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Pirfenidone: drug evaluation

DRUG EVALUATION
Pirfenidone is the first therapy to be licensed for the progressive and invariably fatal lung disease idiopathic pulmonary fibrosis. This article discusses the evidence underpinning the use of pirfenidone in idiopathic pulmonary fibrosis and assesses its likely impact on the delivery of care for patients with this devastating disease.
Toby M Maher MB MSc PhD MRCP 
Consultant Respiratory Physician and Honorary Senior Lecturer,
Interstitial Lung Disease Unit,
Royal Brompton Hospital,
London, UK; National Heart and Lung Institute, Imperial College, London;
Centre for Respiratory Research,
University College London, UK
Keywords: Idiopathic pulmonary fibrosis; clinical trials; pharmacokinetics; pharmacoeconomics; quality of life
Idiopathic pulmonary fibrosis is a progressive and invariably fatal lung disease with a median survival of approximately three years from diagnosis.(1) Despite the devastating nature of IPF, there have only recently been effective therapies available for its treatment. This changed in 2011, with the European Medicines Agency’s licensing of pirfenidone (Esbriet, InterMune, UK). Pirfenidone is a first-in-class, novel anti-fibrotic drug with a range of mechanisms.(2) This article will provide an overview of the pharmacology of pirfenidone and discuss its potential impact on the management of IPF in Europe.
Idiopathic pulmonary fibrosis
IPF affects approximately 5000 individuals in the UK each year and is responsible for a similar, annual number of deaths.(3) Five-year survival of patients diagnosed with the disease is similar to that of individuals diagnosed with lung cancer. IPF occurs most commonly in patients in their sixth and seventh decade and shows a male predominance. As the name suggests, the cause of IPF remains unknown; however, exposure to dusts, previous viral infection and gastroesophageal reflux all appear to be important risk factors for development of the disease.(4)
Clinically, individuals with IPF present with breathlessness, initially only on exertion, but as the disease progresses, they may become breathless at rest. Histologically, and on CT imaging, IPF is characterised by replacement of the normal lung architecture by fibrous scar tissue. Over time, the loss of normal lung tissue results in hypoxia, respiratory failure and death.
Despite this prognosis, there have remained a severe lack of effective, evidence-based, treatments for the condition.(5) The first randomised placebo-controlled trial for IPF, of reference, was published in 2004, and, after a series of a series of compounds gave rise to negative results, pirfenidone has been licensed for treatment the disease.
Pirfenidone
Pirfenidone (5-methyl-1-phenyl-2[1H]-pyridone) is an orally available pyridone derivative that exhibits anti-inflammatory, anti-oxidant and anti-fibrotic properties.(2) Pirfenidone’s precise mechanism of action has not been clearly defined. It seems likely that it is a pluripotent kinase inhibitor. In in vitro and in vivo animal models, pirfenidone exhibits a range of anti-fibrotic effects.
When administered to fibroblasts - the cells responsible for the majority of extracellular matrix synthesis in IPF - pirfenidone abrogates release of the pro-fibrotic cytokine transforming growth factor (TGF)-β; reduces synthesis of collagen proteins; and reduces the synthesis of the pro-inflammatory cytokine tumour necrosis factor (TNF)-α. In a cell-free environment, pirfenidone acts as a free-radical scavenger, thus reducing oxidative stress. In a number of in vivo animal models, pirfenidone attenuates fibrosis by mechanisms that include reducing oxidative stress, inhibiting neutrophilic inflammation and by down-regulating certain cytokines and growth factors.(2)
Pharmacokinetics
Following ingestion, pirfenidone is absorbed within 60 minutes and then rapidly cleared from the plasma and distributed to the tissues. Clearance from the tissues occurs by metabolic degradation, through oxidation, to an initial alcohol and then a carboxylic acid derivative of pirfenidone with these metabolites excreted via the kidneys. After a single dose, over 96% of pirfenidone is cleared through the urine within 24 hours. Recent ingestion of food significantly slows the absorption of pirfenidone. In a study of healthy volunteers, adverse events, principally nausea, were more frequent after fasting.
Consequently, clinical trial advice recommended pirfenidone administration after food.(6) Strong and selective Inhibitors of the cytochrome CYP1A2, such as fluvoxamine, reduce clearance of pirfenidone and should therefore be avoided in patients receiving the drug.(2) Cigarette smoking appears to reduce pirfenidone clearance through a presumed action on CYP1A2. Little is known about the effect of liver or hepatic failure on pirfenidone metabolism and clearance; both states are therefore currently considered contraindications to its use.
Clinical trials in IPF
Clinical trial design in IPF remains in its infancy. Consensus opinion regarding best trial design and choice of endpoints continues to evolve. When contemplating treatment goals in IPF, it is important to recall that individuals with the condition invariably have progressive scarring that ultimately results in gross architectural destruction of the lung with loss of the normal lace-like structure of alveoli.(4) For this reason, even if a therapy were capable of dissolving developed fibrosis in IPF, it would not restore normal structure or function to the fibrotic lung.
 Therefore, the treatment goal in IPF is to slow or, ideally, halt progression of fibrosis. As understanding of the natural history of IPF has improved, it has become clear that, while the disease progresses with an incremental decline in lung function and corresponding deterioration in symptoms in many patients, in a minority, the condition remains stable for considerable periods.
This fact makes clinical trial design in IPF particularly challenging. Typical trials require 300-400 subjects to be studied for at least 12 months; even then, detection of therapeutic efficacy is limited by the rate of decline observed in the placebo arm. 
In the majority of recent trials, change in forced vital capacity (FVC) has become the favoured endpoint. Observational studies, utilising categorical change in FVC >5% or >10% over a six- or 12-month period have demonstrated that deterioration in FVC predicts poorer prognosis.(7,8) It seems likely that, at a population level, change in FVC provides a surrogate measure for long-term survival.
However, studies that definitively prove this to be the case are lacking. Until it is shown that the degree of FVC progression at the population level predicts the magnitude of change in IPF survival, interpretation of the value of progression-altering trial therapies remains a challenge. 
Pirfenidone in clinical trials 
The first Phase IIb study of pirfenidone was published in 2005.(9) Prior to this, some open-label and small placebo-controlled trials had hinted at a treatment effect of pirfenidone. Azuma et al undertook a placebo-controlled trial across multiple Japanese centres and enrolled 107 subjects.(10) The trial was halted early by the data monitoring and safety committee because of a perceived increase in acute exacerbations in the placebo arm - a finding that was not observed in subsequent studies. Consequently, the data failed to achieve its primary endpoint of reduction in lowest saturation of oxygen during the six-minute walk test.
However, there was a significant difference in the secondary endpoint of FVC decline between the pirfenidone-  and placebo-treated groups (-0.03l  and -0.13l, respectively). A subsequent Japanese study of 275 individuals, which has been criticised for a mid-study change in primary endpoint and for the statistical handling of missing values, demonstrated a similar significant reduction in FVC decline (the primary endpoint of the study).(10)
 
These Japanese studies paved the way for two pivotal international, multicentre, randomised, controlled trials of pirfenidone compared with placebo. These studies, Study 004 and 006, shared near identical designs.(11) Both lasted for 72 weeks from randomisation, with the primary endpoint being change in FVC decline. In Study 004, subjects were randomised to receive pirfenidone 2403mg daily (n=174), 1197mg daily (n=87) or placebo (n=174), whereas in Study 006, subjects were administered either pirfenidone 2403mg daily (n=171) or placebo (n=173).
For both studies, treatment with pirfenidone 2403mg daily resulted in similar outcomes at 72 weeks, with an 8.0% FVC decline from baseline in Study 004 and 9.0% FVC decline from baseline in Study 006. In the placebo group in Study 004, FVC declined by 12.4% from baseline, thus giving a statistically significant slowing of disease decline in the high-dose pirfenidone group (p=0.001). By contrast, in the placebo group of Study 006, FVC only declined by 9.6% and the study failed to achieve its primary endpoint. In pooled data from the two studies, there was a trend towards reduced mortality in the pirfenidone treatment arms.
In all studies performed to date, pirfenidone has been reasonably well tolerated. The major side-effects noted have been gastrointestinal upset (nausea, dyspepsia, vomiting or anorexia), photosensitive rashes, and (usually minor) disturbance of liver enzymes. In the CAPACITY studies, 15% of subjects discontinued treatment as a consequence of adverse events. This compared with a discontinuation rate of 9% in the placebo arm.
The European Medicines Agency, in assessing the data from the CAPACITY trials and the earlier Japanese studies, took the decision to license pirfenidone in the European Union in March 2011. The US Food and Drug Administration considered only the results from the CAPACITY studies and did not feel that the data were sufficient to warrant licensing of pirfenidone in the USA. As a consequence, a further multicentre trial of pirfenidone versus placebo (the ASCEND Study, NCT01366209) is ongoing in the US and enrolment was completed in January 2013.
Pharmacoeconomics
Surprisingly little work has been undertaken to define the economic and healthcare utilisation costs associated with a diagnosis of IPF. As the mean age of onset is 63-66 years, IPF is typically a disease that affects individuals at the end of their working lives. However, as IPF ultimately results in respiratory failure, individuals with the condition often place a significant burden on healthcare services. In the placebo arms of IPF clinical trials, 20-25% of subjects per year have required hospitalisation, with 5-6% of these individuals requiring hospitalisation for catastrophic acute exacerbations.(11,12) 
A recent US study suggests that the average length of stay (measured up until 2008) for individuals with IPF requiring hospitalisation is 6-9.7 days and costs between (€30,733-62,242) $40,000-$81,000.13 In addition to costs of hospitalisation, individuals with IPF are likely to place increased demands on primary care services.
The majority of patients ultimately require home oxygen therapy and many rely on palliative care services for symptom control towards the end of life. IPF is the third most common indication underlying the need for lung transplantation in cystic fibrosis and emphysema patients. With an average cost of over £450,000 per transplant, this carries a significant financial cost to the UK health service. Given the previous lack of effective treatments for IPF, drugs have traditionally been a minority component of the costs associated with the disease.
Health-related quality of life 
IPF has been shown to have a major effect on individuals’ health-related quality of life (HRQoL). 
Studies assessing respiratory symptoms, global HRQoL, fatigue, cough and depression have consistently demonstrated a major effect of IPF compared to age-matched healthy individuals.
Neither HRQoL nor healthcare utilisation endpoints were included in the CAPACITY or Japanese pirfenidone studies, and so it is not possible to make a judgement on the efficacy of pirfenidone on this important aspect of the disease. Dyspnoea scores (as measured by the University of California San Diego shortness of breath questionnaire) did not differ in the CAPACITY studies between pirfenidone and placebo groups. 
A report by the German Institute for Quality and Efficiency in Healthcare (available at www.iqwig.de) concluded that the added QoL benefit of pirfenidone, based on the CAPACITY data, was minor. Germany’s Federal Joint Committee classified Esbriet’s additional benefit as stage 4 (not quantifiable benefit) in the rating system established under Germany’s AMNOG pharmaceutical law. A non-quantifiable benefit means that the drug has an additional benefit, which will be defined in the future via experience in daily clinical use or clinical studies. Based on this, a stage of 1-3 will be assigned. 
In the UK, the National Institute for Health and Care Excellence (NICE) has recommended pirfenidone for people with idiopathic pulmonary fibrosis who have a predicted FVC of between 50% and 80%.
Effect on IPF treatment landscape
At present, the majority of IPF is diagnosed and cared for in secondary care by general respiratory physicians. There are currently very few specialist interstitial lung disease clinics and even fewer dedicated tertiary units. Data gathered over the last decade point to the importance of a multidisciplinary approach to the diagnosis of IPF. Such an approach requires the integration of specialist thoracic pathology and radiology together with physicians experienced in the diagnosis and management of interstitial lung disease.
There is growing evidence that specialist centres are better able to diagnose IPF (with important prognostic and therapeutic implications being associated with both the correct and incorrect assignment of a diagnosis of IPF to individuals with fibrosing lung disease). Furthermore, a study in the US has recently demonstrated that survival of individuals with IPF is improved through early referral to a dedicated tertiary unit and this improvement is independent of baseline disease severity.
The latest British Thoracic Society guidelines recommend the development of a ‘hub-and-spoke’ model of care for individuals with IPF14, the suggestion being that regional centres (with access to specialised radiology and pathology services) should lead the diagnosis and initial management of individuals with IPF, with ongoing care then being devolved back to, or shared with, local secondary care physicians.
The relative rarity of IPF, together with its tendency to progress to end-stage respiratory failure, the frequency of disease complications such as lung cancer and pulmonary hypertension, and the need for disease monitoring with lung function testing, limit the direct role played by primary care in monitoring IPF progression. The licensing of pirfenidone for IPF and the high cost of the drug (annual cost in the UK is £26,171.72; in Germany one year of treatment costs €36,000) is likely to accelerate the development of regionalised services for IPF in the UK.
Conclusions
The introduction of a licensed treatment for IPF represents an important and exciting development for individuals with idiopathic pulmonary fibrosis and their clinicians. The forthcoming availability of pirfenidone, combined with the rapid expansion in clinical trials for IPF, are likely to lead to marked changes in the standard of care for the disease in the near future. A number of questions regarding the role of pirfenidone remains to be answered.
Despite the negative outcome of Study 006, a Cochrane review of all studies to date confirms the therapeutic effect of pirfenidone in reducing IPF disease progression.(15) Nonetheless, pirfenidone only slows (but does not halt) disease progression. It therefore seems likely that, even in the absence of clinical trial data, many clinicians will favour combining pirfenidone with the anti-oxidant N-acetyl cysteine - a treatment that has, in a single trial, shown efficacy in slowing disease progression in IPF.(16) This approach may be further refined as studies of novel agents are completed. 
Thus far, clinical trials of pirfenidone have enrolled individuals with mild-to-moderate disease (as measured by lung function parameters). It has yet to be determined whether the drug is effective in advanced disease. The optimal duration of treatment remains to be determined. As yet, there are a lack of short-term markers of response to pirfenidone. It is to be hoped that ongoing biomarker studies will help to determine markers of disease responsiveness and will therefore permit discontinuation of pirfenidone in individuals not benefiting from treatment. With the introduction of a novel treatment for IPF, it will also become necessary for the IPF community to gather data to demonstrate effects of pirfenidone on survival in IPF and also to assess the HRQoL and pharmacoeconomic benefits of treatment in patients with progressive chronic disease.
Key points
  • Idiopathic pulmonary fibrosis (IPF) is a devastating and progressive disease with a median survival of 2.5-3.5 years.
  • Pirfenidone (Esbriet) is the first drug to be licensed in Europe for the treatment of IPF.
  • In clinical trials, pirfenidone has been demonstrated to slow the progression of IPF as measured by change in forced vital capacity over 72 weeks.
  • In the UK, the National Institute for Health and Care Excellence has recommended pirfenidone for people with idiopathic pulmonary fibrosis who have a predicted FVC of between 50% and 80%.
  • The licensing of pirfenidone and the emergence of other potential therapeutic compounds for IPF is likely to drive regionalisation of care for IPF and the development of specialist centres.
References
  1. Raghu G et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183:788-824. 
  2. Maher TM. Pirfenidone in idiopathic pulmonary fibrosis. Drugs Today (Barc) 2010;46:473-82. 
  3. Navaratnam V et al. The rising incidence of idiopathic pulmonary fibrosis in the U.K. Thorax 2011;66:462-7. 
  4. Maher TM, Wells AU, Laurent GJ. Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms? Eur Respir J 2007;30:835-9. 
  5. Maher TM. Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment. Clin Chest Med 2012;33(1):69-83. 
  6. Rubino CM et al. Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulm Pharmacol Ther 2009;22:279-85. 
  7. Zappala CJ et al. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:830-5. 
  8. du Bois R et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis. Am J Resp Crit Care Med 2011;184:1382-9.
  9. Azuma A et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am.J Respir Crit Care Med 2005;171:1040-7. 
  10. Taniguchi H et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:821-9. 
  11. Noble PW et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760-9. 
  12. King TE et al. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet 2009;374:222-8. 
  13. Fioret D, Mannino D, Roman J. In-hospital mortality and costs related to idiopathic pulmonary fibrosis between 1993 and 2008. Chest 2011;140:1038A. 
  14. Bradley B et al. Interstitial lung disease guideline: the British Thoracic Society in collaboration with the Thoracic Society of Australia and New Zealand and the Irish Thoracic Society. Thorax 2008;63:v1-v58. 
  15. Spagnolo P et al. Non-steroid agents for idiopathic pulmonary fibrosis. Cochrane Database Syst Rev 2010:CD003134. 
  16. Demedts M et al. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2005;353:2229-42. 

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