Nintedanib in chILD: a small step, yes… but at least a step forward in a marathon!

Childhood interstitial lung disease (chILD) describes a group of rare lung diseases that can affect infants, children and adolescents, and is associated with a high morbidity and mortality [1]. Typical features of chILD include dyspnoea, the presence of diffuse infiltrates on chest radiographs and abnormal pulmonary function tests with primarily evidence of a restrictive ventilatory defect along with impaired gas exchange. Due to the diversity of conditions ultimately resulting in this clinical phenotype, chILD is difficult to diagnose, and the classification scheme is frequently problematic even in the most specialised centres. This has fostered the formation of multinational collaborative networks [2]. Notwithstanding, despite substantial diversity in the upstream pathophysiological pathways involved in the chILD spectrum of conditions, a subset of these children will develop progressive fibrosing lung disease, which ultimately is fraught with adverse outcomes. The emergence in recent years of multiple drugs targeting the cessation or even reversal of fibrosis in the context of adult ILD prompted a call to arms advocating the judicious use of such agents in children [3].

The pathophysiology of chILD involves diverse biological pathways of epithelial cell integrity, surfactant metabolism, lung development and systemic immune disorders, just to name a few [3]. It is plausible to postulate that the progressive fibrosis characterising a subset of patients with chILD has mechanistic elements similar to what is driving fibrotic lung disease of adults. Studying chILD on a molecular or tissue level beyond genetics is challenging and needs ongoing efforts. However, in this setting, it is intriguing to note that markers known as key drivers of fibrosis in the adult lung, such as transforming growth factor (TGF)-β1 and connective tissue growth factor (CTGF), and markers of elastin destruction are frequently increased in chILD, especially in patients with long disease duration [4]. The overabundance of TGF-β1 and CTGF in lung fibrosis are prime targets for drug development and are tested in ongoing clinical trials [5]. Other central biological mechanisms of fibrosis are mediated by growth factors signalling via tyrosine kinases. Among these, nintedanib, a small molecule inhibitor of several receptor tyrosine kinases, namely platelet-derived growth factor (PDGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) receptors, has been shown to bind to the intracellular ATP binding pocket of these receptors and block their autophosphorylation, and such properties have yielded highly favourable outcomes in the context of trials focused on adult patients with ILD [6]. For example, the efficacy of nintedanib in the treatment of patients with idiopathic pulmonary fibrosis (IPF) was investigated in a set of randomised, double-blind, placebo-controlled, multinational, phase III INPULSIS trials [6], which was followed by an open-label extension showing the long-term safety of this drug in the adult population (INPULSIS-ON) [7]. In real life studies, patients treated with nintedanib or pirfenidone exhibited significantly reduced all-cause mortality compared to untreated matched cohorts [8]. The concept that antifibrotics may have a role beyond IPF and slow disease progression in lung fibrosis other than IPF has meanwhile gained broad support [9, 10].

A recent review of the multiplicity of cell types and signalling pathways targeted by the drug [11, 12] further reinforced the conceptual framework that a subset of children whose primary manifestations of chILD consisted of a fibrotic phenotype may benefit from a therapeutic trial with nintedanib. Indeed, in vitro studies have shown that nintedanib interferes with processes active in fibrosis, such as fibroblast proliferation, migration and differentiation, and the accumulation of the extracellular matrix [13].

In this issue of the European Respiratory Journal, Deterding et al. [14] report on their initial experience with nintedanib in children and adolescents suffering from chILD manifesting as progressive fibrosing lung disease. The study design of this early phase III trial is described in detail in a previous publication [15], and this initial phase was centred around dosing of the drug to achieve comparable levels of nintedanib as those previously shown to be efficacious in adults. Therefore, the study was not necessarily powered to examine clinical outcomes. Overall, 39 patients (26 subjects in the drug arm and the rest in the placebo group) with a mean age of 12.6 years and mean forced vital capacity (FVC) of 59.4% predicted completed approximately 22–24 weeks of treatment during the double-blind period and then an additional 22–24 weeks in the open label period. Despite a much higher frequency of side-effects in the nintedanib group, serious side-effects were not increased while the drug levels reached targeted concentrations in the vast majority. Although no statistically significant improvements in lung function were apparent after the initial blinded period, there were nominal increases in FVC percentiles in the drug-treated cohort as compared to declines in FVC in the placebo group over the same period, a somewhat comforting observation that may indicate favourable lung function outcomes if and when a larger cohort would receive the therapeutic formulation for a more extended period of time. Of course, one has to be aware that the trajectory of lung volumes in a young and growing lung is different to what happens in an ageing and slowly shrinking lung, especially when a dynamic disease process interferes with these changes over time. The overall lung growth trajectory of children with chILD may adopt several directions, depending on the cellular substrates being affected, and not necessarily manifesting as specific improvements in FVC percentiles. As such, it will be important to develop chILD subtype-specific markers of disease activity along with more sensitive measures of pulmonary functional recovery in future studies. Furthermore, the impact of nintedanib on extrapulmonary sites that are affected in the chILD variants that are part of systemic disorders will need to be carefully monitored. Furthermore, considering the heterogeneity of the chILD pathogenetic mechanisms and the ever-growing list of genes and their variants underlying some of these conditions, a consensus regarding which among these entities would be more likely to benefit from nintedanib would be desirable and may ultimately yield more precise therapeutic decisions if such mechanisms are a priori investigated before initiation of treatment [16]. As one awaits the sequel trial and its results, we need to remember that recruitment and retention of a large number of affected and eligible children will require worldwide participation of paediatric pulmonology centres, along with highly committed families and patients. Such effort is not only extremely arduous and non-trivial, but it is also critical for what emerges as the first glimpse of hope in making a difference in the outcomes of these children. In a marathon, we cannot see the finish line when we start the race, but every one of these races starts with a first step. This study clearly represents the first step in the quest for effective treatment of chILD and may further enhance the demolition of silos affecting lung fibrosis in children and adults [17].

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