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Supplements A Managed Care Perspective:Treatment of Idiopathic Pulmonary Fibrosis

Evaluating New Treatment Options

Steven D. Nathan, MD
Idiopathic pulmonary fibrosis (IPF) is the most prevalent type of idiopathic interstitial pneumonia, accounting for at least half of all diagnosed cases. Because it lacks a cure, the goal of treatment for IPF is to stabilize or reduce the rate of disease progression. Nonpharmacologic treatment options for IPF consist of long-term oxygen treatment, lung transplantation, and pulmonary rehabilitation. In the past, pharmacologic therapies for IPF included anticoagulants and anti-inflammatory or immunosuppressive agents. However, in late 2014, 2 therapies were approved by the US FDA for use in IPF: nintedanib and pirfenidone. While treatment of IPF was previously significantly impeded by a lack of effective agents and a paucity of clinical trial data on which to base guideline recommendations, these new agents provide notable breakthroughs in management of IPF, and continued research may break further, new fertile ground for management.
Am J Manag Care. 2017;23:-S0
Clinical Practice Guideline Changes

2011 ATS/ERS/JRS/ALAT Recommendations

Treatment of IPF combines nonpharmacologic and pharmacologic strategies, and goals of treatment focus on halting disease progression and preventing acute exacerbations, which are a potentially life-threatening complication in approximately 5% to 15% of patients.1-5

Over the past 2 decades, the landscape of pharmacologic therapy for IPF has changed dramatically.2 A previous evidence-based clinical practice guideline for the treatment of IPF was published in 2011 by 4 sponsoring organizations: American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Society (ALAT). At that time, the committee involved in guideline preparation believed that the preponderance of evidence to date suggested that pharmacologic therapy for IPF was “without definitive, proven benefit.” For that reason, the committee chose to make recommendations of varying strength against most pharmacologic agents for treatment. Strong recommendations were published against the use of multiple agents, including1:

  • Corticosteroid monotherapy
  • Colchicine
  • Cyclosporine A
  • Combined corticosteroid and immunomodulator therapy
  • Interferon gamma 1b
  • Bosentan
  • Etanercept

In addition, weak recommendations were made against several agents, stating that they should not be used in a majority of patients with IPF, but may be a reasonable choice in the minority of patients1:

  • Combined acetylcysteine, azathioprine, and prednisone
  • Acetylcysteine monotherapy
  • Anticoagulation
  • Pirfenidone

This version of the guidelines strongly recommended long-term oxygen therapy in patients with IPF and clinically significant resting hypoxemia, along with a strong recommendation for lung transplantation in appropriate patients.1 The overall recommendations were based on the committee analysis that current evidence at that time demonstrated no proven pharmacologic therapy for IPF. Although a few studies suggested potential benefits from some pharmacologic agents, the recommendations for use of these agents were a “weak no.” In the case of a well-informed patient with IPF who desires drug therapy, it was suggested that the choice of treatment be made from those that were weakly recommended against their use.1

2015 ATS/ERS/JRS/ALAT Recommendations

In 2015, a similar committee from the same 4 specialty organizations again met to assess new advanced data surrounding management of IPF and to provide an update to the 2011 clinical practice guideline. The purpose of reissuing the recommendations was to update the treatment guidelines with the reappraisal of previously assessed treatment options and new recommendations for novel agents. The goal of the guideline is for it to essentially be a reference of continually evolving recommendations, incorporating new evidence-based data once they become available. The intent is for the guideline committee to perform periodic reviews and updates to bring new evidence-based recommendations into clinical practice in as timely a manner as feasible.6

Strong recommendations against the use of the following drugs were again outlined in the new guideline, with notable changes from 20116:

  • Anticoagulation (warfarin)
  • Imatinib, a selective tyrosine kinase inhibitor (TKI) against platelet-derived growth factor
  • Combination prednisone, azathioprine, and N-acetylcysteine
  • Selective endothelin receptor antagonist (ambrisentan)

Another new set of conditional recommendations was made for the use of the following agents for treatment of IPF6:

  • Nintedanib, a TKI that targets multiple tyrosine kinases, including vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors
  • Pirfenidone, an oral antifibrotic agent with pleiotropic effects

Conditional recommendations were made against the following agents6:

  • Phosphodiesterase-5 inhibitor (sildenafil)
  • Dual endothelin receptor antagonists (macitentan, bosentan)

The key new features in the guideline were the conditional recommendations for the use of nintedanib and pirfenidone. In the case of nintedanib, the recommendation placed a high value on the potential benefit of this agent on essential patient outcomes, including disease progression as measured by rate of forced vital capacity (FVC) decline and mortality, along with a lesser value on the potential adverse effects (AEs) of therapy and the costs associated with nintedanib treatment. It was noted that unlike more selective TKIs, nintedanib appeared to offer some benefit in patient-important outcomes even though no significant effect on mortality was observed.1,6

Pirfenidone was addressed in the 2011 clinical practice guideline with a weak recommendation against its use. However, in the updated recommendations, it was noted that new evidence had become available since the prior edition that led to a new conditional recommendation in favor of treatment with pirfenidone. As with nintedanib, this new recommendation placed a high value on the potential benefit of this agent on patient-important outcomes, including disease progression as measured by rate of FVC decline, and a lesser value on related AEs and costs associated with pirfenidone use.6

Update of Newly Approved Therapeutic Options: Pirfenidone


While only preliminary data surrounding the CAPACITY trials were available when the 2011 clinical practice guideline was published, more complete results were assessed in the preparation of the 2015 guideline update.6 The CAPACITY program of 2 trials was designed to confirm the results of a phase 2 study that suggested the novel antifibrotic pirfenidone reduced deterioration in lung function in patients with IPF. CAPACITY consisted of 2 concurrent trials (004 and 006) of patients with IPF aged 40 to 80 years, randomly assigned to receive either oral pirfenidone or placebo for a minimum of 72 weeks in a total of 110 centers in North America, Europe, and Australia. In study 004, patients were assigned in a 2:1:2 ratio to pirfenidone 2403 mg/day, pirfenidone 1197 mg/day, or placebo. In study 006, the assignment consisted of a 1:1 ratio of pirfenidone 2403 mg/day or placebo. The primary endpoint of the study was change in the percentage predicted FVC after 72 weeks, with analysis by intent to treat.7

In study 004, pirfenidone reduced decline in FVC, with a mean change at week 72 of –8.0% (SD 16.5%) in the 435 patients who received the 2403 mg dosage versus –12.4% (SD 18.5%) for the 174 patients in the placebo group. Mean percentage change in FVC in the 87 patients assigned to receive pirfenidone 1197 mg daily was intermediate to that of those in the higher-dosage pirfenidone cohort and the placebo cohort. In study 006, mean change in FVC at week 72 was –9.0% (SD 19.6%) for the 344 patients who received pirfenidone versus –9.6% (SD 19.1%) for those who were assigned placebo, and the difference in FVC between the 2 groups was not significant. However, this study demonstrated a consistent pirfenidone effect that remained apparent until week 48 (P = .005).7 Patients from both studies who received high-dose pirfenidone reported higher rates of nausea, dyspepsia, vomiting, anorexia, photosensitivity, and rash compared with patients in the placebo group.6,7

The ASCEND Trial

The ASCEND trial was designed to confirm the beneficial effect of pirfenidone on disease progression as measured by decline in FVC seen in the previous phase 3 trials (CAPACITY 004 and a small previous trial of 275 patients conducted in Japan). In ASCEND, 555 patients were randomized to receive either 2403 mg of oral pirfenidone daily versus placebo for 52 weeks. The primary endpoint of the study was the change in FVC or death after 52 weeks.8 However, it must be noted that the ASCEND trial had stricter patient exclusion criteria than did the CAPACITY studies, such as a forced expiratory volume in 1 second (FEV1) to FVC ratio (FEV1/FVC) below 0.8.6,8 Results showed a relative reduction of 47.9% in the proportion of patients with an absolute decline of ≥10 percentage points in percent predicted FVC or who died. A relative increase of 132.5% in the proportion of patients with no decline in FVC was also demonstrated (P <.001). There was also a reduction in decline in 6-minute walk distance (P = .04) and improved progression-free survival in patients treated with pirfenidone (P <.001) (Figure 18). Mortality or dyspnea scores did not differ between the 2 treatment cohorts, although patients who received pirfenidone experienced more treatment-related AEs, which was consistent with the previous trials.7,8

Further Analyses

Multiple other analyses have been performed on the efficacy and safety of pirfenidone in continued therapy using the data from these landmark clinical trials. One study by Nathan et al assessed a patient population who experienced meaningful disease progression during treatment with pirfenidone. This analysis focused on the rate of disease progression variability and examined the effect of continued treatment with pirfenidone in this treated patient population. This study assessed the patients from the CAPACITY and ASCEND trials, who suffered a ≥10% decline in FVC in the first 6 months after randomization, and then compared the proportion of these patients in the treatment and placebo cohort who experienced a further 10% FVC decline or death in the next 6 months. After 6 months of therapy, 34 patients (5.5%) who received pirfenidone and 68 (10.9%) who received placebo experienced a ≥10% FVC decline (P <.001). But during the following 6 months, fewer patients in the pirfenidone cohort versus those who received placebo experienced a 10% FVC decline or death (5.9% vs 27.9%, respectively; P = .009). Interestingly, most of this difference was driven by mortality, with 1 death in the treatment cohort (2.9%) versus 14 (20.6%) in the placebo group. These findings suggest a potential benefit to continued pirfenidone treatment in patients who experience disease progression during therapy. An additional finding from this study was a weak negative correlation between FVC changes during consecutive 6-month intervals in patients who received placebo, indicating substantial variability. This high intersubject and intrasubject variability in the disease progression rate emphasized the inability to reliably assess therapeutic response simply based on serial trends in FVC.9

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