By Brian D. Southern, MD
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FDA-approved drugs offer hope for devastating lung disease
Idiopathic pulmonary fibrosis (IPF) is an incurable and fatal fibrotic lung disorder characterized by excessive connective tissue accumulation and scar formation, creating a cycle of progressive lung deterioration. In the United States, IPF affects between 132,000 and 200,000 people. Approximately 50,000 new cases are diagnosed each year and as many as 40,000 Americans die from IPF each year.
Until recently, clinical trials with negative results were commonplace in IPF. This cycle was broken in May 2014 when positive results from ASCEND and INPULSIS trials were published in the New England Journal of Medicine. Cleveland Clinic participated in the ASCEND trial.
In October 2014, IPF patients and their caregivers finally saw a glimmer of hope with FDA approval of the two novel agents examined in these trials, pirfenidone and nintedanib.
Pirfeinidone Drug Molecule
Pirfenidone’s promising results
Pirfenidone is a small molecule inhibitor of several pathways implicated in fibrosis, including transforming growth factor beta (TGFβ), fibroblast growth factor (FGF) and platelet-derived growth factor (PDGF). Previous Phase III trials assessing the efficacy of pirfenidone, the SP3 trial in Japan and the multinational CAPACITY trials, demonstrated conflicting results. The ASCEND study was designed to determine definitely whether pirfenidone, compared to placebo, slowed progression of disease in patients with mild to moderate IPF. In this study, pirfenidone treatment resulted in significant reduction in the primary endpoint, decline in forced vital capacity (FVC) over one year, a reduced decline in six-minute walk test distance and improved progression-free survival. There was no effect on respiratory symptoms or mortality.
Nintedanib reduced decline in FVC compared to placebo
Nintedanib is a tyrosine kinase inhibitor that blocks the profibrotic pathways mediated by PDGF, FGF and vascular endothelial growth factor (VEGF). Following the encouraging results of the Phase II TOMORROW trial published in 2011, INPULSIS involved two concurrent Phase III studies investigating the effect of nintedanib 150mg twice daily vs. placebo on FVC decline in patients with mild to moderate IPF. In both trials, nintedanib significantly reduced decline in FVC compared to placebo. In only one of the two trials, nintedanib significantly increased time to first exacerbation. There was no detectable difference in mortality.
NINTEDANIB drug molecule
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Which agent to prescribe?
Despite differences in mechanism of action of these two agents, the reductions in FVC decline were strikingly similar, around 100 ml/year. Therefore, when deciding which agent to start, a careful discussion with each patient should involve dosing, potential side effects and expected outcomes of therapy. The most common side effects of pirfenidone are rash, nausea and dyspepsia. In ASCEND, less than 3 percent of patients required discontinuation of medication due to side effects. More than 60 percent of patients receiving nintedanib in the INPULSIS trials experienced diarrhea. This was often adequately controlled with dose reduction or anti-diarrheal medication, with less than 5 percent having to discontinue the medication completely. Elevation of liver function tests (LFT) also occurred in a small number of patients in both studies. Thus, it is recommended to check LFTs monthly for the first three months after starting either therapy, then every three months thereafter. Pill burden may also factor into the decision, as pirfenidone is administered as three tablets three times a day, while nintedanib is given as one tablet twice daily.
Questions remain; further study needed
Although we now have treatment options, many unanswered questions remain.
- What is the effect on more severe disease, i.e. FVC <50% predicted or lung diffusion capacity testing (DLCO) <30% predicted? Several small studies have attempted to answer this question, but the results have not been consistent.
- Are there effects beyond one year of therapy? Extension studies of these trials are ongoing to determine the long-term safety and efficacy of these medications.
- Can these drugs be used in combination or with other agents? A small Japanese study has suggested that the combination is tolerable, but further study is needed.
- Do these drugs work in other fibrotic interstitial lung diseases (ILDs)? As a number of common pathways are implicated, it will be important to evaluate the efficacy of these drugs in diseases such as fibrotic nonspecific interstitial pneumonia, chronic hypersensitivity pneumonitis and connective tissue associated ILDs. The LOTUSS trial recently demonstrated that pirfenidone was well-tolerated and safe in patients with systemic sclerosis-related ILD and plans for efficacy studies are currently underway.
Long-awaited treatment options provide hope; further advances expected
In summary, the approval of pirfenidone and nintedanib for the treatment of IPF has ushered in a long-awaited new era of hope for patients suffering from IPF. Both medications appear to be effective in slowing the rate of decline in mild to moderate IPF. Though many questions remain, we now have useful treatment options to offer and many believe this is only the beginning of an era that will see monumental advances in our understanding and treatment of devastating fibrotic lung diseases.
Dr. Southern is a Staff Physician in the Respiratory Institute and Assistant Professor of Molecular Medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University. He is Associate Staff Scientist in the Lerner Research Institute Department of Pathobiology, where he focuses on IPF.