Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis. IPF appears to be heterogeneous in pathobiology with ∼40% of IPF patients found to have elevated levels of circulating antibodies to the autoantigen type V collagen (col(V)). Following a targeted, precision medicine approach, we conducted a phase 1 study to test the safety and explore potential efficacy of IW001, a col(V) oral immunotherapeutic developed to treat antibody-positive IPF patients. We divided 30 antibody-positive IPF patients into three cohorts for daily dosing over a 24-week period. All patients completed treatment without serious adverse events, acute exacerbations or IPF-related hospitalisations. A decline in lung function occurred in the lowest-dose cohort that was comparable to that reported in placebo arms of published IPF trials. In contrast, the highest-dose cohort showed a trend toward stabilisation of forced vital capacity and matrix metalloproteinase 7, and a reduction in binding of C1q to anti-col(V) antibodies. IW001 may modulate the immune response to col(V) and may represent a new therapeutic for col(V)- reactive IPF patients.

RationaleIdiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease characterized by progressive scarring and matrix deposition. Recent reports highlight an autoimmune component in IPF pathogenesis. We have reported anti-col(V) immunity in IPF patients. The objective of our study was to determine the specificity of col(V) expression profile and anti-col(V) immunity relative to col(I) in clinical IPF and the efficacy of nebulized col(V) in pre-clinical IPF models.MethodsCol(V) and col(I) expression profile was analyzed in normal human and IPF tissues. C57-BL6 mice were intratracheally instilled with bleomycin (0.025 U) followed by col(V) nebulization at pre-/post-fibrotic stage and analyzed for systemic and local responses.ResultsCompared to normal lungs, IPF lungs had higher protein and transcript expression of the alpha 1 chain of col(V) and col(I). Systemic anti-col(V) antibody concentrations, but not of anti-col(I), were higher in IPF patients. Nebulized col(V), but not col(I), prevented bleomycin-induced fibrosis, collagen deposition, and myofibroblast differentiation. Col(V) treatment suppressed systemic levels of anti-col(V) antibodies, IL-6 and TNF-α; and local Il-17a transcripts. Compared to controls, nebulized col(V)-induced tolerance abrogated antigen-specific proliferation in mediastinal lymphocytes and production of IL-17A, IL-6, TNF-α and IFN-γ. In a clinically relevant established fibrosis model, nebulized col(V) decreased collagen deposition. mRNA array revealed downregulation of genes specific to fibrosis (Tgf-β, Il-1β, Pdgfb), matrix (Acta2, Col1a2, Col3a1, Lox, Itgb1/6, Itga2/3) and members of the TGF-β superfamily (Tgfbr1/2, Smad2/3, Ltbp1, Serpine1, Nfkb/Sp1/Cebpb).ConclusionsAnti-col(V) immunity is pathogenic in IPF, and col(V)-induced tolerance abrogates bleomycin-induced fibrogenesis and down regulates TGF- β-related signaling pathways.

Purpose IW001, an oral solution of Type V collagen (col(V)), is a therapeutic agent in clinical development for IPF by ImmuneWorks. ImmuneWorks scientists believe that lung injury might result in the exposure of a normally hidden protein to the immune system, such as col(V). The immune system may recognize this sequestered protein as foreign, initiating an autoimmune cascade, resulting in an attack on the lung. As the autoimmune response expands, a fibrotic response would follow in an attempt to heal the lung. Lung transplantation is the only viable treatment that has shown survival benefit for IPF patients but the survival benefit is still complicated by significant early mortality rates, especially within the first year. High incidence of col(V) autoreactivity was found with IPF patients and associated with a higher incidence of PGD. Pre-clinical studies showed that col(V)-induced immune tolerance abrogated acute rejection in a rat lung transplant model. Methods and Materials ImmuneWorks conducted an open label, multicenter, Phase I clinical trial in IPF patients who tested positive for anti-col(V) antibodies. Study was designed to evaluate the safety, tolerability, and biological/clinical effects of a three doses (0.1mg, 0.5mg, 1.0mg) of IW001, when administered once daily orally for 24 weeks. Results About 40% of IPF patients screened for this study tested positive for anti-Col(V) IgG. A total of 30 IPF patients were enrolled in one of three IW001 dose treatment groups. Absolute changes in %FVC pred from baseline to week 24 were determined and showed a trend toward the stabilization of the lung function with IW001 doses at both 0.5mg and 1.0mg/day. Additional biomarkers will be discussed. Conclusions Our phase I results have demonstrated that IW001 is safe and well tolerated with no unexpected adverse events. IW001 may lead to a possible stabilization of lung function, underscoring the potential of col(V)-induced tolerance to be an effective therapeutic strategy in IPF.

Purpose IW001, an oral solution of Type V collagen (col(V)), is a therapeutic agent in clinical development for IPF by ImmuneWorks. ImmuneWorks scientists believe that lung injury might result in the exposure of a normally hidden protein to the immune system, such as col(V). The immune system may recognize this sequestered protein as foreign, initiating an autoimmune cascade, resulting in an attack on the lung. As the autoimmune response expands, a fibrotic response would follow in an attempt to heal the lung. Lung transplantation is the only viable treatment that has shown survival benefit for IPF patients but the survival benefit is still complicated by significant early mortality rates, especially within the first year. High incidence of col(V) autoreactivity was found with IPF patients and associated with a higher incidence of PGD. Pre-clinical studies showed that col(V)-induced immune tolerance abrogated acute rejection in a rat lung transplant model. Methods and Materials ImmuneWorks conducted an open label, multicenter, Phase I clinical trial in IPF patients who tested positive for anti-col(V) antibodies. Study was designed to evaluate the safety, tolerability, and biological/clinical effects of a three doses (0.1mg, 0.5mg, 1.0mg) of IW001, when administered once daily orally for 24 weeks. Results About 40% of IPF patients screened for this study tested positive for anti-Col(V) IgG. A total of 30 IPF patients were enrolled in one of three IW001 dose treatment groups. Absolute changes in %FVC pred from baseline to week 24 were determined and showed a trend toward the stabilization of the lung function with IW001 doses at both 0.5mg and 1.0mg/day. Additional biomarkers will be discussed. Conclusions Our phase I results have demonstrated that IW001 is safe and well tolerated with no unexpected adverse events. IW001 may lead to a possible stabilization of lung function, underscoring the potential of col(V)-induced tolerance to be an effective therapeutic strategy in IPF.