BIBF 1120 for IPF

BIBF 1120 is developed  by Boehringer Ingelheim. It is a tyrosine kinase inhibitor targeting multiple tyrosine kinase receptors including platelet-derived growth factor receptors (PDGFR) α and β, vascular endothelial growth factor receptors
(VEGFR) 1, 2, and 3, and fibroblast growth factor receptors (FGFR) 1, 2, and 3.

A recent 12-month, randomized, double-blind, placebo-controlled, phase 2 trial (To Improve Pulmonary Fibrosis with BIBF 1120 [TOMORROW]) with 4 doses (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) may have some positive effect (N = 428 patients). Although highest dose was associated with significant side effects, 150 mg twice a day was associated with a trend toward a reduction in the decline in lung function, with fewer acute exacerbations and preserved quality of life. Although the differences in primary end point among the study groups were not statistically significant, the benefits observed in the study were indeed clinically relevant.

It is encouraging that the trial was, at least, not another failed IPF trial, compared to others (pirfenidone, systemic glucocorticoids, azathioprine and cyclophosphamide, interferon-γ-1b, phosphodiesterase-5 inhibitors, or endothelin receptor antagonists).

I do hope that phase III trial gives more positive news. Since lower doses did not show much, I would guess that next  trial uses highest dose, 150 mg b.i.d.

References:
Richeldi L, et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med. 2011 Sep 22;365(12):1079-87. PubMed PMID: 21992121.
NEJM link: http://www.nejm.org/doi/full/10.1056/NEJMoa1103690.


Downey GP. Resolving the scar of pulmonary fibrosis. N Engl J Med. 2011 Sep
22;365(12):1140-1. PubMed PMID: 21992127.
NEJM link: http://www.nejm.org/doi/full/10.1056/NEJMe1108558.

FoxO3a and Lung Fibrosis

Dr. Henke and associates recent suggested that FoxO3a is largely inactive in IPF fibroblasts to promote IPF fibroblast proliferation. They previously demonstrated that lower Pten activity in IPF fibroblasts, higher PI3K-AKT activity on collagen matrix. In this study, the authors showed that phosphorylated, inactive, FoxO3 is higher, whereas total FoxO3 is lower, in IPF fibroblasts on collagen. They went on to show that p27 was lower in IPF.  They proposed model: 

Reference:
Nho RS, Hergert P, Kahm J, Jessurun J, Henke C. Pathological Alteration of
FoxO3a Activity Promotes Idiopathic Pulmonary Fibrosis Fibroblast Proliferation
on Type I Collagen Matrix. Am J Pathol. 2011 Sep 3. [Epub ahead of print] PubMed PMID: 21893017.

Human Lung Stem Cells?

Recently, Dr. Piero Anversa of Brigham and Women’s reported identification of human lung stem cells, appeared in May 12, 2011, issue of New England Journal of Medicine. The flow cytometric identification was based on c-kit antigen. The authors showed that the stem cells isolated were clonal and pluripotent. c-kit+ cells expressed KLF4, nanog,, oct4, and sox2. In a cryo injury mouse model, the authors showed that c-kit+  cells were, amazingly, able to promote lung regeneration!

In an editorial, Dr. Chapman of UCSF stated that "Kajstura et al. resets the starting point for clinical investigation into the role of stem cells and progenitor cells in lung disease". 

However, several scientists in the field were more skeptical. In Nature Medicine Community Corner, Dr. Stripp and Dr. Hogan of Duke questioned the experimental methodology (eg, RT-PCR and antibody staining) and proper controls.  They urged that more vigorous validation is needed. More importantly, the c-kit-CreER mice is needed to trace if the c-kit+ cells in the LUNG are pluripotent, hierarchical differentiation. Dr. Thannickal of UAB also suggested “The phenotype and fate of endogenous lung stem cells and associated alterations of their tissue niche in disease states will need to be characterized.” He also questioned if there is any deficiency in c-kit+ cells in COPD or IPF. In a reply, Dr. Anversa sounded very angry implying that the comments by Drs. Hogan and Stripp were "border on personal attacks".

Dr. Anversa's early work "Bone marrow cells regenerate infarcted myocardium" published in Nature 2001, stated that Lin- c-kit+ bone marrow cells were able to generate myocardium de novo. Dr. Weissman demonstrated that BM hematopoietic stem cells (KTLS) robustly reconstituted peripheral blood leukocytes, but did not contribute appreciably to any nonhematopoietic tissues, indicating that "transdifferentiation" of circulating HSCs and/or their progeny is an extremely rare event, if it occurs at all. 

References

Kajstura J, Rota M, Hall SR, Hosoda T, D'Amario D, Sanada F, Zheng H, Ogórek B, Rondon-Clavo C, Ferreira-Martins J, Matsuda A, Arranto C, Goichberg P, Giordano G, Haley KJ, Bardelli S, Rayatzadeh H, Liu X, Quaini F, Liao R, Leri A, Perrella MA, Loscalzo J, Anversa P. Evidence for human lung stem cells. N Engl J Med. 2011 May 12;364(19):1795-806. PubMed PMID: 21561345.

Chapman HA. Toward lung regeneration. N Engl J Med. 2011 May
12;364(19):1867-8. PubMed PMID: 21561353.

Hogan, B., Stripp, B. & Thannickal, V.J. Lung stem cells: looking beyond the hype. Nat Med. 2011 Jul 7;17(7):788-9. doi: 10.1038/nm0711-788. PubMed PMID: 21738157.

Anversa P, Kajstura J, Leri A, Loscalzo J. Tissue-specific adult stem cells in the human lung. Nat Med. 2011 Sep 7;17(9):1038-9. doi: 10.1038/nm.2463. PubMed PMID: 21900912.

Orlic D, Kajstura J, Chimenti S, Jakoniuk I, Anderson SM, Li B, Pickel J,
McKay R, Nadal-Ginard B, Bodine DM, Leri A, Anversa P. Bone marrow cells regenerate infarcted myocardium. Nature. 2001 Apr 5;410(6829):701-5. PubMed PMID:11287958. 

Wagers AJ, Sherwood RI, Christensen JL, Weissman IL. Little evidence for developmental plasticity of adult hematopoietic stem cells. Science. 2002 Sep 27;297(5590):2256-9. Epub 2002 Sep 5. PubMed PMID: 12215650.