The 264-patient study, called PANTHER-IPF, began in December 2009 as a randomized, double-blind trial to assess whether the combination of the drugs NAC, prednisone and azathioprine could slow disease progression and improve lung function in patients with mild to moderate IPF. Previously published guidelines on the management of IPF sponsored by the joint American Thoracic and European Respiratory Societies (AJRCCM 2000) had recommended treatment with prednisone, a corticosteroid, plus azathioprine, an immunosuppressant, for patients with IPF. The recommendations were based on the consensus of an expert panel and not on information from a randomized clinical trial. In PANTHER-IPF, patients were assigned to one of three study arms, where they received either the three-treatment combination or a placebo substitute; NAC alone; or placebo.

The National Heart, Lung, and Blood Institute, which funded the study, stopped the triple-therapy arm in October 2011 because of safety concerns. The study resumed in January 2012 comparing NAC alone against a placebo.

The investigators are reporting on that phase now. They found no significant difference between the treatment groups in reduction in lung function impairment over 60 weeks, as measured by a person's capacity to exhale with force after inhaling as deeply as possible—a measurement known as forced vital capacity. In addition, a subgroup analysis showed no difference between patients who took NAC alone before the original trial stopped and those who took NAC in the revised, two-arm trial. Overall, NAC was associated with more cardiac events and fewer gastrointestinal events compared to placebo.

Boehringer Ingelheim today announced that the European Medicines Agency (EMA) has accepted an accelerated marketing authorisation application for the review of nintedanib*, an investigational tyrosine kinase inhibitor (TKI) for the treatment of idiopathic pulmonary fibrosis (IPF).[2] The acceptance of this marketing authorisation application marks the beginning of the review process in the European Union for this potential new treatment.

. . . . .

The marketing authorisation application for nintedanib* included results from two Phase III trials with identical design, INPULSIS(TM)-1 and INPULSIS(TM)-2, which showed that nintedanib* significantly slowed disease progression in patients with IPF (p<0.001).[1] Data from the two 52-week trials, recently published in the New England Journal of Medicine, demonstrate that nintedanib* met the primary endpoint by significantly reducing the annual decline in forced vital capacity by approximately 50% compared to patients taking placebo.[1]

Nintedanib*, taken as one capsule twice daily, is the first targeted treatment for IPF that has consistently demonstrated the ability to slow disease progression by significantly reducing decline in lung function (p<0.001) with a manageable side effect profile.[1]

The Company is pleased to present the results of its pre-clinical studies of PTL-202. PTL-202 and its separate constituents were tested in 5 experiments in a recognized mouse model of pulmonary fibrosis. These studies provided the data required for the recently granted European patent covering the proprietary technology utilized in PTL-202.

In order to support the use of PTL-202 for fibrosis treatment, we have conducted proof-of-concept animal studies to evaluate the relative efficacy of stand-alone or combination treatments in a standard animal model of pulmonary fibrosis induced by bleomycin. These studies strongly suggest that more than a single pathway is responsible for the therapeutic activities of the components of PTL-202, but it is likely that these 2 molecules exert potent antifibrogenic effect by affecting a complex network of pro-fibrosis cytokines such as TNF-alpha and TGF-beta1, proliferation of fibroblasts and synthesis of the extracellular matrix (ECM) components.

Analysis of the pathology of the lungs from the mice showed that the combination significantly reduced the damage to the lungs whereas the separate components did not. In addition the combination significantly improved lung weight in the mice whereas the separate components did not.

To quantify lung collagen content as an indicator of pulmonary fibrosis, the hydroxyproline content in the lung was measured. In the fibrotic stage of the fibrosis model hydroxyproline was significantly reduced by the combination.

Moreover, we found no deaths or abnormal reactions with a daily administration of PTL-202 during the experiments.

The results suggest PTL-202 is safe and effective agent for the treatment of pulmonary fibrosis.