A Cost-Effectiveness Analysis of Nintedanib in Idiopathic Pulmonary Fibrosis in the UK.

BACKGROUND: International guidelines recommend nintedanib (OFEV®) as an option for the treatment of idiopathic pulmonary fibrosis (IPF). OBJECTIVE: The objective of this study was to assess the cost effectiveness of nintedanib versus pirfenidone, N-acetylcysteine and best supportive care (BSC) for the treatment of IPF from a UK payer's perspective. METHODS: A Markov model was designed to capture the changes in the condition of adults with IPF. Efficacy outcomes included mortality, lung function decline and acute exacerbations. Treatment safety (serious adverse events) and tolerability (overall discontinuation) were also considered. The baseline risk of these events was derived from patient-level data from the placebo arms of nintedanib clinical trials (TOMORROW, INPULSIS-1, INPULSIS-2). A network meta-analysis (NMA) was conducted to estimate the relative effectiveness of the comparator treatments. Quality of life and healthcare resource use data from the clinical trials were also incorporated in the economic model. RESULTS: Nintedanib showed statistically significant differences against placebo on acute exacerbation events avoided and lung function decline. In the cost-effectiveness analysis, the results were split between two treatments with relative low costs and modest effectiveness (BSC and N-acetylcysteine) and two that showed improved effectiveness (lung function) and higher costs (nintedanib and pirfenidone). All comparators were assumed to have similar projected survival and the difference in quality-adjusted life-years (QALYs) was driven by the acute exacerbations and lung function estimates. In the base-case deterministic pairwise comparison with pirfenidone, nintedanib was found to have fewer acute exacerbations and resulted in less costs and more QALYs gained. CONCLUSIONS: Compared with BSC (placebo), nintedanib and pirfenidone were the only treatments to show statistical significance in the efficacy parameters. We found substantial uncertainty in the overall cost-effectiveness results between nintedanib and pirfenidone. N-Acetylcysteine was largely similar to BSC but with a worse survival profile. INPULSIS-1 and INPULSIS-2 ClinicalTrials.gov numbers, NCT01335464 and NCT01335477.

Nintedanib in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) conveys a median survival of 3 years and until recently has lacked effective therapies. Nintedanib, an orally available, small-molecule tyrosine kinase inhibitor with selectivity for vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) receptors has recently been shown, in two pivotal phase III studies, to effectively slow IPF disease progression. Consequently, nintedanib was given accelerated approval by the FDA in October 2014 for the treatment of IPF. This monograph explores the preclinical rationale for the antifibrotic role of nintedanib and provides an overview of the available data on pharmacokinetics, efficacy and safety.

Idiopathic pulmonary fibrosis: Recent advances on pharmacological therapy.

Idiopathic pulmonary fibrosis (IPF) is the most common and lethal of the idiopathic interstitial pneumonias with an estimated 5-year survival of approximately 20%. In the last two decades our understanding of disease pathogenesis has substantially evolved and novel compounds have been developed consequent to the increasing knowledge of the mechanisms underlying disease pathobiology. The disease appears to be driven - following chronic injury - by abnormal/dysfunctional alveolar epithelial cells that promote fibroblast recruitment and proliferation, resulting in scarring of the lung and irreversible loss of function. With very few exceptions, clinical trials evaluating novel potential therapies have provided disappointing results. More recently, pirfenidone and nintedanib, two compounds with pleiotropic mechanisms of action, have proven effective in slowing functional decline and disease progression in IPF patients with mild to moderate functional impairment, highlighting the importance of timely diagnosis and administration of treatment in early stages of disease. However, due to the complexity and uncertainties intrinsic to IPF, it is essential that each therapeutic strategy be tailored to the individual patient, after evaluation of potential benefits and risks. This article provides an overview of the most recent clinical trials in IPF and discusses how their results are going to change the clinical and clinical research landscape in IPF. A number of agents with high potential are currently being tested and many more are ready for clinical trials. Their completion is critical for achieving the ultimate goal of curing patients with IPF.

Significance of connective tissue disease features in idiopathic interstitial pneumonia.

In idiopathic interstitial pneumonia (IIP), the significance of connective tissue disease (CTD) features in the absence of a specific CTD diagnosis remains unclear. We studied the clinical and prognostic utility of a diagnosis of undifferentiated CTD (UCTD) in patients with biopsy-proven IIP. IIP patients undergoing surgical lung biopsy (1979-2005) were studied (nonspecific interstitial pneumonia (NSIP), n = 45; idiopathic pulmonary fibrosis, n = 56). UCTD was considered present when serum autoantibodies were present and symptoms or signs suggested CTD. The relationship between UCTD and NSIP histology was evaluated. A clinical algorithm that best predicted NSIP histology was constructed using a priori variables. The prognostic utility of UCTD, and of this algorithm, was evaluated. UCTD was present in 14 (31%) NSIP and seven (13%) IPF patients. UCTD was not associated with a survival benefit. The algorithm predictive of NSIP (OR 10.4, 95% CI 3.21-33.67; p<0.0001) consisted of the absence of typical high-resolution computed tomography (HRCT) features for IPF and 1) a compatible demographic profile (females aged <50 yrs) or 2) Raynaud's phenomenon. In patients with an HRCT scan not typical for IPF, this algorithm predicted improved survival (hazard ratio 0.35, 95% CI 0.14-0.85; p = 0.02) independent of IIP severity. UCTD is associated with NSIP histology. However, the diagnostic and prognostic significance of UCTD in IIP patients remains unclear.

Pirfenidone in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a dismal prognosis for which, until recently, there were no effective treatments. Pirfenidone (5-methyl-1-phenylpyridin-2[1H]-one) is a novel antifibrotic agent that has been demonstrated to slow disease progression in patients with IPF. In vitro and in vivo animal models of pulmonary fibrosis have shown that pirfenidone exerts its effect by reducing inflammatory cytokines such as TNF-α, by downregulating the transcription of key profibrotic growth factors including TGF-ß, and through reductions in lipid peroxidation and oxidative stress. In three of four multicenter, randomized, placebo-controlled trials in patients with IPF, pirfenidone has been shown to slow disease progression as measured by decline in forced vital capacity over 36-72 weeks. In general, in these clinical trials, pirfenidone was safe and well tolerated. Reported adverse effects include nausea, anorexia and photosensitivity dermatitis. A number of questions remain concerning the long-term efficacy and safety of pirfenidone and whether slowing of lung function decline will translate into improved survival for patients with IPF. These questions notwithstanding, pirfenidone represents an important development in the treatment of IPF and is a much needed addition to the previously inadequate therapeutic armamentarium for this devastating disease.

Idiopathic pulmonary fibrosis: multiple causes and multiple mechanisms?

Idiopathic pulmonary fibrosis (IPF) is a devastating condition that carries a prognosis worse than that of many cancers. A recent classification of the idiopathic interstitial pneumonias has redefined the diagnostic criteria necessary to determine a diagnosis of IPF. The present authors believe that this redefinition is incorrect, relying as it does on subtle histological differences for the definition of separate disease categories. A further issue affecting IPF research is the polarisation of views around two competing pathogenetic hypotheses. One argues for the primacy of inflammation as the trigger that initiates fibrosis, and the other proposes that fibrosis arises as a consequence of chronic epithelial injury and failure of repair due to aberrant epithelial-mesenchymal interactions. The present authors believe that this schism is hampering understanding of IPF and skewing research priorities. It is argued here, instead, that abnormalities in multiple pathways involved in wound healing and inflammation lead to the development of idiopathic pulmonary fibrosis, and it is suggested that a new rationale for clinical classification and pathogenesis may be more productive in driving the search for novel therapies in the future.

Vascular density does not predict future metastatic disease in clinical stage 1 non-seminomatous germ cell tumours of the testis.

AIM: This study aimed to determine whether patients with stage 1 testicular non seminomatous germ cell tumours (NSGCT) with high vascular density have a greater risk of disease recurrence than those with a low vascular density. METHODS AND RESULTS: Orchidectomy specimens from 42 patients with stage 1 NSGCT, treated by orchidectomy and surveillance alone, were studied. Vessel density was counted in tumour sections immunohistochemically stained for CD34. The mean of the three highest counts (x250, field size 0.67 mm2) for each tumour was used. Tumour vessel density was very similar for relapsing and non relapsing patients. Vascular invasion was the only variable significantly predictive of disease recurrence at 2 years post-orchidectomy (P = 0.025). There was wide variation of vessel counts between different blocks of a tumour, compared with interobserver variation. The tumour tissue type in the area of highest vessel density was embryonal carcinoma in 50% and teratoma (mature or immature) in 38%. CONCLUSIONS: We confirmed the value of vascular invasion as a prognostic marker in stage 1 NSGCT. Tumour vessel density was of no prognostic value. Two factors may contribute to this. First, there was wide variation of vessel density between different blocks of a tumour. Second, the most vascular area in a tumour was frequently in low-grade tumour.