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The role of pirfenidone in the treatment of idiopathic pulmonary fibrosis

Cottin Respiratory Research 2013, 14(Suppl 1):S5http://respiratory-research.com/content/14/S1/S5 The role of pirfenidone in the treatment ofidiopathic pulmonary fibrosis From AIR: Advancing IPF Research. Working together to translate IPF research into practiceBerlin, Germany. 4-5 November 2011 Idiopathic pulmonary fibrosis (IPF) is a progressive disease, with a median survival time of 2–5 years. The search foreffective treatment has involved numerous clinical trials of investigational agents without significant success.
However, in 2011, pirfenidone was the first drug to be approved for the treatment of IPF in Europe. Four keyclinical trials supported the efficacy and tolerability of pirfenidone.
In the two recently published Phase III CAPACITY trials evaluating pirfenidone (studies 004 and 006), patients withmild-to-moderate IPF were treated with pirfenidone or placebo. Study 004 and pooled analysis of primaryendpoint data from both studies showed that pirfenidone significantly reduced decline in percent-predicted forcedvital capacity (FVC) compared with placebo (p<0.005). Evidence of beneficial effects of pirfenidone treatment wasalso observed with regard to several secondary endpoints. Pirfenidone was generally well tolerated, with the mostcommon side effects being gastrointestinal and photosensitivity. Data from the RECAP extension phase of theCAPACITY studies, where patients were treated with pirfenidone for up to three years, further support themanageable tolerability profile of pirfenidone. The efficacy data, coupled with long-term safety data, provide furtherevidence of a clinically-meaningful treatment effect with pirfenidone in patients with IPF.
with a nearly five-fold increase in the risk of mortality.
Idiopathic pulmonary fibrosis (IPF) is a debilitating dis- However, whilst serial FVC measurements are a ease, occurring predominantly in adults of around 60–75 validated marker of chronic disease progression, and years of awith an estimated prevalence of IPF of frequently used as an endpoint in clinical trials,] it is 1.6–1.7/10,000The disease course is progressive and not a proven surrogate for mortality. Nevertheless, agents ultimately fatal, with a median survival of 2–5 years ,] that attenuate the decline in FVC are anticipated to play – worse than a number of malignancies Progressive an important role in IPF management.
deterioration of pulmonary function occurs, which Pirfenidone has been shown to reduce the decline in increasingly limits the patient's ability to perform normal FVC in patients with IPF. This is an orally available drug physical activities] The speed and extent of this dete- that exhibits anti-fibrotic and anti-inflammatory properties rioration is often unpredictable,with patients who gen- in vitro and in vivoThere is evidence to show that erally appear to have stable disease often suffering pirfenidone diminishes fibroblast proliferation, secretion of episodes of acute exacerbation the fibrosis-associated proteins and cytokines, biosynthesis A decline in both relative and absolute changes in the and accumulation of extracellular matrix as well as accu- forced vital capacity (FVC) has been shown consistently to mulation of inflammatory cells and tumour necrosis predict mortality in patients with A decline in factor-a synthesis.[ FVC of 10% or more in a six-month period is associated Clinical trials of pirfenidone in patients with IPFFollowing evaluation in Phase II and Phase III clinical Correspondence: Hospices Civils de Lyon, Hôpital Louis Pradel, Service de pneumologie – trials in patients with IPF.pirfenidone was Centre de référence national des maladies pulmonaires rares, Université approved by the European Commission in February 2011 Claude Bernard Lyon 1, Lyon, France 2013 Cottin; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative CommonsAttribution License ), which permits unrestricted use, distribution, and reproduction inany medium, provided the original work is properly cited.
Cottin Respiratory Research 2013, 14(Suppl 1):S5 Pirfenidone is indicated for the treatment of patients with to treatment with either oral pirfenidone or oral placebo.
mild-to-moderate IPF. Mild-to-moderate disease was char- In study 004, patients were assigned to pirfenidone 2403 acterised in two pivotal Phase III studies using the follow- mg/day, 1197 mg/day or placebo in a 2:1:2 ratio. In study ing functional criteria: FVC ≥50% of predicted value, 006, patients were assigned to pirfenidone 2403 mg/day or carbon monoxide diffusing capacity (DLCO) ≥35% of pre- placebo in a 1:1 ratio. Pirfenidone was administered with dicted value and a 6 minute walk test (6MWT) distance of food three times a day and increased to the full dose (2403 mg/day) over two weeks. The lower dose of 1197 mg/day Based on the positive results of a Phase II study by was included in study 004 to investigate any dose-response Azuma et al.,] a multicentre, double-blind, placebo-con- effect in terms of trolled, randomised Phase III clinical trial was conducted The primary endpoint of both studies was change in in Japan to determine the efficacy and safety of pirfenidone percentage predicted FVC from baseline to week 72. Sec- in 275 patients with Patients were randomised to ondary endpoints at week 72 included categorical decline pirfenidone 1800 mg per day, pirfenidone 1200 mg per day in FVC ≥10%, progression-free survival (time to confirmed or placebo using a 2:1:2 ratio, with 267 patients evaluated ≥10% decline in percentage predicted FVC, ≥15% decline for the efficacy of pirfenidone. The dose of pirfenidone was in percentage predicted DLCO or death), mean change in increased in a stepwise manner up to the treatment dose 6MWT distance, mean change in percentage predicted over four weeks. The primary endpoint was vital capacity DLCO, mean change in dyspnoea score, mean percentage (VC) from baseline to 52 weeks. This was changed before change in worst SpO2 during 6MWT and time to worsen- unblinding of the study (it was previously the lowest arter- ing of IPF. Mortality was included as an exploratory end- ial oxygen saturation measured by pulse oximetry (SpO2) point. Categorical change in high-resolution computed during the six-minute steady state exercise test). This deci- tomographic (HRCT)-diagnosed fibrosis was included as a sion was based on the evolved knowledge of assessment secondary endpoint in study 006.
with objective measurements in IPF, along with the lack of In study 004, pirfenidone 2403 mg/day significantly validation of the steady state exercise test and problems in reduced mean decline from baseline to week 72 in percen- reproducing SpO2 measurements. Secondary endpoints tage predicted FVC, compared with placebo (-8.0% [±16.5] included progression-free survival (this was defined as time vs -12.4% [±18.5], respectively; p=0.001), as well as the pro- until the first progressive event, i.e. either decrease in VC portion of patients with FVC decline ≥10%. This treatment of >10% or death) and change in the lowest SpO2 during effect was evident between weeks 24 and 72. A pirfenidone the six-minute steady state exercise effect was confirmed (p=0.0007) after repeat-measured Statistically significant differences were observed analysis of the predicted percentage change in FVC across between the pirfenidone 1,800 mg group and the placebo all assessment timepoints. In the pirfenidone 1197 mg/day group for both the primary and secondary endpoints.
group, the primary endpoint outcomes were intermediate Pirfenidone was associated with a 44% reduction in the to those of the 2403 mg/day pirfenidone and placebo VC decline compared with placebo (-0.09 L vs -0.16 L; p=0.0416), along with a significant increase in progression- While the difference between groups in mean FVC free survival (p=0.0280).[] Pirfenidone was relatively well change at Week 72 was not significant in Study 006 tolerated, the most common adverse event observed with (-9.0% [SD 19.6] and -9.6% [19.1] respectively, p=0.501), pirfenidone was photosensitivity, which was rated as mild this may have been due to a lower than expected rate of in the majority of pand has previously been FVC decline in Study 006 after 1 year in the placebo documented as a side effect associated with pirfenidone Moreover, a consistent pirfenidone effect was treatment.[The data from this Phase III trial led to apparent until Week 48 (p=0.005) and also in an analysis the approval of pirfenidone in Japan in 2008 for the treat- of all study timepoints (p=0.007). Thus, the data from ment of IPF.
this study generally supported those from Study 004, Two concurrent, similarly designed Phase III trials (stu- with a positive treatment effect of pirfenidone being dies 004 and 006, the "CAPACITY" studies), were con- observed at all timepoints from weeks 12 to 48 but not at ducted at 110 sites across North America, Australia and 11 European countries. Both were randomised, double- The effect of pirfenidone treatment on percentage pre- blind, placebo-controlled studies with treatment periods of dicted FVC at week 72 was supported by pooled analysis 72 weeks.The studies were designed to confirm the of data from both studies. Mean decline in percentage pre- results of a Phase II study suggesting that pirfenidone dicted FVC was -8.5% and -11.0% for the pirfenidone 2403 reduced the deterioration in lung function in patients with mg/day and placebo groups, respectively (p=0.005).
Additionally, the pooled analysis demonstrated a 30% Patients aged 40–80 years with mild-to-moderate IPF, reduction in the percentage of patients with a categorical diagnosed within the previous 48 months, were randomised decline in FVC ≥10% at week 72 (p=0.003), a 31% reduction Cottin Respiratory Research 2013, 14(Suppl 1):S5 in the mean decline in 6MWT distance (p>0.001) and a years (range, 1-4). A number of patients (n=114) had 26% reduction in the risk of death or disease progression been treated at the full dose for at least three years.
(HR 0.74; 95% CI 0.57, 0.96; Data from the RECAP extension study confirm the tol- Exploratory analysis of mortality data revealed that the hazard ratios for all-cause mortality (p=0.315) and mortal- Common adverse events and those considered treat- ity related to IPF at any time during the study (p=0.117), ment-emergent occurred in a very similar proportion of although not significant, numerically favoured pirfenidone patients to those reported during the CAPACITY studies.
over placebo. This was also the case with on-treatment Almost all patients (98%) reported at least one treatment- IPF-related mortality, which occurred in 3% of patients emergent adverse event, compared with 99% of patients treated with pirfenidone and 7% of those given placebo in the CAPACITY studies across both treatment arms.
Similar proportions of patients in RECAP experiencedserious adverse events to those in the CAPACITY studies Cochrane meta-analysis of treatment effect (33% vs 33%). The incidence of common adverse events Meta-analyses performed by the Cochrane Collaboration, was very similar to that observed in the CAPACITY stu- published in 2010, investigated the treatment effect of dies, and were generally mild to moderate in severity. No pirfenidone using data from the clinical trials performed new or unexpected safety issues were to date. Data from the two Japanese studies were eligible Rash or photosensitivity occurred in fewer patients from for a meta-analysis as they both included the endpoint of the RECAP extension study than in the CAPACITY studies absolute change in A statistically significant dif- (20% vs 44%). This was more common among patients ference was observed in terms of decline in VC in favour initiating treatment with pirfenidone compared with those of pirfenidone, underlining the beneficial effect of pirfeni- who were continuing with treatment (28% vs 12%). These done on the change in VC compared to baseline. As pro- data provide further important information on treatment gression-free survival was also used as an endpoint in the with pirfenidone and demonstrate its tolerabili Phase III study by Taniguchi et ] it was possible tocombine the data from this study and perform a meta- analysis with data from the CAPACITY studies. The There has been a considerable advance in terms of overall result of this meta-analysis suggested that pirfeni- research into prognostic factors, with decline in % FVC done reduced the risk of disease progression by 30% (HR being found to be a predictor of mortality risk. Until 0.70, 95% CI 0.56 to 0.88) in patients with recently, therapeutic developments had lagged somewhat,but the increase in the number of clinical trials has been Tolerability in patients with IPF encouraging. However, many of these trials either failed Regarding safety, pirfenidone was shown to be generally to show significant treatment benefit against this challen- well tolerated at the 2403 mg/day dose in the CAPACITY ging disease. Further studies are required to evaluate the There was no significant difference in the num- potential benefit of other agents, such as N-acetylcysteine ber of patients experiencing serious treatment-emergent (NAC) [and nintedanib (BIBF in IPF. The adverse events between the pirfenidone (pooled data) and first major step forward has been the European approval placebo groups (33% and 31% respectively). The majority of of pirfenidone for patients with mild-to-moderate IPF.
patients treated with pirfenidone 2403 mg/day experienced Pirfenidone has demonstrated statistically-significant and at least one treatment-emergent adverse event, with the clinically-meaningful effects in clinical trials. Overall, pir- most common adverse events being gastrointestinal, skin fenidone provides a significant treatment benefit for disorders and dizziness. These adverse events were consis- patients with IPF and represents an appropriate option as tent with the known safety profile of pirfenidone and were first-line therapy for these patients.
usually mild to moderate in severity.[Adverse eventsleading to discontinuation occurred in 15% of pirfenidone- treated patients and 9% of placebo-treated patients. Themost common cause of study discontinuation was IPF (3% Competing interests of patients in each group). The only other causes of treat- Vincent Cottin has received fees for speaking from Intermune, Boehringer ment discontinuation in the pooled pirfenidone group was Ingelheim, and Actelion, and has participated as a member of steering nausea (1%) and rash ( committees, a member of data safety monitoring boards or as aninvestigator to clinical trials sponsored by Actelion, Boehringer Ingelheim, An extension phase of the CAPACITY studies (called Gilead, and Intermune Inc.
RECAP) was designed to assess the safety of pirfenidonebeyond the duration of the Phase III studies. At Week AcknowledgementsThe author thanks C. Trenam, I. Mandic and M. Smith of IntraMed 72 of the RECAP extension study, patients had been Communications for editorial assistance in the preparation of the manuscript.
treated with pirfenidone for a mean duration of 2.9 Development of this article was supported by InterMune AG.
Cottin Respiratory Research 2013, 14(Suppl 1):S5 J Pharmacol Exp Ther 1999, This article has been published as part of Respiratory Research Volume 14 Supplement 1, 2013:IPF in 2011 – Key updates on guidelines and Gurujeyalakshmi G, Hollinger MA, Giri SN: Pirfenidone inhibits PDGF therapeutics. The full contents of the supplement are available online at isoforms in bleomycin hamster model of lung fibrosis at the Publication of this translational level. Am J Physiol 1999, 276:311-318.
supplement was supported by IntraMed Communications with funding from Iyer SN, Gurujeyalakshmi G, Giri SN: InterMune, AG. InterMune is the manufacturer of pirfenidone, a product mentioned in this article. The supplement originates from presentations J Pharmacol Exp Ther 1999, 289:211-218.
given at the "AIR Event: Advancing IPF Research. Working together to Oku H, Shimizu T, Kawabata T, et al translate IPF research into practice" held in Berlin in November 2011. The publication was proposed by IntraMed Communications and developed in consultation with the journal. All articles in the supplement have undergone 2008, 590:400-408.
the journal's standard peer review process.
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