Brian Murphy, PhD, is a medical/science writer and educator who has written over 300 resource articles about rare diseases. He holds a BS from Georgia Institute of Technology and a PhD from Case Western Reserve University, both in Biomedical Engineering. After graduation, Brian worked as a clinical neural engineer to help restore movement in spinal cord injured patients by reconnecting their brain to their paralyzed muscles using experimental medical devices. In addition to resource pages, Brian has also authored/co-authored several research articles in journals including The Lancet, Journal of Neural Engineering, and PLOS ONE.
Idiopathic pulmonary fibrosis (IPF) is a rare, progressive fibrosing interstitial lung disease. Symptoms usually include chronic cough and exertional dyspnea.1 The disease course of IPF is variable; some patients experience a rapid decline and some a slower decline, whereas in others, periods of relative stability are punctuated by acute exacerbations of lung decline.1 The median survival of patients without treatment is 3 to 4 years.1 Only 2 disease-modifying treatments have been approved by the US Food and Drug Administration (FDA) to date. These 2 drugs slow the progression of IPF and may reduce the risk for acute exacerbations, but they do not stop or cure the disease, so that the use of supportive therapies is necessary to alleviate symptoms.2
Before 2014, no disease-modifying treatments for IPF were available, and patients were given mainly immunosuppressants and supportive care.3 A combination of prednisone, azathioprine, and N-acetylcysteine (NAC) was widely used as the standard of care for patients with IPF until the results of the PANTHER-IPF clinical trial (NCT00650091) showed that this combination actually increased the risk for hospitalizations and mortality in comparison with placebo.4 After successful clinical trials, the FDA in 2014 finally approved 2 drugs for the treatment IPF: pirfenidone (Esbriet®) and nintedanib (Ofev®).3
The exact mechanism of action of pirfenidone is unknown, but the drug has shown antifibrotic, anti-inflammatory, and antioxidant properties while inhibiting fibroblast proliferation and differentiation as well as collagen synthesis.3 In a Japanese clinical trial of 275 patients randomized to a dose of 1800 or 1200 mg/d or to placebo, pirfenidone appeared to decrease decline in forced vital capacity (FVC) and improve progression-free survival.5 In addition, pirfenidone at a dose of 2403 mg/d given over a 72-week period was compared with placebo in 2 other trials, CAPACITY 004 (NCT00287716) and CAPACITY 006 (NCT00287729).6 CAPACITY 004 also investigated a dose of 1197 mg/d. A significant decrease in FVC decline over the treatment period was observed in CAPACITY 004, although CAPACITY 006 failed to show the same significant decrease.6 The FVC decline in the placebo group in the latter study was much smaller than usual, which may have masked the effects of treatment.6
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Pirfenidone was further investigated in the ASCEND clinical trial (NCT01366209), in which 555 patients with IPF received either pirfenidone at 2403 mg/d or placebo for 52 weeks.7 In this trial, in a comparison of the patients treated with pirfenidone vs those treated with placebo, a relative reduction of 47.9% in the proportion of those who had a decline of 10 percentage points or more in predicted FVC was noted in the patients who received pirfenidone.7 Pirfenidone also reduced decreases in 6-minute walk distance (6MWD) and progression-free survival.7 The RECAP (NCT00662038) open-label extension trial and the observational PASSPORT study (NCT02699879) showed safety profiles similar to those in previous clinical trials.6
Treatment with pirfenidone is started at 267 mg 3 times per day and titrated up to 801 mg 3 times per day (total of 2403 mg/d). Liver enzymes should be monitored during treatment. The side effects of pirfenidone include rash, photosensitivity, and gastrointestinal discomfort. Photosensitivity can be managed by limiting sun exposure and using sunblock. Gastrointestinal discomfort may be alleviated by taking the medication with meals. Antacids may be used, but omeprazole should be avoided. Omeprazole can interfere with pirfenidone levels because it is metabolized primarily by cytochrome P450 1A2 (CYP1A2) enzymes.6
Nintedanib is an inhibitor of multiple tyrosine kinases, including fibroblast growth factor (FGF) receptor, platelet-derived growth factor (PDGF) receptor, vascular endothelial growth factor (VEGF) receptor, and the non-receptor Src family of kinases,3 thereby interfering with the proliferation, migration, and differentiation of fibroblasts, as well as the secretion of extracellular matrix components in the lungs.3 Nintedanib has also shown anti-inflammatory and anti-fibrotic properties in animal models.3
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Nintedanib was evaluated in a Phase 2 clinical trial called TOMORROW (NCT00514683) and in a rollover study (NCT01170065), which showed its ability to slow FVC decline in treated patients in comparison with placebo.8 These trials were then followed by 2 Phase 3 clinical trials: INPULSIS-1 (NCT01335464) and INPULSIS-2 (NCT01335477). Both of these trials lasted for 52 weeks and showed that treatment with nintedanib decreased FVC decline in comparison with placebo.9 A long-term open-label extension of the INPULSIS trials, INPULSIS-ON (NCT01619085), showed the continued effectiveness of nintedanib with no new safety concerns.
Nintedanib is recommended to be administered at a dose of 150 mg twice a day. As with pirfenidone, liver enzymes should be monitored. Some of the most common adverse reactions reported were gastrointestinal issues, including diarrhea and nausea, which can be managed with antidiarrheal and antiemetic agents.6
Both pirfenidone and nintedanib do not stop or reverse the progression of IPF; they merely delay progression. Therefore, supportive care is still necessary to manage symptoms and comorbidities and improve the quality of life of patients. Up to 80% of patients have chronic cough, which is often refractory to antitussive treatments. The benefits of oral corticosteroids and opiates in treating cough are unclear. It is recommended that physicians investigate possible comorbidities or factors triggering cough, such as gastroesophageal reflux, obstructive sleep apnea, infections, and the use of angiotensin-converting enzyme (ACE) inhibitors.2
Gastroesophageal reflux is common in patients with IPF, and the 2015 clinical guidelines from the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society (ATS/ERS/JRS/ALAT) weakly recommend the use of antacids.11 Some more recent evidence suggests that antacid treatment does not improve outcomes and may actually increase the risk for pneumonia.6
Many patients with advanced IPF have significant resting hypoxemia.1 Supplemental oxygen therapy may improve exercise capacity and quality of life, but results regarding its effect on exertional dyspnea have been conflicting.1 Pulmonary rehabilitation has also been recognized as a therapy to improve exercise capacity and quality of life.12
Pulmonary hypertension (PH) is another common problem in patients with advanced IPF. Inhaled treprostinil (Tyvaso®) was recently approved by the FDA to treat PH in patients with interstitial lung diseases such as IPF.13 The approval followed the results of the Phase 2/3 INCREASE trial (NCT02630316), which showed that treatment improved exercise capacity from baseline.14
Many patients with IPF may experience depression and anxiety as a consequence of their disease and symptoms such as dyspnea, which can be frightening.12 Depression may be present in approximately 50% of patients with IPF.6,15 Depression can reduce patients’ quality of life and interfere with adherence to treatment.2 For this reason, it is recommended that patients be referred to psychological support.2
- Quinn C, Wisse A, Manns ST. Clinical course and management of idiopathic pulmonary fibrosis. Multidiscip Respir Med. 2019;14(1):35. doi:10:1186/s40248-019-0197-0
- Sgalla G, Iovene B, Calvello M, Ori M, Varone F, Richeldi L. Idiopathic pulmonary fibrosis: pathogenesis and management. Respir Res. 2018;19:32. doi:10.1186/s12931-018-0730-2
- Pleasants R, Tighe RM. Management of idiopathic pulmonary fibrosis. Ann Pharmacother. 2019;53(12):1238-1248. doi:10:1177/1060028019862497
- The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. doi:10.1056/NEJMoa1113354
- Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J. 2010;35(4):821-829. doi:10.1183/09031936.00005209
- Saito S, Alkhatib A, Kolls JK, Kondoh Y, Lasky JA. Pharmacotherapy and adjunctive treatment for idiopathic pulmonary fibrosis (IPF). J Thorac Dis. 2019;11(Suppl 14):S1740-S1754. doi:10.21037/itd.2019.04.62
- King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083-2092. doi:10.1056/NEJMoa1402582
- Richeldi L, Kreuter M, Selman M, et al. Long-term treatment of patients with idiopathic pulmonary fibrosis with nintedanib: results from the TOMORROW trial and its open-label extension. Thorax. 2018;73(6):581-583. doi:10.1136/thoraxjnl-2016-209701
- Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082. doi:10.1056/NEJMoa1402584
- Crestani B, Huggins JT, Kaye M, et al. Long-term safety and tolerability of nintedanib in patients with idiopathic pulmonary fibrosis: results from the open-label extension study, INPULSIS-ON. Lancet Respir Med. 2019;7(1):60-68. doi:10.1016/S2213-2600(18)30339-4
- Raghu G, Rochwerg B, Zhang Y, et al. An official ATS/ERS/JRS/ALAT clinical practice guideline: Treatment of idiopathic pulmonary fibrosis. An update of the 2011 clinical practice guideline. Am J Respir Crit Care Med. 2015;192(2):e3-19. doi:10.1164/rccm.201506-1063ST
- Somogyi V, Chaudhuri N, Torrisi SE, Kahn N, Müller V, Kreuter M. The therapy of idiopathic pulmonary fibrosis: what is next? Eur Respir Rev. 2019;28(153):190021. doi:10.1133/16000617.0021-2019
- United Therapeutics Corporation. United Therapeutics announces FDA approval and launch of Tyvaso® for the treatment of pulmonary hypertension associated with interstitial lung disease. PR Newswire. April 1, 2021. Accessed July 9, 2021.
- Waxman A, Restrepo-Jaramillo R, Thenappan T, et al. Inhaled treprostinil in pulmonary hypertension due to interstitial lung disease. N Engl J Med. 2021;384(4):325-334. doi:10.1056/NEJMoa2008470
- Akhtar AA, Ali MA, Smith RP. Depression in patients with chronic idiopathic pulmonary fibrosis. Chron Respir Dis. 2013;10(3):127-133. doi:10.1177/1479972313493098
Reviewed by Debjyoti Talukdar, MD, on 7/11/2021.