Highlights of the ATS congress 2018- By Francesco Bonella

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.

New article on the importance of early diagnosis and treatment in idiopathic pulmonary fibrosis

A new call to improve IPF diagnosis has been launched by some Spanish experts in May 2018.

With an article that recalls the challenges of an early and correct diagnosis of this rare condition, the authors show the benefits of a rapid provision of treatment on the prognosis and quality of life for IPF patients. The authors conclude with recommendations to improve the current state of play: enhanced care management, better coordination among stakeholders, and increasing funding for IPF research and management.

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Challenges in the diagnosis of IPF

IPF shares a challenge with many rare diseases, as its symptoms are often confused with other general respiratory conditions, and this can lead to a significant amount of patients being initially misdiagnosed with asthma, chronic obstructive pulmonary disease (COPD), or pneumonia, among other diseases. In this regard, detection of velcro-like crackles during chest auscultation, which are strongly associated with the presence of lung fibrosis, has been proposed as a feasible and sensitive measure to improve early detection. However, most patients who refer the first symptoms at the primary care physician are symptomatically treated, and only when no improvement is warned, are referred to the respiratory physician.

Diagnosis of IPF requires the presence of a pattern of usual interstitial pneumonia (UIP) on high-resolution computed tomography (HRCT), or combinations of UIP patterns on HRCT and on tissue samples from lung biopsies. Some hope to improve early diagnosis is also given by several clinical trials that are trying to identify molecular markers that are associated with the manifestation of IPF.

Benefits of early diagnosis and treatment of IPF

An early intervention is crucial to improve IPF prognosis. The ATS/ERS/JRS/ALAT guideline for the treatment of IPF includes recommendations for the use of nintedanib, pirfenidone, and antacid therapy, as well as of non-pharmacological treatments such as pulmonary rehabilitation, long-term oxygen therapy, and lung transplantation. Importantly, real world data from a multi-center, prospective, observational registry support the beneficial effect of anti-fibrotic therapy on survival (Hazard Ratio (HR) 0.56, 95%CI 0.34–0.92, p = 0.022) and transplant-free survival independent of baseline disease severity, compared to non-anti-fibrotic therapy.

Need for improved management, better coordination among stakeholders, and increasing funding

A rapid and accurate diagnosis of IPF requires a multidisciplinary discussion among physicians specialized in interstitial lung diseases (ILDs); however,  multidisciplinary teams (MDTs) are only available in tertiary care reference centers. Thus, prompt referral from primary care or non-specialist pulmonology services to centers of expertise is essential for early diagnosis. Lack of quick referral or coordination among centers hinders rapid and accurate treatment and is detrimental to the patient. For instance, an accurate early diagnosis could prevent the misdiagnosis with COPD and treatment with corticosteroids, discouraged in IPF patients.

Despite the widely accepted benefits of referral to a reference center, some respiratory physicians still do not seek support from MDTs for early diagnosis and treatment. In addition, a stronger information flow and support among physicians and patients would be desirable, to manage expectations and avoid misinformation.  An integral multidisciplinary approach in IPF patient will eventually help improve quality of life and treatment adherence.

All these management measures translate into more funding requirements. Since IPF is a rare disease, National Health Systems (NHS) should play a main role in the funding of disease management strategies. Without Health Authorities participation, improvement of management is compromised.

Highlights of the ATS congress 2017- By Marlies Wijsenbeek and Francesco Bonella

Marlies Wijsenbeek and Francesco Bonella, members of the EU-IPFF Scientific Advisory Board participated in the American Thoracic Society Conference (ATS) which took place in Washington from 19-24 May 2017. With around 17,000 attendees, the ATS conference is one of the largest conferences offering ground-breaking research in pulmonary, critical care, and sleep medicine. This year’s congress provided an excellent opportunity to discuss different aspects and up to date research in IPF treatment and care:

Factors influencing  IPF onset anddisease course

A study onIPF patients monitored at home revealed that exposure to air pollution could increase the risk of acute exacerbations and mortality (Johannson K.A.). Another study assessing the effect of occupational exposure to metal, wood and agricultural dust on IPF found that the occupational exposure was associated with IPF disease burden. Prevention measures in the workplace could potentially reduce thedisease burden by as much as 13% (Cummings K.J et al).

In addition, Toby Maher from Royal Brompton Hospital reported that the bacterial composition in IPF patients lungs affect the hosts’ immune response and can significantly influence progression-free survival. Also fungicould be involved in the worsening of IPF; however, these new findings require further investigation.

Use of supplemental oxygen during routine daily activities

Although oxygen is often provided for patients with fibrotic interstitial lung disease (fILDs), little research on its benefit exists. A group of UK researchers investigated the impact of supplemental oxygen on routine daily activities and quality of life for people with fILDs. Using patient reported outcome measures, the study showed a significant improvement in breathlessness and activity with the use of ambulatory oxygen. However, no improvement in the psychological domain was found.

Views on IPF management

 A study on patients’ and physicians’ views on IPF management (Mahler) found that only 56% of interviewed patients feel that they received enough information at diagnosis, while less than half discussed disease prognosis and were told about treatment options. Most patients felt that the ability of anti-fibrotic drugs to slow disease progression was more important than side effects. Among the patients who had received antifibrotic therapy, 86% felt confident in managing those side effects.

Meanwhile, physicians with more of a watch-and-wait attitude (initiation of anti-fibrotic treatment more than 4 months after diagnosis) were less likely to discuss prognosis and were more concerned about side effects. On the other side, proactive physicians (initiation of anti-fibrotic treatment less than 4 months after diagnosis) were more concerned about disease progression and more likely to discuss prognosis.

Role of the multidisciplinary team in diagnosis and treatment

When it came to diagnostic tools for IPF and ILDs, the focus was on the role of the multidisciplinary discussion (MDD) to reach a definitive diagnosis and to decide the appropriate treatment for patients. A study conducted by Walsh et al came to the conclusion that ILD experts diagnosed IPF correctly more often than non-experts, thereby confirming the diagnostic value of the MDD as a valid tool, especially within reference centres. Another study found that the involvement of a rheumatologist in the MDD led to a diagnosis of connective-tissue disease-related ILD in about 20% of IPF patients, thereby further increasing diagnostic accuracy (Israeli-Shani L. et al).

 Current and future treatment options for IPF

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 from the clinical trials. Interestingly, treatment with pirfenidone or nintedanib has not found to be associated with cardiac, bleeding or airway complications in IPF patients who received lung transplantation (Dorey-Stein et al). Moreover, the results of a phase IV single-arm, open-label study on the combined use of pirfenidone and nintedanib in IPF did not suggest a different safety profile to that expected for either treatment alone (Flaherty et al). It should be stressed that for the moment combination treatment can only be used in the context of controlled trials.

Several phase 2 trials with promising preliminary results are ongoing. Prometic‘s PBI-4050 is an orally active lead drug candidate which demonstrated a strong safety profile and promising efficacy, either alone or in combination with nintedanib or pirfenidone.

TD139, an inhibitor of galectin-3 that affects receptor signalling including the pro-fibrotic molecule TGF-β – has been tested against a placebo in 24 IPF patients for two weeks. The compound appeared to be safe and well tolerated and the results regarding efficacy in terms of suppressed Gal-3 expression on BAL macrophages were promising.

In conclusion, the ATS conference 2017 provided new insights in the pathogenesis, management and treatment of IPF and ILD in general, confirming that research and clinical practice are close each other in this rare disease group.

EU must do more to combat disease described as 'more lethal than most cancers'

Idiopathic pulmonary fibrosis sufferers across Europe are struggling to receive consistent and equal access to care, argues Andrey Kovatchev.

It starts out as shortness of breath and dry cough. But it’s more rapidly lethal than most cancers. Idiopathic pulmonary fibrosis (IPF).

It is one of the most frightening diseases you’ve never heard of. There is no known cause for this disease, which makes it increasingly difficult for the patient to breathe as it thickens the lungs. Only one or two out of five IPF patients survive five years.

An estimated 80,000 to 110,000 people in Europe live with IPF, and up to 35,000 new cases are identified each year. These numbers, however, do not reflect the full magnitude of the disease.

IPF is often difficult to diagnose with initial symptoms resembling those of other, more common, diseases. What’s worse is that IPF treatment options are limited and there are huge discrepancies in access to care between and within EU member states.

Access to the best available healthcare is a right for all European citizens. As an elected citizens' representative to the European parliament, it is my duty to voice the recommendations of the patient organisations that have come together to create the first European charter for patients suffering from IPF, calling for consistent and equal access to care and treatment.

This includes early and accurate diagnosis, better access to palliative care and end-of-life care as well as a holistic approach to standardise the management of the disease.

The EU has done a lot to ensure a high level of human health protection, yet there are still simple measures that should be implemented at both European and national level to improve the situation of thousands of patients living with this disease.

First, the EU can play a decisive role in the improvement of standards for IPF care across Europe by ring-fencing funding for research within the Horizon 2020 framework.

Second, the EU can create a Solidarity Fund to allow access to orphan drugs that, though having received European medicines agency (EMA) approval, are not yet sold in some member states due to delays in approval by national regulators.

Along with more than a dozen other members of the European parliament, I will formally endorse the first European IPF patient charter.

We will also send a joint letter to the delegates of the expert meeting on chronic respiratory diseases to underline the importance of establishing multidisciplinary teams and regional networks to provide optimal care for IPF patients.

I firmly believe that the EU institutions must work together with member states to drive changes in national healthcare systems. National governments have a responsibility to influence clinical practice in partnership with local health authorities, medical societies and patient organisations.

If adopted, which we hope it will, the charter’s recommendations will improve quality of life for all IPF patients across Europe, supporting the development of better long-term treatments and hopefully contributing towards finding a cure.

First European Patient Charter on IPF Presented in European Parliament by 11 Patient Organizations


For the first time ever, a new European Patient Charter for patients who suffer from idiopathic pulmonary fibrosis (IPF) was developed by a group of advocates and presented to the European Parliament on September 30, during IPF World Week 2014. Biotechnology company InterMune, which is dedicated to research, development, and commercialization of innovative therapies in pulmonology and orphan fibrotic diseases, lobbied hardest for the release of the charter.

The first of its kind European Patient Charter was developed in a collaboration with 11 patient organizations and healthcare professionals from nine different EU countries as a way of advocating for improved quality of life for patients living with IPF. The purpose of the charter is to promote the standardization of care provision among patients, as well as equality of access to diagnosis and treatment procedures among IPF patients all over Europe.

“The development of the Charter represents the greatest joint effort that was ever realized by the IPF community in Europe. For the first time patient organizations from across Europe spoke with a unified voice to shed light on the needs of IPF patients,” stated Rosalba Mele, the president of the Italian association AMA Fuori dal Buio, one of 11 organizations that is promoting the initiative.

“This would not have happened without the support of InterMune, which has supported us and provided the opportunity for patient groups across Europe to come together, share their challenges and develop this Charter which we hope will support the need for change in the management of IPF and give a better future to patients living with IPF.”

Representing top priorities for IPF patients, the charter is a result of a series of meetings between advocacy groups and healthcare professionals, who are seeking to make their case to policy makers with one voice. It is composed of recommendations not only about diagnosis and therapy accessibility, but also about managing the disease in a holistic manner, and making updates to palliative care. Presenting at the European Parliament is a way of garnering attention about the issues related to the disease in order to raise awareness among European policy makers.

“We are proud to play our part in supporting the Charter initiative, which will be essential for improving care and access to healthcare services across Europe. The development of a Charter provides clinicians, patient advocacy groups and patients the opportunity of working together to identify the key concerns that can and must be addressed by policy makers,” said the executive vice president and managing director of InterMune in Europe, Giacomo di Nepi.

The charter is also expected to engage key stakeholders in each country of the EU, in order to conduct changes in their countries and improve patients’ lives. The initiators of the charter are now looking to collect 35,000 signatures through an online public petition as a symbolic act, since 35,000 is the number of people that are newly diagnosed every year in Europe with the irreversible, progressive and deadly disease that causes scarring of the lungs, irreversible destruction of the lungs, and hindering breathing. The disease has a survival rate of only 20-40% after 5 years.