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regulatory WatCH designed,” he says. “Since the clinical syndrome of IPF may result from the activation of First drug for idiopathic pulmonary different biological pathways, identification of patients most likely to benefit from targeting approved in Japan these pathways may allow for the development of more effective, patient-specific drug Shionogi and InterMune have announced the decline in lung function, and in this context, therapies. Identification of patients with early marketing approval of pirfenidone (Pirespa) the Shionogi findings, as yet unpublished disease and of biomarkers that reliably predict for the treatment of idiopathic pulmonary in a peer-reviewed journal, may represent a meaningful clinical end points represent fibrosis (IPF) in Japan, making it the first significant breakthrough.” additional future challenges.” approved therapy for IPF in a major market. Oxidative stress is also implicated in IPF, InterMune have also released a progress Shionogi developed pirfenidone in Japan and and like N-acetyl cysteine — which slowed report on the CAPACITY trials (http://www. has rights in Japan, Taiwan and South Korea, the rate of lung function decline when added capacitytrials.com/wt/page/index). So far, and InterMune is currently conducting a to a traditional patient visits at week 72 of the trial, at which Phase III programme known as CAPACITY regimen in a Phase III trial (N. Engl. J. Med. the primary end point forced VC is measured, to support approval in other markets. 353, 2229–2242; 2005) — pirfenidone has have been completed for 97% of enrolled IPF is characterized by worsening anti-oxidant activity, notes Victor Thannickal, patients. “If the CAPACITY studies produce pulmonary function, dyspnoea and cough. University of Michigan Medical Centre, similar findings to that of the Shionogi studies, The precise aetiology of IPF is unknown, USA. “It is intriguing that two different this will be good news for patients with IPF,” but lung injury and excessive pulmonary small molecules with anti-oxidant activity says du Bois. InterMune is hoping to announce deposition of fibrotic tissue have a key role in have shown the greatest promise so far in top-line results early next year, and if data are disease pathogenesis. There are presently no the treatment of IPF, and hopefully, more positive, is on track for submission of a new drugs approved specifically for IPF by the FDA effective anti-oxidant strategies for IPF will be drug application to the FDA in mid-2009. or the EMEA, and standard therapy based on corticosteroids and immunosuppressants has Table 1 | Current development status of therapies for idiopathic * shown only very limited benefit in reducing Drug (company) Properties Development status disease progression in patients with IPF. PRX-08066 (EPIX Pharmaceuticals) 5-HT receptor antagonist Discovery However, several types of novel 2B therapies are being investigated (Curr. Opin. Cintredekin besudotox Chimeric human IL13 conjugated Discovery Pharmacol. 6, 284–292; 2006), including (NeoPharm)‡ to a genetically engineered anti-inflammatory agents, antifibrotics and Pseudomonas exotoxin immune modulators (Table 1). Pirfenidone Roflumilast (Nycomed)§ PDE4 inhibitor Preclinical seems capable of tackling some IPF FG-3019 (Fibrogen) Anti-connective tissue growth Phase I characteristics through inhibition of factor human mAb synthesis, downregulation of profibrotic GC-1008 (Genzyme/MedImmune) TGF-β human mAb Phase I cytokine production and blockade of fibroblast Treprostinil (United Therapeutics/ Prostacyclin analogue Phase I proliferation. Importantly, pirfenidone met the Aradigm) primary end point of reducing decline in vital BIBF-1120 (Boehringer Ingelheim) VEGF, FGF and PDGF receptor Phase II capacity (VC) in Shionogi’s Phase III trials. inhibitor “The key challenges in drug development Phase II for IPF are to identify agents that will reverse -α (Amarillo Biosciences) Interferon-α ligand the fibrosing disease process and are safe Tetrathiomolybdate (Adeona Copper chelating agent Phase II || to use,” says Ron du Bois, National Jewish Pharmaceuticals) Health, Denver, Colorado, USA, who is also QAX-576 (Novartis) IL13 modulator Phase II a co-chair for the CAPACITY trials steering *Information was obtained from the Investigational Drugs Database from Thompson Reuters. committee. “But, until these drugs are found, ‡Under license from the National Institutes of Health. §Acquired ALTANA Pharma in 2006. ||Under license from the University of Michigan, USA. 5-HT2B, 5-hydroxytryptamine 2B; FGF, fibroblast ; novel treatments are not expected to achieve IL13, interleukin 13; mAb, monoclonal ; PDE4, phosphodiesterase 4; PDGF, platelet-derived much more than improving the rate of growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor.

NATURE REVIEwS | Drug Discovery VOlUME 7 | DECEMBER 2008