During the second session about the treatment of patients with idiopathic pulmonary fibrosis (IPF), a lot of evidence from post-hoc, subgroup and/or pooled analyses were presented. However, the first lecture was about another topic: refractory chronic cough, which significantly improved with the use of inhaled PA101.
Up to 80% of patients with IPF are bothered by dry cough, which is associated with a poor quality of life (QoL). Cough is an independent predictor of disease progression. Unfortunately, there is no appropriate treatment.
From pathophysiology to therapy
Cough results from activation of sensory nerves. Mast cells release mediators, such as histamine, which in turn sensitises nerves via P2X receptors. The sensory nerves then release mediators, such as substance P, that degranulate mast cells. Substance P induces cough in IPF, but not in healthy subjects. There are increased numbers of mast cells in IPF. Mast cells stimulate the activation and migration of fibroblasts in IPF. Cromoglicic acid (cromoglycate) is an old asthma drug that has poor bioavailability. It has some pleitropic effects, including a decrease in both mast cell degranulation, sensory c-fibre activation and activation of inflammatory cells (eosinophils and neutrophils). A new drug, PA101B, which is administered via an eFlow nebuliser, overcomes some of the limitations of cromoglycate.
A randomised, placebo-controlled, double blind, cross-over phase 2 trial studied the effectiveness of nebulised PA101/eFlow for IPF-related cough. PA101 led to a significant reduction in objective cough counts versus placebo. Furthermore, positive trends in cough-specific QoL and cough severity and a good safety profile were found.
Post-hoc analysis of nintedanib
Toby Maher (St. Albans, Hertfordshire, United Kingdom) presented a post-hoc subgroup analysis of pooled data from the INPULSIS® trial. Because of the study’s design he advises that the data be interpreted with the known caveats and precautions. Interestingly, there were more exacerbations in patients with more advanced disease. Possible explanations for this are: perhaps those patients are more prone to or more susceptable to exacerbations. Adverse events (AEs) were similar between the groups.
Nintedanib reduced the annual rate of decline in FVC, independently of DLco% predicted at baseline. A greater proportion of patients with DLco ≤40% predicted than >40% predicted at baseline had an acute exacerbation, but the treatment effect of nintedanib was consistent between the subgroups. Patients with DLco ≤40% predicted at baseline had a greater increase (deterioration) in total score of the St. George’s respiratory questionnaire (SGRQ) than patients with baseline DLco >40% predicted and experienced a more pronounced treatment effect of nintedanib.
Cardiovascular risk factors and comorbidities are frequent in patients with IPF, so many patients are prescribed statins to lower their cholesterol levels. Some studies have reported a link between statin use and the development of interstitial lung disease (ILD). In contrast, other analyses have suggested that statins may have a beneficial effect on clinical outcomes in IPF, and may result in a reduced decline in lung function in elderly people. A possible explanation is that statins have anti-inflammatory and antioxidant effects. However, the potential effect of statins in combination with anti-fibrotic treatment is unknown. Using pooled data from the two INPULSIS trials, post-hoc subgroup analyses of patients receiving versus not receiving statin at baseline were conducted. The aim was to assess whether statin use at baseline influenced the treatment effect of nintedanib. Michael Kreuter (Heidelberg, Germany) found that the annual rate of decline in FVC was numerically lower in patients receiving statins at baseline. Furthermore, the effect of nintedanib on reducing disease progression and risk of acute exacerbations was consistent across subgroups by statin use at baseline. His advise is to perform prospective clinical trials to investigate the potential impact of statins on clinical outcomes in patients with IPF.
Hannah Toellner (Burntisland, United Kingdom) presented data about clinical experience with nintedanib for IPF in three UK tertiary referral centres. The focus of her analyses was on the type and frequency of adverse events (AEs) and the impact of AEs on treatment continuation.
In a multicenter, retrospective, observational study , data were collected from clinical letters. Although AEs with nintedanib were common, she concludes that there was an acceptable AE profile. Furthermore, no signal of increased risk of cardiovascular events or bleeding was found. She also mentioned some strengths and limitations of the design of this study (Table 1).
Table 1. Strengths and limitations of the design of this study.
Patient cohort with:
Source: Session 710, IPF treatment II. September 7th, 10:45-12:45, Room C.