Francesco Bonella, chairman of the EU-IPFF Scientific Advisory Board, participated in the American Thoracic Society Conference (ATS) in San Diego from 18-23 May 2018. Find below a short overview of the most recent advances in the research and care of IPF, as highlighted at the conference.
New data on pathogenesis and biology of IPF
The issue of immunological pathways in IPF seems to be attracting more attention than ever from researchers. The activation of lymphocytes through the IL17 pathway (Th17 lymphocytes play also a role in autoimmune diseases and asthma) and overexpression of PD1 (an immune checkpoint protein which can also prevent the immune system from killing cancer cells), on macrophages, fibroblasts and lymphocytes, which in turn trigger TGF-β fibrotic pathway (Geng Y, et al. ATS San Diego 2018; C73: PA5782), could open the way to new treatments in IPF.
Preservation of mitochondrial DNA is essential for the survival of cells. Its instability as a consequence of oxidative stress seems to be associated with activation of profibrotic pathways and defective cellular death (Kim S. ATS San Diego 2018; C85). Mitochondria directed therapeutics could therefore become an option for lung fibrosis.
New clinical trials in IPF:
The RIFF study was a phase II study on the efficacy of humanized monoclonal antibody binding IL-13, lebrikizumab, in IPF. It showed no benefit on lung function or mortality of 250 mg subcutaneous lebrikizumab given every month over 52 weeks in patients with IPF. Results suggest that targeting the IL-13 pathway alone may not be sufficient for achieving a therapeutic benefit in patients with IPF (Swigris JJ, et al. ATS San Diego 2018; D12: OA6167).
The ESTAIR Study was a phase II trial to test monoclonal antibody binding to IL-13 and IL-4, SAR156597, in IPF. The study found no difference between treatment and placebo group in lung function, death or all-cause mortality. The safety profile of SAR156597 was also unfavorable (Raghu G, et al. ATS San Diego 2018; A93: OA2441).
For many years, the role of gastroesophageal reflux in the pathogenesis of IPF and as a trigger of acute exacerbations has been under debate. The phase II trial “weighing risks and benefits of laparoscopic anti-reflux surgery in patients with IPF” (WRAP-IPF) did not show any benefit of this procedure on changes in FVC (Forced vital capacity) over 48 weeks. However, treatment was associated with fewer acute exacerbations and deaths, as well as fewer patients with 10% FVC decline. Further investigation is needed to confirm these results (Raghu G, et al. ATS San Diego 2018; A93: OA7698).
…and positive results
Several phase 2 trials with promising preliminary results are ongoing.
A randomized, placebo-controlled, double blind phase II clinical trial to assess primary outcomes (safety and tolerability), pharmacokinetics, and pharmacodynamics of autotaxin inhibitor GLPG1690 (n=15) vs placebo (n=5) over 12 weeks in patients with IPF showed that adverse events were comparable in the treatment and placebo arm. Although the study was not designed or powered to investigate efficacy, FVC and functional respiratory imaging results provided promising preliminary efficacy signals (Maher TM, et al. ATS San Diego 2018 and Lancet Respir Med 2018 May 18. Epub ahead of print)
The results of the randomized, double-blind, placebo-controlled, multicenter trial to test the effect of 28 weeks of recombinant human pentraxin-2 (n=77) on change from baseline in mean FVC % predicted (primary endpoint) vs placebo (n=39) in patients with IPF show a significant effect of recombinant human pentraxin-2 (PRM 151) vs placebo on the mean change in FVC percent predicted over time. Moreover, patients in the treatment arm experienced stabilization in the 6-minute walk test over time, whereas patients in the placebo arm experienced a decline. Adverse events were similar between treatment groups (Raghu G, San Diego 2018 and JAMA 2018 May 20. Epub ahead of print).
A lot of new data from long-term observational studies, as well as real-life experiences with the two approved drugs pirfenidone and nintedanib, confirmed the results on safety and efficacy signals which were already known from the clinical trials. Moreover, promising new data is emerging from quality of life investigations in patients under antifibrotic treatment (benefit on 6-minute walking test and symptoms burden).
The new guidelines on IPF diagnosis were also shortly presented by Raghu Ganesh in an oral session presentation; however, they are still under revision.
In short, the conference was one of the most exciting ones since 2014 – the year in which the results of the phase III trials were published. Just as the 2014 conference led to the approval of pirfenidone and nintedanib as treatment for IPF, the ATS Conference 2018 also gives us new hope for innovative treatments for IPF in the future.