IDIOPATHIC PULMONARY FIBROSIS TREATMENT IN IPF Treatments tried

IDIOPATHIC PULMONARY FIBROSIS

TREATMENT IN IPF

Treatments tried in IPF Antifibrotic Activity Pirfenidone Interferon-g 1 b Pirfenidone Endothelin receptor antagonists Sildenafil Etanercept ACEIs Statins NAC Anti-inflammatory Immunosuppressants Corticosteroids Treatment options include corticosteroids, immunosuppressive/cytotoxic agents (e. g. , azathioprine, cyclophosphamide) , and antifibrotic agents alone or in

Recommendation on Steroid/ N-AC monotherapy : New *ATS/ERS/JRS/ALAT International IPF guidelines 2011 Patients with IPF should not be treated with corticosteroid monotherapy (strong recommendation, very low-quality evidence) Majority of patients with IPF should not be treated with N acetylcysteine monotherapy, but this therapy may be a reasonable choice in a minority (weak recommendation, low-quality evidence)

Recommendation on combination therapy : New *ATS/ERS/JRS/ALAT International IPF guidelines 2011 Patients with IPF should not be treated with combination corticosteroid and immunomodulator therapy (strong recommendation, low-quality evidence) The majority of patients with IPF should not be treated with combination corticosteroid, azathioprine, and acetylcysteine therapy, but this therapy may be a reasonable choice in a minority (weak recommendation, low quality evidence) Am J Respir Crit Care Med 2011; 183: 788– 824

Recommendations for Treatment: ATS/ERS/JRS/ALAT International IPF guidelines 2011 Treatment recommendations for specific therapies are the following (the quality of evidence is presented as one to four plus signs) A. The recommendation against the use of the following agents for the treatment of IPF is strong (most people in this situation would not want the intervention and only a small proportion would) Corticosteroid monotherapy + Colchicine + Cyclosporine A + Combined corticosteroid and immune-modulator therapy ++ Interferon gamma 1 b ++++ Bosentan +++ Etanercept +++ Am J Respir Crit Care Med 2011; 183: 788– 824

Recommendations for Treatment: ATS/ERS/JRS/ALAT International IPF guidelines 2011 B. The recommendation against the use of the following agents for the treatment of IPF is weak For the well-informed patient who strongly desires pharmacologic treatment, it is suggested that the choice of agent may be made from therapies that received a weak recommendation against their use Combined acetylcysteine and azathioprine and prednisone ++ Pirfenidone ++ N - Acetylcysteine monotherapy ++ Anticoagulation + Am J Respir Crit Care Med 2011; 183: 788– 824

PANTHER- IPF trial Most clinicians typically are treating patients with a combination of prednisone, azathioprine, and Nacetylcysteine as triple therapy based on the positive results from the IFIGENIA trial PANTHER-IPF is the three arm multi-center clinical trial Trial tests prednisone, azathioprine, and Nacetylcysteine (NAC) triple therapy vs. placebo, and NAC alone vs. placebo, on lung function and other health outcomes in patients with newly-diagnosed with IPF

PANTHER- IPF trial National Heart, Lung, and Blood Institute(NHLBI) halted the triple therapy arm when it noted significantly higher mortality, hospitalization, and adverse event rates compared with the placebo and NAC arms without evidence of benefit Also patients assigned to the triple- therapy arm had lower treatment adherence vs. other arms(78 % adherence versus 98 % adherence)

Anticoagulation trial NHLBI suspended enrolment and treatment in the phase 3, randomised, double-blind, placebo-controlled ACE-IPF trial designed to test the effectiveness of warfarin (anticoagulation) in IPF patients This trial was stopped by Data and Safety Monitoring Board as results showed that warfarin is ineffective and potentially harmful as a therapy for patients with this disease

Hence among the options available Combined acetylcysteine and azathioprine and prednisone Pirfenidone × Acetylcysteine monotherapy × ? ? ? Anticoagulation (warfarin) × √ Pirfenidone showed clinical improvement Am J Respir Crit Care Med 2011; 183: 788– 824

Conventional treatment is it safe? Combined prednisolone (tapering from 0. 5 mg/day to 10– 20 mg/ day) with azathioprine (2 mg/kg, maximum 150 mg/ day) and NAC (600 mg three times daily): based on the results of the IFIGENIA trial in IPF However this recommendation is now being challenged in wake of the results from the recently halted prednisone, azathioprine, and NAC (triple therapy) arm of the PANTHER study in IPF patients because of safety concerns Participants treated with triple therapy had more mortality, more serious adverse events, and more drug discontinuations, without evidence of benefit

Why the need for an antifibrotic? Most diagnosed patients with IPF are in the fibroproliferative phase and not in the early inflammatory stage hence the need for an antifibrotic drug 1 Evolving hypothesis suggests that fibrosis results from epithelial injury and abnormal wound healing 2 Little evidence that inflammation is prominent in early disease and may not be relevant to the development of fibrosis 2 Anti-inflammatory therapy does not improve disease outcome 2 Hence IPF is a result of fibroblast dysfunction rather than dysregulated inflammation 2 1. Am J Respir Crit Care Med 199; 159: 1061 -106 2. Ann Intern Med. 2001; 134: 136 -151

PIRFENIDONE First and only approved treatment of IPF

Pirfenidone : First and only approved drug in IPF Only approved drug for the treatment of IPF Pirfenidone, is a novel anti-fibrotic agent, which has been approved for IPF treatment in Japan, Europe and in India and evaluated in the largest number of IPF patients in clinical trials A recent Cochrane meta-analysis, concluded that pirfenidone is the only agent proven to produce a clinically relevant effect Slow down the decline in lung function and has a significant 30% improvement in progression-free survival in IPF The starting dose is 600 mg/day, which is stepped up gradually to 1, 200 mg/day over 2 weeks and, finally, to 1, 800 mg/day over the next 2 weeks 1. ID Drugs 2004; 7: 166 -172 2. Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No. : CD 003134

Pirfenidone Japanese Phase III studies : Effect on VC/Progression free survival • Significant lesser VC decline with high-dose pirfenidone (-0. 09 L) compared to placebo ( -0. 16 L) (p=0. 04) • Significantly improved progression free survival time with highdose pirfenidone as compared to placebo (p=0. 0280) Eur Resp J Dec 2009 epub Eur Respir J 2010; 35: 821– 829.

CAPACITY TRIALS: Pirfenidone pooled analysis • Significantly lesser FVC decline with pirfenidone compared to placebo (-8. 5% vs. -11. 0%; p = 0. 005) Lancet. 2011; 377(9779): 1760 -9.

CAPACITY TRIALS: Pirfenidone pooled analysis Significantly lesser FVC decline with pirfenidone as compared to placebo in IPF Significant reduction in risk of death or progression of disease with pirfenidone as compared to placebo Preservation of walk distance during 6 MWT (Week 72) with pirfenidone as compared to placebo Fewer patients had % predicted FVC decline ≥ 10% with pirfenidone as compared to placebo

Meta-analysis of Pirfenidone trials: Presented at the American Thoracic Society Meeting May 2010 Conclusion: N = 1054 Hazard ratio: of 0. 71 for PFS Effect on FVC/VC Effect on progression free survival (PFS) Pirfenidone reduced the risk of death or disease progression by 29% in patients of IPF

Other novel agents N-acetylcysteine (N-AC): Epithelial injury in IPF may be mediated by oxygen radicals; hence antioxidant strategies like NAC might prove beneficial Anticoagulation: There is limited data from earlier studies, also a recent trial showed that treatment with warfarin was associated with an increased risk of mortality Am J Respir Crit Care Med. 2000; 161: 646 -664.

Interferon Gamma-1 b Lancet 2009; 374: 222 -28.

• No effects of bosentan were observed in changes from baseline to 1 year in health-related quality of life or dyspnea • Small , nonsignificant delay in the time to IPF worsening (excluding death) • Small differences favoring the bosentan treatment group in changes from baseline to 1 year in absolute FVC and DLCO Kaplan–Meier survival estimate for each treatment group AJRCCM 2010

ACE-IPF study : Warfarin in IPF All-Cause Mortality or All-Cause Hospitalization Kaplan-Meier Plot Due to a low probability of benefit, and an increase in mortality observed in the subjects randomized to warfarin (14 warfarin vs. 3 placebo deaths; p=0. 005), an independent Data and Safety Monitoring Board recommended stopping the study after • No benefit for warfarin in the treatment of patients with progressive IPF • Treatment with warfarin was associated with an increased risk of mortality in an IPF population who lacked other indications for anticoagulation Am J Respir Crit Care Med. 2012; 186: 88 -95.

Nonpharmacologic Therapies § § q Lung transplantation Supplemental oxygen : strongly recommended in patients with clinically significant resting hypoxemia (commonly defined by a resting Sp. O 2 of <88%) Pulmonary rehabilitation Improvement in general and disease-specific health status Increased exercise tolerance Mechanical ventilation: associated with high mortality in IPF; hence, it should be used only after discussion with patients and their caregivers Screen for pulmonary hypertension, obstructive sleep apnea, cough, gastroesophageal reflux disease etc Am J Respir Crit Care Med 2011; 183: 788– 824.

Treatment of Selected Complications and Comorbid Conditions Acute exacerbation of IPF Majority of patients should be treated with corticosteroids however there are no specific recommendations regarding the dose Pulmonary hypertension associated with IPF In patients with moderate-to-severe pulmonary hypertension after right heart catheterization trial of vasomodulatory therapy may be indicated Asymptomatic Gastroesophageal reflux in patients with IPF Weak recommendation to medically treat asymptomatic GERD in the majority of patients with IPF Obesity, emphysema, and obstructive sleep apnea No data to make recommendations for the treatment of these in the setting of IPF Chronic cough in IPF Corticosteroids and thalidomide may be beneficial Am J Respir Crit Care Med 2011; 183: 788– 824.

Causes of death Death rates increase with increasing age, consistently higher in men than women Seasonal variation, with the highest death rates seen in the winter, even when infections are excluded With the revised diagnostic criteria for IPF, only 20 to 30% of subjects were alive 5 years after diagnosis Most deaths occur from progression of lung fibrosis rather than from commonly occurring comorbid conditions Frequent hospitalizations for respiratory problems are common events and are often associated with death Chest 2009; 136: 16– 22. Ann Intern Med 2005; 142: 963– 967. Lancet 2009; 374: 222– 228.

Features associated with an increased risk of mortality in IPF Baseline factors* Longitudinal factors Level of dyspnea† Increase in level of dyspnea† DLCO <40% predicted Decrease in FVC by >10% absolute value Desaturation ≤ 88% during 6 MWT Extent of honeycombing on HRCT† Pulmonary hypertension *Baseline FVC is of unclear predictive value. Decrease in DLCO by >15% absolute value Worsening of fibrosis on HRCT† † Currently, there is no uniformity in approach to quantification. Am J Respir Crit Care Med 2011; 183: 788– 824.

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