Guidelines for Treatment of Idiopathic Pulmonary Fibrosis: The 2015 Update

The large amount of evidence generated over the last 5 years has led to a revision of the 2011 clinical practice guidelines, which were updated in a new joint statement in 2015. Similar to the 2011 document, the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) methodology was adopted to rate the quality of available evidence and express recommendations for or against the use of the treatments evaluated, with only the substitution of the term “weak” with “conditional” as compared with the 2011 document. While no pharmacologic treatment received a strong recommendation for use in IPF, the original document was amended substantially based on the available evidence as summarized in the following text. Table 4.1 provides a comparison of the 2011 and 2015 recommendations.

The previously widely accepted “triple therapy” (consisting of the combination of prednisone, azathioprine, and N -acetylcysteine [NAC]), which received a weak recommendation against use in the 2011 guidelines, ultimately proved to be associated with increased mortality as compared with placebo and with NAC alone in the three-arm PANTHER-IPF study (Prednisone, Azathioprine, and N -Acetylcysteine: A Study That Evaluates Response in IPF), which was conducted by National Heart, Lung, and Blood Institute–sponsored IPFnet. In this trial, patients with mild to moderate lung function impairment were randomized in a 1:1:1 ratio to receive prednisolone, azathioprine, and NAC; NAC alone; or placebo over a 60-week period. Following a prespecified safety and efficacy interim analysis, the independent data and safety monitoring board recommended termination of the combination therapy arm at a mean follow-up of 32 weeks, following the observation that the combination therapy was associated with a statistically significant increase in all-cause mortality, all-cause hospitalizations, and treatment-related severe adverse events. The evidence that the “triple therapy”—considered the standard of care in IPF for a decade—is actually harmful should be regarded as groundbreaking and demonstrates that, even if negative, a properly designed randomized-controlled trial (RCT) can importantly inform guidelines, clinical practice, and future trial design. The PANTHER trial, which continued as a two-arm only study, showed no difference between NAC and placebo in terms of change of percentage predicted forced vital capacity (FVC) at 60 weeks and the majority of the secondary outcome measures. The combination of prednisone, azathioprine, and NAC received a strong recommendation against use in the 2015 document, whereas the recommendation for NAC monotherapy remained unchanged (conditional recommendation against use). Despite the negative results of the PANTHER trial, NAC continues to be widely used in clinical practice, mostly because of its good safety and tolerability profile and low cost. Nebulization of NAC via aerosol may represent a more efficient way of delivering the drug directly to the lung parenchyma. A post hoc analysis of the PANTHER trial dataset looked at the influence of polymorphisms in TOLLIP and MUC5B genes (two well-established associations with IPF susceptibility and survival) on response to NAC, the rationale being that such polymorphisms are linked to alteration in the lung immune response through oxidative signaling. NAC treatment was associated with improved survival in patients homozygous for the T allele of the rs3750920 TOLLIP polymorphism, whereas those carrying the GG genotype had a worse prognosis. Although it remains unclear whether a mechanistic link between oxidative stress and TOLLIP -related signaling exists, these data suggest that NAC might be effective in a subset of patients.

Anticoagulation, considered for years a potential therapy for IPF based on a small study that showed survival benefit in hospitalized patients treated with warfarin, was also ultimately associated with increased mortality in a recent, early discontinued RCT (ACE-IPF—AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) and received a strong recommendation against use in the 2015 treatment guidelines.

The dual endothelin receptor antagonists (ERAs) bosentan and macitentan were given a conditional recommendation against use, based on the results of two Phase II and one Phase III trials. Conversely, ambrisentan, a selective ERA, received a strong recommendation against use because of the lack of benefit and high likelihood of harm observed in the ARTEMIS (a Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF study) trial, which was prematurely discontinued. Sildenafil is an oral phosphodiesterase-5 inhibitor that has been studied in IPF in two RCTs. Sildenafil was given a conditional recommendation against use because of the lack of benefit in any outcome measures apart from a marginal improvement in quality of life.

The recommendation on antacid treatment (AAT) remained unchanged (conditional recommendation for use), although the only data suggesting a beneficial effect of AAT in patients with IPF derive from retrospective analysis of longitudinal cohorts and pooled analyses of patients randomized to placebo in three RCTs of different pharmacologic therapies. Indeed, the role of AAT in IPF remains a matter of intense debate.

The antifibrotic drugs pirfenidone and nintedanib have been consistently demonstrated to slow down functional decline and disease progression in IPF and have been approved worldwide. Accordingly, both pirfenidone, which had received a weak recommendation against use in 2011, and nintedanib, which had not been previously addressed, received a conditional recommendation for use in patients with IPF in the 2015 guideline document.

Pirfenidone

Pirfenidone is an orally administered pyridine with pleiotropic antifibrotic, antiinflammatory, and antioxidant properties, although its precise mechanisms of action remain unknown. This drug, which is the first agent licensed for treatment of patients with mild to moderate IPF, was initially approved for clinical use in Japan, Europe, India, and Canada following regulatory appraisal of the data on safety and efficacy coming from two multicenter trials performed in Japan and two large international multicenter clinical trials (CAPACITY 1/PIPF-006 and CAPACITY 2/PIPF-004). Conversely, the US Food and Drug Administration (FDA) denied approval and required a new placebo-controlled Phase III trial, because of concerns regarding inconsistent evidence of efficacy (study PIPF-006 met the primary endpoint of change in percentage predicted FVC at week 72, while study PIPF-004 did not) along with the lack of a clear survival benefit. The ASCEND (Assessment of pirfenidone to Confirm Efficacy and Safety in Idiopathic Pulmonary Fibrosis) study assessed the effect of pirfenidone on disease progression (defined as decline of 10% or more in percentage predicted FVC, or death from any cause) in 555 patients randomly assigned to receive either pirfenidone 2403 mg per day or placebo for 52 weeks. In the pirfenidone group, there was a relative reduction of 47.9% in the proportion of patients who had disease progression. In addition, there was a relative increase of 132.5% in the proportion of patients with no functional decline in the pirfenidone as compared with the placebo arm. Rates of all-cause or IPF-related mortality did not differ significantly between the two groups, although in a prespecified pooled analysis incorporating results from three Phase III trials (CAPACITY 1, CAPACITY 2, and ASCEND) the between-group difference favoring pirfenidone was significant for both all-cause and IPF-related mortality. Gastrointestinal and skin-related adverse events were more common in the pirfenidone group than in the placebo group, but they were generally of mild to moderate intensity. Indeed, a similar proportion of patients in the pirfenidone (14%) and placebo (10%) group discontinued the study drug because of adverse events. Based on these findings, in October 2014 the FDA approved pirfenidone for treatment of IPF.

Postauthorization data on the use of pirfenidone in clinical practice are available from both international collaborative studies and real-life experiences in Japan and Europe, where pirfenidone was approved in 2010 and 2011, respectively. Interim reports from RECAP, an open-label extension study that enrolled patients who completed the CAPACITY program and from PASSPORT (Pirfenidone Post-Authorization Safety Registry), which prospectively collected data from pirfenidone-treated patients from 10 different countries, confirmed the safety and tolerability of the drug. A number of studies have provided additional information, although most of them reflect single-center experience. A German study conducted at a tertiary referral center showed that the majority of IPF patients treated with pirfenidone (62%) remained stable during treatment, although the rate of functional decline did not differ significantly from the pretreatment period. Interestingly, reports from both Europe and Japan showed that patients with a more pronounced functional decline tend to respond better to the drug. These studies confirmed the good safety and tolerability profile of pirfenidone, although weight loss and fatigue occurred more frequently than in the RCT setting.

Nintedanib

Nintedanib is an orally available inhibitor of different tyrosine kinase receptors, including PDGF receptors α and β; VEGF receptors 1, 2, and 3; and FGF receptors 1, 2, and 3. Activation of these receptors has been implicated in lung fibrosis pathogenesis and in the murine model of bleomycin-induced fibrosis nintedanib was shown to prevent the development of lung fibrosis.

The safety and efficacy of nintedanib at four different oral doses (50 mg once a day, 50 mg, 100 mg, or 150 mg twice daily) have been evaluated in a 52-week Phase II randomized, double-blind, placebo-controlled trial (TOMORROW—To Improve Pulmonary Fibrosis With BIBF 1120). The primary outcome was the annual rate of decline in FVC, while secondary endpoints included rate of acute exacerbations (AE-IPF), quality of life, and total lung capacity. Nintedanib at a dose of 150 mg twice daily showed a trend toward reduction of the decline in lung function. Specifically, the adjusted annual rate of decline in FVC was 0.06 L/year in the group receiving nintedanib 150 mg twice daily and 0.19 L/year in the placebo group, corresponding to a reduction of 68.4% in the rate of FVC loss ( P = .06 using a closed testing procedure for multiplicity correction [primary analysis] and P = .01 using hierarchical testing, both prespecified). In addition, compared with placebo, significantly fewer patients in the group receiving nintedanib 150 mg twice daily had a decline in mean FVC of ≥10% or ≥200 mL (23.8 vs. 44.0%, respectively; P = .004). The highest dose of nintedanib was also associated with fewer AE-IPF and improved quality of life as assessed by St. George’s Respiratory Questionnaire (SGRQ). The most frequent adverse event in the group receiving 150 mg nintedanib twice daily was diarrhea (55.3% vs. 15.3% in the placebo group), followed by nausea (23.5% vs. 9.4%) and vomiting (12.9% vs. 4.7%). The adverse events most frequently leading to study discontinuation were also diarrhea, nausea, and vomiting, but the proportion of patients who discontinued the study medication because of adverse events did not differ between the group receiving nintedanib 150 mg twice daily and the placebo group. The INPULSIS-1 and INPULSIS-2 trials were two parallel 52-week, randomized, double-blind, placebo-controlled, Phase III studies designed to confirm the efficacy and safety of nintedanib compared with placebo in patients with IPF. A total of 1066 patients were randomized 3:2 to nintedanib 150 mg twice daily (n = 309 in INPULSIS-1 and n = 329 in INPULSIS-2) or placebo (n = 204 in INPULSIS-1 and n = 219 in INPULSIS-2). Both trials met the primary endpoint (e.g., nintedanib significantly reduced the rate of decline in FVC over the 52-week study period). Specifically, the adjusted annual rate of change in FVC was −114.7 mL in the nintedanib arm and −239.9 mL in the placebo arm in INPULSIS-1 (between-group difference: 125.3 mL; P < .001) and −113.6 mL and −207.3 mL in INPULSIS-2 (between-group difference: 93.7 mL; P < .001). Moreover, a number of prespecified sensitivity analyses confirmed the robustness of the results of the primary analysis. As for the two key secondary endpoints (i.e., time to the first AE-IPF as reported by the site investigator and the change from baseline in the total score on the SGRQ), the two trials provided inconsistent results. In fact, at week 52 the time to the first AE-IPF was significantly increased in the nintedanib arm in INPULSIS-2 (HR: 0.38, P = .005) but not in INPULSIS-1 (HR: 1.15, P = .67); on the other hand, the increase in the total SGRQ score was significantly smaller in the nintedanib group than in the placebo group (consistent with less deterioration in health-related quality of life) in INPULSIS-2, whereas in INPULSIS-1 there was no significant between-group difference in the adjusted mean change in the SGRQ total score from baseline to week 52. Similar to the TOMORROW trial, the most frequent adverse event in the nintedanib groups in both INPULSIS-1 and INPULSIS-2 was diarrhea (∼60% within the first 3 months of treatment), which overall led to premature discontinuation in 4.4% of patients in the nintedanib group. However, in both trials, the proportion of patients with serious adverse events was similar in the nintedanib and placebo arms. Similar to pirfenidone, in October 2014 nintedanib was approved by the FDA for treatment of IPF and has become commercially available worldwide in 2016.

Limitations of Pharmacologic Treatment

Having two drugs approved for IPF is an outstanding achievement. Yet, there are limitations to the current therapeutic approach, and a number of questions regarding the most appropriate management of individual patients with IPF remain unanswered. Neither pirfenidone nor nintedanib is a cure, and most patients continue to experience disease progression despite treatment; it is unclear whether and to what extent these drugs remain effective beyond 52 weeks; it remains to be determined whether the beneficial effect on functional decline translates to a longer survival (measuring this outcome appears prohibitive because of the number of patients and study duration required for an adequately powered study) ; neither of the drugs significantly improves symptoms or quality of life; finally, it is unknown whether the results of the pirfenidone and nintedanib trials, which have enrolled highly selected patients, are generalizable to the more general IPF population.

Pirfenidone and nintedanib are broadly comparable in their efficacy and safety and tolerability profiles. In addition, they exhibit similar side effect profiles with regard to gastrointestinal effects (mainly nausea and diarrhea) and liver enzyme elevation. Hence, it remains unclear which of these drugs should be used first and in which patients, although the initial choice should be based on careful consideration of patient clinical features, comorbidities, side effect profiles of the two drugs, as well as patient personal preferences. Whatever the initial choice, physicians may consider switching from one drug to the other in the presence of intolerable side effects or clear evidence of “treatment failure” (e.g., FVC decline >10% over 6 months despite treatment). A small retrospective study, in which seven patients were switched to nintedanib based on clinical grounds because of adverse events (mainly asthenia) while on pirfenidone, suggested that nintedanib may be better tolerated. On the other hand, there are no data on patients switched from nintedanib to pirfenidone.

Timing for treatment initiation is also controversial. As with any inexorably progressive disease such as IPF, once the diagnosis is established, treatment should be started as early as possible to prevent functional decline and prolong survival. However, in asymptomatic patients with preserved or marginally impaired lung function it may not be unreasonable to opt for a close clinical/functional monitoring after careful evaluation of the risks and benefits of such approach as well as the high cost of both medications. Conversely, it is unknown whether pirfenidone and nintedanib are safe and efficacious also in patients with severe functional impairment (e.g., FVC < 50%). Although there are concerns that patients with advanced disease may be less likely to respond to treatment (also because of the frequent coexistence of pulmonary hypertension) and may experience more frequent and severe adverse events, there are no convincing data in this regard.