Progressive Pulmonary Fibrosis (PPF) is an area which is progressing itself and an area of medicine that is quickly evolving as treatment options expand. Now that nintedanib (OFEV) is available on the Pharmaceutical Benefits Scheme (PBS), the limbic sat down with Dr Tamera Corte to understand what’s changing in the PPF space.^1,2 Dr Corte is a Consultant Respiratory Physician and Director of Interstitial Lung Disease in the Department of Respiratory Medicine at Royal Prince Alfred Hospital Sydney and an Associate Professor at the University of Sydney.

“This can be a complex area of medicine,” explained Dr Corte. “The first thing to remember is that PPF is not a diagnosis. It’s a description of disease behaviour for the variety of fibrosing interstitial lung diseases (ILDs) that are non-idiopathic pulmonary fibrosis (IPF). Patients are diagnosed with an underlying condition/cause of their fibrosis, and PPF is a way to categorise their disease progression.”

A case of defining progression

“Consider a young woman with connective tissue disease and moderate pulmonary fibrosis (PF). She has a forced vital capacity of 70% predicted and a diffusing capacity for carbon monoxide of 60%,” Dr Corte began. “How do we monitor her for and define when she has disease progression? The PBS criteria for nintedanib follows the framework used in the INBUILD trial and is used to map pulmonary fibrosis progression against the severity and baseline criteria.”

INBUILD – a 52-week, Phase III, randomised double-blind placebo-controlled parallel group study of 663 patients with PF-ILD³

In the overall population analysis from INBUILD, the adjusted rate of decline in FCV over the 52-week period (primary endpoint) was -80.8 mL/year in the nintedanib group vs -187.8 mL/year with placebo; p<0.001.³ Diarrhoea was the most frequent adverse event reported (66.9% with nintedanib and 23.9% with placebo).³  Overall, over 52 weeks of treatment, 7.8% of patients on nintedanib died or had an acute exacerbation versus 9.7% on placebo (hazard ratio [HR] 0.8; 95% confidence interval [CI] 0.48 to 1.34).³  The percentage of patients in the overall population who died over the 52 weeks was 4.8% in the nintedanib group vs 5.1% in the placebo group (HR 0.94; 95% CI 0.47 to 1.86). ³

PBS Criteria for nintedanib

 Dr Corte described the PBS criteria as the following;

“Helping to identify patients with clinically significant disease progression. The criteria were adapted from the INBUILD clinical study with multiple compartments that describe the underlying ILD, the severity of the fibrosis and its progression over 24 months.”

Dr Corte explained how the clinical criteria can be mapped back to the fundamentals of baseline condition, progression, and severity:

UNDERLYING ILD DIAGNOSIS:

The condition must be diagnosed through a multidisciplinary team, AND

The condition must have chest imaging through high resolution computed tomography (HRCT) that is no older than 12 months, to support the diagnosis of the PBS indication, AND

The condition must not be interstitial lung disease due to idiopathic pulmonary fibrosis (apply under the correct PBS listing if it is), AND

The condition must not be due to reversible causes (e.g., drug toxicity).

Patient must have a forced expiratory volume in 1 second to forced vital capacity ratio (FEV1/FVC) greater than 0.7. 

BASELINE SEVERITY OF PULMONARY FIBROSIS:

The condition must display, through HRCT, an affected area of no less than 10% (after rounding to the nearest multiple of 5),

AND

Patient must have a current forced vital capacity (FVC) measurement of no less than 45% predicted, AND

Patient must have diffusing capacity of the lungs for carbon monoxide (DLCO) corrected for haemoglobin that is both: (i) at least 30% predicted, (ii) no greater than 80% predicted.

PROGRESSION:

The condition must be of a progressive nature, observed by, within the 2 years leading up to this authority application, any of: (i) a worsening in relative FVC% predicted measurement of no less than 10%, (ii) a worsening in relative FVC% predicted measurement in the range 5-10%, combined with worsening of respiratory symptoms, (iii) a worsening in relative FVC% predicted measurement in the range 5-10%, combined with increases in fibrosis observed on HRCT;

AND

Patient must not have had an acute respiratory infection at the time of measurement of lung function.

If we go back to Dr Corte’s hypothetical case, she posed the following question;

“How often to follow the patient to observe progression? We don’t want to wait 24 months to see if there is progression in this case.  The timing of follow up is a very individualised decision. You may follow the patient every 4-6 months with clinical examination and pulmonary function tests and perform high resolution CT scans when concerned that progression has occurred,” she explained.

Clinical considerations

Practically speaking, what does the INBUILD trial data mean for clinicians and patients?  In PPF patients, antifibrotic therapy with nintedanib is reportedly the backbone of treatment for slowing lung function decline.⁴ The INBUILD data coupled with the expanded indication of nintedanib for PPF patients, Dr Corte explained the impact these data could have, stating, “Previously there were few/no options for patients with progression. Now there are options, depending on the underlying condition and the nature of the progression. Keep in mind that globally, the description and definition of PPF may change – but for now the PBS criteria helps guide who may be suitable for treatment with nintedanib.”

Based on the trial data, there are several things for clinicians to consider

1. The definition of “progressive” in the clinical setting informs subsequent treatment: As Dr Corte explained, PPF isn’t a diagnosis, but rather it’s a measure of disease behaviour. She also noted that the PBS requires patients to be assessed by a multidisciplinary team (MDT).² So, in line with the recent expansion, and available clinical trials as guideposts, MDTs will need to carefully determine how to assess patients.³ Dr Corte provided a final but important point for MDTs, “reaching out to your nearest ILD clinic and presenting your patient at their ILD MDT is important. The Lung Foundation website also has a simple patient case template to fill out that can be used for discussion at the regular (MDT) patient meetings.”
2. Monitor patients frequently for progression so you can treat patients as early as possible, considering treatment is designed to slow progression. ^5,6
3. The INBUILD trial also assessed PPF phenotypes including connective tissue disease-associated (CTD) ILD, idiopathic non-specific interstitial pneumonia (NSIP) and hypersensitivity pneumonitis (HP).⁷ These occurred in patients with rheumatoid arthritis, scleroderma, dermatomyositis/ polymyositis, NSIP and unclassifiable ILD.^4,7 So treating rheumatologists should also look carefully at any patients they think might be at risk and undertake the relevant diagnostic assessments.
4. Finally, it’s important to note that by definition, PPF refers to those patients who decline while on optimal treatment. In IPF, the use of antifibrotic agents and avoidance of immunosuppression is part of the treatment approach, yet with CTD-ILD immunosuppression is the first line therapy. ⁸ Looking ahead, nintedanib may be more routinely used alongside other medications in PPF treatment algorithms.⁵

This article is sponsored by Boehringer Ingelheim. Any views expressed in the article are those of the expert alone and do not necessarily reflect the views of the sponsor. Before prescribing, please review the OFEV product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References

1. Commonwealth of Australia. Department of Health. Expanded PBS listing for lung disease medication. Ministers Department of Health. 2022 May 1 [Cited June 2022]. Available from: https://www.health.gov.au/ministers/the-hon-greg-hunt-mp/media/expanded-pbs-listing-for-lung-disease-medication.
2. Commonwealth of Australia. Department of Health. Nintedanib. The Pharmaceutical Benefit Scheme [Cited June 2022]. Available from: https://www.pbs.gov.au
3. Flaherty KR, et al. N Engl J Med 2019;381(18):1718–27.
4. Copeland CR and Lancaster LH, Front Med 2021;8:743977.
5. Makino S, Modern Rheum, 2021;31(1):13–19.
6. Collard HR, et al. Eur Respir J 2017;49:1601339.
7. Flaherty KR, et al. N Engl J Med 2019;381(18): Supplementary Appendix
8. Moore I, et al. BMC Pulm Med 2020;20(1):257.