PIRFENIDONE. London New Drugs Group APC/DTC Briefing Document. December 2011

Transcription

1 Page 1 London New Drugs Group APC/DTC Briefing Document PIRFENIDONE Contents Summary 1 Background 4 Current Therapy 4 Pirfenidone 4 CAPACITY studies 5 Supportive studies 7 Safety 9 Place in therapy 9 Reference list 10 Appendices 12 Produced for the London New Drugs Group by: Varinder Rai, Principal MI Pharmacist Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: nwlh-tr.medinfo@nhs.net Further copies of this document are available from URL: The drug and the review Pirfenidone (Esbriet ) received EU approval for the treatment of Idiopathic Pulmonary Fibrosis (IPF), a progressive lung disease, in February The UK launch is planned for mid The exact mechanism of action is unknown, but pirfenidone has both anti-fibrotic and anti-inflammatory properties. This review evaluates the evidence supporting pirfenidone use in patients with IPF and considers its potential place in therapy. Background The NICE appraisal on pirfenidone for treating IPF is in the NICE work plan, and a NICE clinical guideline on the treatment of IPF is anticipated in August No specific pharmacological therapy is considered the treatment of choice for management of IPF but pirfenidone is now approved in the EU for management of IPF. Collaborative European and American guidelines (2011) made a weak recommendation against the use of pirfenidone. This means that the majority of patients should not be treated with pirfenidone but it may be a reasonable choice in a minority of patients. The annual incidence of IPF in the UK has been reported as 4.6 per 100,000 patients and has increased in recent years. Most people develop symptoms between the ages of years and there is a poor prognosis with an estimated median survival time of two to five years. Literature We searched: Medline (pirfenidone.af and *IDIOPATHIC PULMONARY FIBROSIS/dt); Embase (PIRFENIDONE/ and *FIBROSING ALVEOLITIS/). This was supplemented with information from the manufacturers InterMune. The pivotal phase 3 studies are CAPACITY 004 and 006 and a pooled analysis of these. Supportive studies considered in the review are a phase 3 Japanese study, a phase 2 Japanese study, an open label study and a long term safety study (RECAP). A further study (ASCEND) is currently in progress. Main efficacy studies CAPACITY 004 and 006 Pivotal double-blind, randomised trials compared pirfenidone with placebo for the treatment of IPF. In CAPACITY 004, patients received pirfenidone 2403mg/day PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 (n=174), pirfenidone 1197mg/day (n=87) or placebo (n=174) and in CAPACITY 006, pirfenidone 2403mg/day (n=171) or placebo (n=173) for a minimum of 72 weeks in both studies. In CAPACITY 004 there was a significantly reduced mean decline in the primary endpoint, change in percentage of predicted Forced Vital Capacity (FVC) at week 72, for pirfenidone 2403mg/day compared to placebo (- 8% vs %, p=0.001) but this effect was not seen in CAPACITY 006 (-9.0% vs. -9.6%, p=0.501). The positive treatment effect was evident in CAPACITY 004 by week 24 and was seen in CAPACITY 006 from week 12 until week 48 but diminished at week 72. The pooled population analysis of the CAPACITY studies continued to show a significant treatment effect of pirfenidone 2403mg/day on the primary endpoint compared to placebo (-8.5% vs %, p=0.005). Outcomes in the pirfenidone 1197mg/day group were intermediate to the pirfenidone 2403mg/day and placebo group suggesting a dose dependent response. Overall 8% of patients died in the pirfenidone 2403mg/day group and 10% in the placebo group; 5% of patients died in the pirfenidone group due to IPF related causes and 8% in the placebo group. The differences in mortality rates between placebo and pirfenidone were not statistically significant (HR 0.77 ( ), p=0.315; HR 0.62 ( ), p=0.117 respectively). A phase 3 double-blind randomised trial (n=267) in Japanese patients compared smaller doses (considered to be comparable to the 2403mg/day on a weight-normalised basis) of pirfenidone, 1800mg/day (n=108) and 1200mg/day (n=55), to placebo (n=104) for the treatment of IPF over 52 weeks. The results favoured pirfenidone as significant differences were seen in the primary outcome of change in Vital Capacity at 52 weeks (mean adjusted value); -0.09L vs L (p=0.0416) for high dose vs. placebo and L for the low dose pirfenidone (p=0.0394). There were limitations to this trial including selection bias of patients with mild IPF, a change in the primary endpoint during the trial and use of statistical analysis to handle missing data. Safety The ASCEND study is a one year study of pirfenidone in patients who are more likely to experience decline in lung function and disease progression. The primary outcome is lung function, as measured by change in FVC from baseline to week 52. The first patient has been recruited and results are due mid The safety of pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients. The most commonly reported effects were nausea (32.8% vs. 13.3%), dyspepsia (16.8% vs. 5.5%), diarrhoea (21.7% vs. 13.5%), rash (28.7% vs. 8.6%), photosensitivity (12.2% vs. 1.7%) and fatigue (22.3% vs. 13.3%); a dose response in frequency was noted. Photosensitivity was generally transient and can be managed by sunblock, avoidance of sun exposure and reducing the dose of pirfenidone. Persistent gastrointestinal side effects can also be managed with a dose reduction. These side effects may affect patient compliance. Elevations in ALT and AST>3x upper limit of normal (ULN) have been reported and it is recommended that liver function tests should be conducted prior to initiation of treatment and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. Consideration should be given to dosage reduction or discontinuing treatment. Pirfenidone is contra-indicated in severe hepatic impairment, end stage liver disease, severe renal impairment, end stage renal disease requiring dialysis. Pirfenidone can interact with medicines, such as fluvoxamine, that inhibit and induce liver enzymes.

3 Page 3 Critical evaluation The cause of IPF remains unknown and pathogenesis is unclear, making it a difficult condition to study. Furthermore, there remains a lack of clarity surrounding the best endpoint to use when studying IPF but the European Medicines Agency have stated that percentage change in predicted FVC and 6 Minute Walk Test (6MWT) are regarded the most sensitive and well recognised measures of IPF disease progression and prognosis. However it is not clear what changes in these parameters are considered clinically significant in individual patients. As patients with IPF have a very limited lifespan of 2-5 years once diagnosed, response to therapy should be evaluated at 6 months and 12 months to determine whether therapy has a favourable or stabilising effect or if the patient has failed to respond. The studies referred to in this review were considered to be of adequate length of duration to assess efficacy. The evidence in IPF is limited; the studies are small and have limitations. However this would be expected as IPF is a rare condition. The CAPACITY studies provide the best available evidence to date and were powered to demonstrate a statistically significant treatment effect, although a positive treatment effect in the primary endpoint was only seen in CAPACITY 004. There is a lack of information in the CAPACITY studies in certain patient groups; those on concomitant immunosuppressant therapy, those suffering from severe stages of IPF and those with acute exacerbations. From the information available the benefit risk balance would appear to be favourable for pirfenidone as benefit has been shown in a condition which has to date responded poorly to treatment and the adverse effects seen with pirfenidone use are not serious. The treatment effect is dose dependent with the licensed dose of 2403mg/day showing the greatest benefit, however long term efficacy in practice still remains to be seen. Potential benefits over existing technologies Pirfenidone will be the first UK licensed treatment for IPF and clinicians may prefer to use a licensed therapy in an area where there is little evidence for treatment. Potential disadvantages over existing technologies There is little comparative data with pirfenidone and other recognised therapies for IPF therefore it is difficult to establish potential disadvantages. Pirfenidone may not be suitable for patients with poor compliance or those unable to follow the dose titration over 14 days. Cost Data Currently not available for the UK Issues for consideration In the absence of guidance recommending the choice of therapy for IPF it is difficult to define pirfenidone s place in therapy. Pirfenidone should only be initiated under specialists with experience in treating IPF. Patient preference will be a strong influencing factor on treatment decisions but they would need to be aware of and accept any possible adverse effects in comparison to any likely benefit with pirfenidone treatment. Pirfenidone is metabolised by a number of CYP isoenzymes, so the potential for drug interactions with concomitant medication must be taken into consideration. The cost of three monthly liver function testing recommended by the manufacturers should be taken into consideration. This document reflects the views of the London New Drugs Group and may not reflect those of the reviewers.

4 Page 4 Background In February 2011, pirfenidone (Esbriet ) was the first drug to obtain EU approval for the treatment of Idiopathic Pulmonary Fibrosis (IPF) and its UK launch is planned for mid ;2. Evidence based guidelines for the diagnosis and management of IPF were published in 2011 as a collaborative statement on behalf of the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS) and Latin American Thoracic Association (LATA). A NICE appraisal on pirfenidone for treating IPF is in the workplan, and a clinical guideline on the treatment of IPF is anticipated in August ;4. Idiopathic Pulmonary Fibrosis IPF is a progressive, irreversible fibrotic lung disease and is considered the most common form of interstitial lung disease 5;6. The incidence of IPF in the UK has been reported as 4.6 per 100,000 person-years which is annual incidence of 4.6 per 100,000 patients and has increased in recent years 7;8. Most people develop symptoms between the ages of years and there is a poor prognosis with an estimated median survival time of three to five years 5;8;9. There are no known causes for IPF although risk factors such as smoking and family history have been associated with the disease 10. Recent studies have suggested that IPF develops from chronic epithelial cell injury, disregulated wound healing and progressive fibrosis 5;6. Current Therapy Currently there is insufficient evidence to support the use of any specific pharmacological therapy for patients with IPF. The Collaborative European and American guidelines state that pharmacological therapy for IPF is without definite proven benefit and recommendations of varying strength were made against most therapies. The recommendations against therapies such as corticosteroid monotherapy, colchicine, cyclosporine and combined corticosteroid and immune-modulator therapy were strong i.e there is insufficient evidence to support the routine use of these therapies. Other treatment recommendations were weak; therapies such as acetylcysteine monotherapy and pirfenidone should not be used in the majority of patients with IPF but may be a reasonable choice in a minority 4. Treatment choice tends to be on an individual basis weighing up individual risks versus benefits with the patient 4. Pirfenidone currently has an "orphan designation" which means that it is used to treat life-threatening or chronically debilitating conditions that affect no more than five in 10,000 people in the European Union, or are medicines which, for economic reasons, would be unlikely to be developed without incentives 11. Pirfenidone Mechanism of action The mechanism of action of pirfenidone has not been fully established. However, existing data suggest that pirfenidone exerts both antifibrotic and antiinflammatory properties in experimental models of pulmonary fibrosis 5;12. It has been shown to reduce the accumulation of inflammatory cells in response to stimuli and attenuate fibroblast proliferation, production of fibrosis-associated proteins and cytokines, and increased biosynthesis and accumulation of extracellular matrix in response to cytokine growth factors 12. Dosing The recommended daily dose is three of the 267mg capsules, three times a day with food. The dose should be titrated to the recommended daily dose over a 14-day period: Days 1-7: One capsule, three times a day (801mg/ day) Days 8-14: Two capsules, three times a day (1602mg/day) Day 15 onwards: Three capsules, three times a day (2403mg/day) 12. Special populations No dose adjustment is necessary in elderly patients years and older, patients with mild to moderate hepatic impairment or mild to moderate renal impairment. However patients with mild to moderate hepatic impairment should be monitored closely for signs of toxicity as plasma levels may be increased in some individuals. Pirfenidone should not be used in patients with severe hepatic impairment, end stage liver disease, severe renal impairment (CrCl<30ml/ min) or end stage renal disease requiring dialysis. There are no data for the use of pirfenidone in pregnancy and hence should be avoided in pregnant women. It is unknown whether pirfenidone or its metabolites are excreted in milk and therefore the benefits or breastfeeding versus benefits of pirfenidone therapy must be considered 12. Interactions

5 Page 5 Pirfenidone is primarily metabolised by CYP1A2 and to some extent by other CYP isoenzymes including CYP2C9, 2C19, 2D6 and 2E1. Consumption of grapefruit should be avoided during pirfenidone treatment as it is an inhibitor of CYP1A2. Pirfenidone is contra-indicated in patients with concomitant use of fluvoxamine, a potent inhibitor of CYP1A2 and use is cautioned in those treated with other CYP1A2 inhibitors such as ciprofloxacin, amiodarone and propafenone. Smoking induces CYP1A2 production and should be avoided during pirfenidone treatment due to potential lowering of pirfenidone plasma levels. Other potent CYP isoenzymes inducers such as rifampicin should also be avoided 12. Clinical efficacy Once a patient is diagnosed with IPF their life expectancy is 2-5 years. The ATS/ERS Joint Statement recommend response to therapy should be evaluated at 6 months and 12 months to determine whether therapy has a favourable or stabilising effect or if the patient has failed to respond. It is unclear what the best study endpoint is for IPF and a range of parameters have been proposed including carbon monoxide diffusing capacity (DLco) and SpO 2 (blood oxygen saturation). However, percentage change in predicted Forced Vital Capacity (FVC) and 6 Minute Walk Test (6MWT) are regarded the most sensitive and well recognised measures of IPF disease progression and prognosis 13. The main studies are CAPACITY 004 (n=435) and CA- PACITY 006 (n= 344) 14 and a pooled analysis of the CAPACITY studies (n=692) 14. Further supportive studies include a Japanese phase 3 and phase 2 study (n= 267;107) 5;15 and an open label study (n=83) 13. A total of 770 patients have received the recommended dose 2403mg/day in combination of phase 2 and phase 3 studies 13. Clinical efficacy CAPACITY studies The CAPACITY studies are two similar multinational, randomised, double-blind, placebo-controlled trials conducted over 72 weeks in Australia and a number of European countries including the UK 14. Patients eligible for enrolment were those aged years with a diagnosis of IPF in the previous 48 months and no evidence of improvement over the preceding year. The eligible patients must have had a confident clinical and radiographic diagnosis of IPF and the inclusion criteria represented the heterogeneity of disease progression and severity of the condition: Predicted FVC of at least 50%, predicted DLco of at least 35%, either predicted FVC or predicted DLco of 90% or less and a 6MWT (6 minute walk test) distance of at least 150 metres. Patients younger than 50 years and those not meeting protocol criteria for definite IPF by use of High Resolution CT (HRCT) were required to have a lung biopsy showing Usual Interstitial Pneumonia (UIP). Exclusion criteria included COPD, connective tissue disease, alternative explanation for interstitial lung disease and being on a waiting list for a lung transplant. In study 004, patients were randomised 2:1:2 to receive pirfenidone 2403mg/day (n=174), pirfenidone 1197mg/day (n=87) or placebo (n=174) and in study 006 patients were randomised 1:1 to pirfenidone 2403mg/day (n=171) or placebo (n=173). The study drug was administered in three daily doses with food. Dose modification guidelines were provided for expected adverse effects including fatigue, gastrointestinal symptoms, skin reactions and raised LFTs. There was a wash-out period where patients discontinued concomitant treatments except short courses of azathioprine, cyclophosphamide, corticosteroids or n- acetylcysteine for protocol defined acute IPF exacerbation, acute respiratory decompensation or progression of disease. The primary endpoint was change in percentage of predicted FVC from baseline to week 72. Additional secondary endpoints included categorical change in FVC (5-level scale), progression-free survival (time to confirmed 10% decline in percentage predicted FVC, 15% decline in percentage predicted DL CO or death), worsening IPF, dyspnoea and 6MWT distance. Mortality was prespecified as an exploratory endpoint and death related to IPF assigned. All patients who had been randomly assigned to a treatment group were included in the intention-to-treat analysis. There was a 97% power to detect a 50% reduction in the rate of FVC progression after 72 weeks 13. Overall the treatment groups were well balanced with regard to all baseline characteristics including predicted FVC values. There was a significantly reduced mean decline in the primary endpoint in study 004 for pirfenidone 2403mg/day compared to placebo (-8% vs %,

6 Page 6 p=0.001) at the end of the study but this effect was not seen in study 006 (-9.0% vs. -9.6%, p=0.501). Outcomes in the pirfenidone 1197mg/day group fell between those seen in the pirfenidone 2403mg/day and placebo group suggesting a dose dependent response. However the pooled population analysis still showed a significant treatment effect of pirfenidone 2403mg/day on the primary endpoint compared to placebo (-8.5% vs %, p=0.005) (see Table 1 for results). The difference in efficacy between pirfenidone and placebo peaked around weeks and then fell slightly, but statistical significance was maintained in study 004 and the pooled data. The majority of the secondary or exploratory parameters (see appendix 1) did not demonstrate statistical significance compared with placebo, with the exception of categorical change in FVC 10% (absolute difference 14.4, 95%CI , p=0.001) and progression-free survival (hazard ratio 0.64, 95% CI , p=0.023) with high dose pirfenidone in study 004 and the 6MWT (absolute difference 31.8 metres, 95%CI , p=0.0009) in study 006. This effect was supported in the pooled data (see appendix 1 for secondary efficacy endpoints). Overall 8% of patients died in the pirfenidone 2403mg/day group and 10% in the placebo group; 5% of patients died in the pirfenidone group due to IPF related causes and 8% in the placebo group [HR 0.77 ( ), p=0.315; HR 0.62 ( ), p=0.117 respectively]. A total of 94% of patients completed both studies and compliance (defined as those who received 80% of scheduled doses) was considered high in the pirfenidone and placebo group (88% vs. 93%). Premature discontinuation was more common in the active groups compared to placebo; 15%, 17-18% and 10% in the pirfenidone 1197mg/day, pirfenidone 2403mg/ day and placebo group respectively. Number and the percentage of patients with an adverse event leading to a dose reduction or interruption were: 37 (42.5%), 160 (46.4%) and 64 (18.4%) in the 1197mg/day, 2403mg/day and placebo treatment arms respectively 16. It is worth pointing out that during the study enrolment period the sample size was increased by 75 patients and 60 patients in study 004 and study 006 respectively and duration of treatment was extended from 60 to 72 weeks. The power calculations were based on these numbers. Table 1: CAPACITY study - Mean change from baseline in percentage predicted FVC for Pirfenidone 2403mg/day 14. Study CAPACITY 004 [Pirfenidone 2403mg/day (n=174), Placebo (n=174)] CAPACITY 006 [Pirfenidone 2403mg/day (n=171), Placebo (n=173)] Pooled population [Pirfenidone 2403mg/day (n=345), Placebo (n=347)] Week 12 Week 24 Week 36 Week 48 Week 60 Week 72 Absolute difference 1.4% 2.5% 4.6% 4.8% 4.1% 4.4% Relative difference * 53.5% 65.2% 63.7% 52.3% 38.3% 35.3% P value (95% CI, absolute difference) Absolute difference -0.4% 2.8% 2.4% 1.9% 0.6% 0.6% Relative difference* -31.5% 62.1% 48.2% 27.3% 7.6% 6.5% P value (95% CI, absolute difference) (0.7 to 9.1) (-3.5 to -4.7) Absolute difference 0.5% 2.7% 3.5% 3.3% 2.4% 2.5% Relative difference* 28.5% 63.6% 57.5% 41.6% 25.1% 22.8% P value < < < *Relative difference = Absolute difference/ Percentage of predicted FVC for placebo

7 Page 7 Clinical efficacy supportive studies Further efficacy data comes from a Japanese phase 3 double-blind, placebo-controlled trial (n=267) conducted over 52 weeks 5. Eligible patients were adults (20-75 years) with a confirmed diagnosis of IPF and with an oxygen desaturation of 5% difference between resting SpO 2 and the lowest SpO 2 during a 6 minute steady state exercise test (6MET) plus the lowest SpO 2 during the 6MET of 85% while breathing air. Exclusion criteria included a decrease in symptoms during the preceding 6 months, use of immunosuppressants and/or oral corticosteroids at dose>10mg (prednisolone or equivalent)/day during the preceding three months, clinical features of idiopathic interstitial pneumonia other than IPF or evidence of known respiratory conditions such as pulmonary hypertension, asthma, tuberculosis. Patients were randomised to receive pirfenidone 1800mg/day (n=108), pirfenidone 1200mg/day (n=55) and placebo (n=104) in a ratio of 2:1:2 over a total of 52 weeks including the dose escalation period. The primary endpoint was change in Vital Capacity (VC) from baseline to week 52 and secondary endpoints were progression-free survival (PFS) time and the change in the lowest SpO 2 during the 6MET. Progression of disease was defined by death and/or 10% decline in VC from baseline; if VC data could not be obtained due to worsening of respiratory symptoms the case was also classified as disease progression. No significant differences were seen in the three groups except smoking history; there were a smaller percentage of patients smoking in the high dose pirfenidone group (1800mg/day, 4.6%; 1200mg/day, 18.2%; placebo, 12.5%). A high percentage of patients, 92%, had not received any prior treatments for IPF. A high percentage of patients discontinued therapy for a variety reasons. The most common reasons for withdrawal were progression of disease (7.4%, 0%, 14.4%), adverse events (13.9%, 16.4%, 6.7%) and consent withdrawal (11.1%, 3.6%, 3.8%), respectively for high dose pirfenidone, low dose pirfenidone and placebo group. Eleven patients (4.1%) died during the study: three, four and five in the high dose, low dose and placebo groups respectively. The results showed significant differences in the primary outcome of change in VC (mean adjusted value); L vs L (p=0.0416) for high dose vs. placebo and -0.08L for the low dose pirfenidone (p=0.0394). Secondary endpoints included Progression Free Survival (PFS) time and change in lowest Sp0 2 during the 6MET. There was also a difference in PFS favouring both the pirfenidone groups compared to placebo at the end of the study (high dose; n=45, p=0.0280; low dose; n=26, p=0.0655; placebo n=40). There were no significant differences between the high dose, low dose and placebo groups in change in the lowest SpO 2 (adjusted mean ±SE; -1.70±0.35, -0.84±0.48, ±0.35 respectively) and acute exacerbations (5.6%, 5.5%, 4.8% respectively). There are significant limitations to this trial. Firstly there was a selection bias of patients with mild IPF and there was an exclusion of patients with decrease in symptoms during the preceding 6 months suggesting patients had stable disease which means the results may not be applicable to all patients with IPF. A decision was made to change the primary endpoint of oxygen desaturation during exercise to the pulmonary function endpoint VC as it was considered a more appropriate predictor of mortality in patients with IPF and also there were difficulties in the reproducibility of the SpO 2 during the 6MWT. This change was done prior to unblinding, nevertheless, a change in primary endpoint during a trial can compromise the integrity of the trial. One-third of subjects discontinued the study before the week 52 primary efficacy assessment and last observation carried forward analysis was the statistical method used to handle the missing data, which assumes that the patient s condition remains static at the last observation. No statistical method for handling missing data however is without potential for error 17. The authors maintain that the 80% power of the study remained despite these issues. The highest dose used (1800mg) is below the approved dose (2403mg). The smallest and weakest study is a small phase 2 double-blind, randomised, placebo-controlled trial (n=107) conducted in Japan 15. On recommendation of the data and safety monitoring board this trial was discontinued prematurely at 9 months in favour of pirfenidone after acute exacerbation was found significantly more frequently in the placebo group (0% vs. 14%), resulting in incomplete data. Patient with well-defined IPF were randomised in 2:1 ratio to 1800mg/day pirfenidone or placebo and were assessed for change in the lowest SpO 2 during a 6MWT, the primary endpoint. As discussed in the paragraph on the previous trial this is not considered a validated primary endpoint and it was found that only 80 pa-

8 Page 8 tients could complete the entire duration of the 6MWT. Statistical significance was not reached for mean change in the primary endpoint at 6 or 9 months (6 months, 0.64% vs %, p=0.1489;9 months, 0.47% vs %, p=0.0722, for active and placebo groups respectively) for the full set analysis but there is a suggestion of beneficial effect at both 6 and 9 months for the 80 patients who completed the baseline 6MET (0.56% vs. -1.9%, p=0.0069, 6 months; 0.46% vs % p=0.0305, 9 months, respectively for active and placebo groups). Positive treatment effect was demonstrated in the secondary endpoint change in VC measurements at 9 months (p=0.0366) and episodes of acute exacerbation of IPF occurring exclusively in the placebo group during the 9 months (p=0.0031). One of the patients died after acute exacerbation and there were no deaths in the pirfenidone group. At 9 months only 54% of patients were able to tolerate the maximum dose of 1800mg/day and half of the patients who were unable to tolerate this dose, were able to tolerate 1200mg/day. The doses used in both the Japanese studies are lower than the recommended licenced dose in the UK (2403mg/day) although considered to be comparable to the 2403mg/day dose on a weight-normalised basis 18. Both studies used un-validated endpoints, so the results should be interpreted with caution. ASCEND is a new randomised, double-blind, placebo controlled phase 3 study of pirfenidone which has enrolled patients with IPF that are more likely to experience decline in lung function and disease progression during the study 19. The trial will enrol approximately 500 patients who will be randomly assigned to receive pirfenidone 2403mg/day or placebo. The primary endpoint is lung function, as measured by change in FVC form baseline to week 52. The results of this multinational one year study are expected in mid An on-going open-label, phase 2 study enrolled patients with PF/IPF into three groups; patients already receiving oral pirfenidone or who had received pirfenidone within 4 weeks before enrolment, patients initiating therapy with pirfenidone or reinitiating therapy after a lapse of greater than 4 weeks and patients who had not previously received pirfenidone 13. The objectives of this study are to assess the safety and efficacy of treatment with pirfenidone (up to 3600 mg/day) in patients with PF/ IPF and to provide PF/IPF patients with early access to pirfenidone. A total of 83 patients were enrolled across 27 sites; 97.6% had a diagnosis of IPF and 88% had not previously received pirfenidone. A total of 13 patients rolled over from other pirfenidone trials and 10 patients had received pirfenidone in their original study; the other 3 patients had received an active control. As of the interim database cut-off of 30 April 2009, 50 patients (60.2%) had prematurely withdrawn from the study. The most frequent reasons for early withdrawal were adverse events (17 patients, 20.5%) and death (15 patients, 18.1%). Results showed: Median percent predicted FVC was 65.6% at baseline (n=79), 66.8% at week 48 (n=57), 68.7% at week 96 (n=47), 65.2% at week 144 (n=35), and 70.9% at week 192 (n=11). Median Hgb (haemoglobin)-corrected percent predicted DLco was 36.5% at baseline (n=73), 35.2% at Week 48 (n=55), and 38.3% at Week 96 (n=44), 37.9% at week 144 (n=34), and 41.1% at week 192 (n=11). Median resting oxygen saturation by pulse oximetry on room air was 95.0% at Baseline (n=71), Week 48 (n=47), Week 96 (n=36), and Week 144 (n=30) and 96.5% at week 192 (n=8). Of the 41 patients who were not receiving supplemental oxygen at start of study, 19 (46.3%) started supplemental oxygen during the study. The Kaplan -Meier estimate of median time to first supplemental oxygen use was weeks. At the April 2009 data cut-off, most patients had not experienced a protocol-defined IPF exacerbation while enrolled in the study (63/83, 75.9%); 20 patients (24.1%) had an IPF exacerbation while on study. Of these 20 patients, 5 died due to IPF, 3 discontinued study drug due to adverse effects, 4 discontinued due to non-adverse-effect-related reasons, and 8 remained on treatment as of 30 April A total of 15 patients died during the study (18.1%); 14 deaths (16.9%) were treatment emergent; and 12 deaths (14.5%) were IPF related.

9 Page 9 Safety The safety of pirfenidone has been evaluated in clinical studies including 1345 healthy volunteers and patients 12. Early treatment discontinuation due to adverse effects was higher in the pirfenidone group; 14.8% in the pirfenidone 2403mg/day group compared to 8.6% in the placebo group. IPF was the most common adverse effects leading to discontinuation in all three groups of patients treated with pirfenidone 2403mg/day, 1197mg/day and placebo (range 2.3% to 2.9%) 13. The type and frequency of adverse effects are consistent with the known safety profile of pirfenidone, including gastrointestinal events, photosensitivity and rash 14. In the clinical studies the most commonly reported effects (>10%) for the 2403mg/day group compared to placebo were nausea (32.8% vs. 13.3%), dyspepsia (16.8% vs. 5.5%), diarrhoea (21.7% vs. 13.5%), rash (28.7% vs. 8.6%), photosensitivity (12.2% vs. 1.7%) and fatigue (22.3% vs. 13.3%); a dose response in frequency was noted 12;14. There was a small increase in adverse effects associated with connective tissues (2% vs. 1.2% placebo) which may be due to antifibrotic action of pirfenidone 13. Photosensitivity presented as a transient rash (up to 18 months after initiation of therapy) and incidence was closely associated with an increased exposure to sunlight 13. The manufacturers recommend the use of sunblock, avoidance of sun exposure and a dosage reduction in those patients who experience a mild to moderate photosensitivity reaction. Those experiencing persistent gastrointestinal side effects may have to firstly be reminded to take tablets with food, after which the dosage may be reduced and then reescalated as symptoms resolve. Elevations in ALT and AST>3x upper limit of normal (ULN) have been reported in patients receiving pirfenidone. It is recommended that LFTs should be conducted prior to initiation of treatment and subsequently at monthly intervals for the first 6 months and then every 3 months thereafter. In the event of significant elevation of liver aminotransferases the dose should be adjusted according to the manufacturers recommendations or treatment discontinued (see SPC for dosage reduction recommendations) 12. RECAP is an open-label safety extension study of 603 patients from the CAPACITY studies. At week 72 in RECAP, mean exposure to pirfenidone 2403mg/day across both studies was 2.9 years (range, 1-4years); 114 patients had received pirfenidone for at least three years. Long term treatment emergent adverse events and common adverse events were similar to those in the CAPACITY studies; 98.2% of patients reported 1 treatment-emergent adverse event (TEAE) vs. 98.6%, and 32.8% of patients has serious TEAE in both the RECAP and CAPACITY studies. Common adverse events in RECAP were similar as to those in the CAPACITY study and were generally mild to moderate in severity. Rash and photosensitivity were more common among patients newly initiating treatment with pirfenidone vs. those who were continuing treatment (CAPACITY, 44.4% vs. RECAP, 19.7%); however patients who received placebo during CAPACITY had a higher incidence than those who received pirfenidone (28.1% vs. 12.3%) 20. Conclusions and place in therapy IPF is a progressive lung disease that carries a poor prognosis and has a heterogeneous pathogenesis making it a very difficult condition to study. The most recent evidence based guidelines which place a high value on side-effects and cost but a low value on the possible small reduction in pulmonary function decline 21, state that pharmacological therapy for IPF is without definite proven benefit and recommendations of varying strength were made against most therapies. The recommendations were strong against most treatment therapies such as corticosteroid monotherapy, colchicine, cyclosporine and combined corticosteroid and immune-modulator therapy i.e there is insufficient evidence to support the routine use of these therapies. Other treatment recommendations were weak i.e. therapies such as acetylcysteine monotherapy and pirefenidone should not be used in the majority of patients with IPF but may be a reasonable choice in a minority 4. However these guidelines were written prior to the EU approval of pirfenidone for IPF. The studies submitted for approval of pirfenidone have shown some benefit compared to placebo in reducing the rate of loss in pulmonary function using recognised parameters for determining prognosis in IPF patients. The methodological imperfections of the studies and heterogeneity of results in the various studies should be acknowledged. For example, the CAPACITY-006 study only showed a positive effect in the absolute change in predicted FVC at week 48 and not at week 72. The reduction in mortality rates seen with pirfenidone in the CAPACITY studies are derived from very small numbers, so outcomes measured over a

10 Page 10 period of several years would be needed before benefits on mortality could be claimed. The effect is dose dependent with the licensed dose of 2403mg/ day showing the greatest benefit. Undesirable adverse effects primarily affect the gastrointestinal and skin systems which are likely to affect patient compliance. There is a lack of information on the efficacy of pirfenidone in certain groups of patients such as those on concomitant immunosuppressant therapy and those suffering from severe stages of IPF 13. The efficacy and safety in these patients and those with acute exacerbations needs to be established. The new ASCEND study in patients who are more likely to experience decline in lung function and disease progression has started enrolment and will add to pirfenidone s body of evidence 19. Based on the information available the benefit risk balance would appear to be favourable for pirfenidone as benefit has been shown in a condition which has to date responded poorly to treatment and the adverse effects seen with pirfenidone use are not serious. In the absence of guidance recommending the choice of therapy for IPF it is difficult to define its place in therapy. Pirfenidone should only be initiated under specialists with experience in treating IPF. Patient preference will be a strong influencing factor on treatment decisions but they would need to be aware of and accept possible adverse consequences in comparison to any likely benefit with pirfenidone treatment 8;21. Produced by the London New Drugs Group. Correspondence to Varinder Rai, Principal MI Pharmacist, London Medicines Information Centre, Northwick Park Hospital, Watford Road, Harrow, Middlesex. HA1 3UJ. varinder.rai@nhs.net This document reflects the views of the LNDG and may not reflect those of the reviewers. InterMune has commented on this review. Reference List (1) EPAR summary for the public for Esbriet. January European Medicines Agency. Available at Doc Ref: EMA/174479/2011. (2) Pirfenidone. New Drugs Online. Available at Date of access: 20/07/2011. (3) NICE. Available at (4) Raghu G, Collard HR, Egan JJ. American Thoracic Society Documents. An official ATS/ JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and managment. Am J Resp Crit Care Med 2011; 183: (5) Taniguchi H, Ebina M, Kondoh Y et al. Pirfenidone in idiopathic pulmonary fibrosis. Eur Resp J 2010; 35: (6) Ryu JH, Daniels CE. Advances in the management of idiopathic pulmonary fibrosis. Medicine Reports 2010; 2(28):1-4. (7) Hui Hoo Z, Whyte MKB. Idiopathic pulmonary fibrosis. Thorax 2011; /thoraxjnl (8) Klingsberg RC, Mutsaers SE, Lasky JA. Current clinical trials for the treatment of idiopathic pulmonary fibrosis. Respirology 2010; 15: (9) Interstitial lung disease guidelines. Appendix 6: Patient information for idiopathic pulmonary fibrosis. September British Thoracic Society Available at (10) Idiopathic pulmonary fibrosis. InterMune (11) Pirfenidone - Orphan designation. European Medicines Agency. Available at Doc Ref: EU/3/04/241 (12) Summary of Product Characterstics. Esbriet 267mg hard capsules. InterMune Europe Ltd. (13) Committee for Medicinal Products for Human Use (CHMP). Assessment report for Esbriet. December Available at Procedure No: EMEA/ H/C/

11 Page 11 (14) Noble PW, Albera C, Bradford W et al. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: (15) Azuma A, Toshihiro N, Tsuboi E et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: (16) InterMune. Personal communication. September (17) Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir J 2010; 35: (18) Carter NJ. Pirfenidone in idiopathic pulmonary fibrosis. Adis drug profile 2011; 71 (13): (19) Print News Article - Pirfenidone. BioSpace. Available at Date of access: 18/07/2011. (20) Chiesi. Abstract 174: The long-term safety of pirfenidone in patients with idiopathic pulmonary fibrosis (IPF): interim data from the RECAP extension study. September (21) Bouros D. Pirfenidone for idiopathic pulmonary fibrosis. Lancet 2011; 377:

12 Page 12 Appendix 1: CAPACITY study - secondary endpoints at week Study 004 Study 006 Pooled data Endpoint Categorical change in FVC 10%* Progression-free survival time (HR) Mean change in 6MWT distance (m) Mean change in DLco (% predicted) Mean change in dyspnoea score+ Mean change in worst SpO2 during 6MWT (%) Time to worsening in IPF (HR) Categorical change in HRCT-diagnosed fibrosis Pirfenidone 2403mg/ day (n=174) Placebo (n=174) 35 (20%) 60 (35%) Absolute difference (95% CI) 14.4 (7.4 to 21.3) 0.64 (0.44 to 0.95) 16.4 (-10.9 to 43.7) 2.0 (-0.4 to 4.4) -3.1 (-8.5 to 2.3) 0.8 (-0.2 to 1.8) 0.84 (0.50 to 1.42) P- value Pirfenidone 2403mg/ day (n=171) Placebo (n=173) (23%) 46 (27%) Absolute difference (95% CI) 3.8 (-2.7 to 10.2) 0.84 (0.58 to 1.22) 31.8 (3.2 to (-3.2 to 2.2) -2.0 (-7.6 to 3.6) -0.5 (-1.7 to 0.7) 0.73 (0.43 to 1.24) P- value Pirfenidone 2403mg/ day (n=345) Placebo (n=347) (21%) 106 (31%) Absolute difference (95% CI) 9.1 (4.3 to 13.9) 0.74 (0.57 to 0.96) 24.0 (4.3 to 43.7) 0.7 (-1.1 to 2.5) to 1.4) 0.1 (-0.7 to 0.9) 0.78 (0.54 to 1.14) NA NA NA NA NA NA NA NA NA NA NA P- value Overall mortality ± (HR) Ontreatmen ts (HR) All-cause 27 (8%) 34 (10%) IPF-related 18 (5%) 28 (8%) All-cause 19 (6%) 29 (8%) IPF-related 12 (3%) 25 (7%) 0.77 ( ) 0.62 ( ) 0.65 ( ) 0.48 ( ) * Based on five categories (severe decline 20%; moderate decline <20% but 10%; mild decline <10% but 0; mild improvement >0 but < 10%; and moderate improvement 10%. + Based on the university of California San Diego Shortness of Breath Questionnaire total score ranges from 0 to 120, with larger scores indicating greater shortness of breath. $ Based on five categories: much better, better, same, worse or much worse. Hazard ratio (HR) ± Time from randomisation to death Time from randomisation to 28 days after the last study dose