Senolytics show promise against intractable lung disease
Lung from an IPF patient, showing “honeycombing” caused by fibrotic scarring. Case courtesy of Prof Frank Gaillard,  Radiopaedia.org  case  8621

Lung from an IPF patient, showing “honeycombing” caused by fibrotic scarring. Case courtesy of Prof Frank Gaillard, Radiopaedia.org case 8621

A first-in-human pilot study published online this week has shown that a drug cocktail that targets senescent cells has beneficial effects in patients with idiopathic pulmonary fibrosis (IPF), a devastating lung disease associated with aging.

What is IPF?

As the name implies, IPF is characterized by fibrotic changes—scarring—in the lung tissue. As the scars accumulate, the lung tissue becomes less elastic, dramatically decreasing their ability to take in oxygen. the iminished aerobic capacity reduces patient quality of life and ultimately makes breathing impossible. Progression is rapid, with a median survival of less than 4 years after diagnosis. Although drugs such as pirfenidone and nintedanib can slow the rate of scarring, no curative treatment is available.

The risk of IPF rises sharply with aging, and preclinical studies in mice have strongly implicated cellular senescence in its pathogenesis. In mouse models of IPF, the lung tissue contains high levels of senescent cells and senescence-associated biomarkers. Consistent with that circumstantial evidence, the senolytic cocktail dasatinib+quercetin (DQ)—which extends lifespan and ameliorates several other age-related diseases in mice—alleviates IPF symptoms and improves pulmonary function.

Inspired by the mouse studies, a multi-institution research collaboration performed a small-scale, single-arm trial of DQ in human patients with IPF. (Many of the authors also contributed to the mouse work, as well as the fisetin study we covered recently.) As is standard for early-phase trials of this type, the primary endpoint of the study was feasibility, as reflected by the rate at which subjects completed the study. (When a regimen is associated with serious adverse consequences, retention rates tend to fall precipitously.)

DQ improves physical performance—but not lung function—in IPF patients

The results revealed that DQ was well tolerated (100% of the subjects completed the study) with few adverse side effects, implying that the drug regimen the authors selected is appropriate for use in larger-scale, placebo-controlled studies.

More exciting, however, was a significant finding related to a secondary endpoint: The patients exhibited clinically relevant improvements in physical performance, as measured by simple exercise tests such as six-minute walking distance (6WMD) and the ability to repeatedly stand from a seated position. This is unprecedented: The disease itself is “relentlessly progressive,” in the words of the authors, who went on to point out that “in large IPF drug trials, no improvements in 6MWD have been observed.” The currently approved medications, pirfenidone and nintedanib, slow the progression of IPF but do not reverse its effects.

However, the authors observed no change in several metrics of pulmonary function. This is puzzling: if IPF patients suffer from diminished physical performance due to progressive reduction in lung capacity, how might a drug regimen improve performance without affecting pulmonary function? The authors acknowledge that resolution of pulmonary scarring may take longer than clearance of senescent cells, but I find this explanation unsatisfying, in the sense that it sidesteps what is presumably a directional, causative relationship between lung damage and physical decline.

One potential explanation for this surprising result is that DQ, which as noted above, attenuates a broad spectrum of age-related pathology, is improving physical performance via a beneficial effect on some exercise-related tissue outside the lung itself, e.g., the vasculature. (Consistent with this notion, the study that originally identified quercetin as a senolytic reported that it was particularly effective against senescent vascular endothelial cells.)

Alternatively, it may be that senescent cells in the lung contribute to physical decline in some manner other than (or in addition to) decreasing the ability to take in oxygen, although that seems harder to imagine. It is also possible that some aspect of the study (e.g., the small sample size or the single-arm, open-label design) obscured a benefit to pulmonary function that might be revealed in a future larger-scale effort.

What’s next?

A notable aspect of the regimen was that it was pulsatile: the drugs were delivered for three days in a row on each of three consecutive weeks, rather than every day. Moreover, the physical performance benefits were observed in tests performed a week or two after the final dose, much longer than the drugs’ half-lives. This argues that DQ, unlike many drugs, does not exert its effect by binding a specific receptor. Instead, the findings are consistent with the predicted “hit and run” mechanism of action, in which the cocktail eliminates senescent cells that are actively contributing to IPF pathology.

This is consistent with the consensus model for how senolytic drugs work, and provides further evidence that this approach is generally valid for treatment of age-related disease: Even though the diseases of aging are chronic, senotherapeutics will not have to be administered chronically in order to work effectively—instead, they can be administered in an intermittent or pulsatile fashion, with a frequency dictated by the rate at which senescent cells accumulate. (By analogy, having a well-trimmed lawn doesn’t mean you need to keep the mower running all the time: you cut the grass once, and then put the mower in the garage until the grass gets long again.)

The results of this early-phase trial are by definition preliminary, and it is too soon for clinical action: as the authors state, “We emphasize that physicians should not prescribe senolytics and IPF patients should not take these agents outside of clinical trials, unless and until further studies clearly demonstrate safety and efficacy.” However, the results of this study are unquestionably promising: the adverse effect profile suggests that the regimen will be well tolerated, and the significant improvements in physical performance data clearly warrant testing in a larger cohort.

Such larger-scale studies might also enable a more detailed investigation of mechanism, including the role of the senescence-associated secretory phenotype (SASP) in IPF. Hopefully, they will also address the conundrum of how a drug can improve physical condition in patients with a lung disease without improving lung function, if the latter is indeed the case.