pilot did not establish that senescent cells were removed from participants’ lungs. The paper also discusses the lack of clinically validated circulating markers that can reliably measure cellular senescence. Without a dependable way to connect a biomarker change to senescent-cell clearance and then to patient outcomes, a future trial could still show a laboratory difference without proving that people breathe or move better.

The next scientific challenge is thus not simply to count completed doses. It is to connect treatment exposure, biological change, symptoms and clinically meaningful function in a population large enough to distinguish a real effect from chance variation.

What this could change

People with pulmonary fibrosis could eventually have another way to preserve breathing and everyday activity by treating a cellular contributor to scarring rather than only slowing the downstream process. Dasatinib and quercetin could support that possibility only if larger, longer trials show a clinically useful benefit, establish an acceptable burden of harm and clarify whether the biological target is actually changing in patients.

This pilot made that path more testable by showing that a placebo-controlled, intermittent regimen could be completed in a carefully selected group. It did not make the treatment ready for clinical use. The potential future capability is conditional on proving that a feasible treatment experience can become a safe and meaningful improvement in patients’ lives.

Key Sources

• Primary source: Senolytics dasatinib and quercetin in idiopathic pulmonary fibrosis: results of a phase I, single-blind, single-center, randomized, placebo-controlled pilot trial on feasibility and tolerability.
  DOI or Journal Page · Clinical Trial · 2023-02-28