View Abstract

A7785 - Randomized, Double-Blind, Placebo-Controlled, Multiple Dose, Dose-Escalation Study of BG00011 (Formerly STX-100) in Patients with Idiopathic Pulmonary Fibrosis (IPF)
Author Block: G. Raghu1, M. Mouded2, D. A. Culver3, M. J. Hamblin4, J. A. Golden5, S. Veeraraghavan6, R. I. Enelow7, L. H. Lancaster8, H. J. Goldberg9, A. E. Frost10, L. C. Ginns11, B. J. Maroni2, D. Sheppard5, N. Kaminski12, I. O. Rosas13, M. Arjomandi5, A. Prasse14, C. Stebbins2, G. Zhao2, G. Song2, M. Arefayene2, R. Christmann de Souza15, S. M. Violette2, D. C. Gallagher16, K. F. Gibson17; 1Univ of Washington Medical Ctr, Seattle, WA, United States, 2Biogen, Cambridge, MA, United States, 3Cleveland Clinic, Cleveland, OH, United States, 4University of Kansas, Kansas City, KS, United States, 5University of California San Francisco, San Francisco, CA, United States, 6Emory University School of Medicine, Atlanta, GA, United States, 7Medicine, Micro/Immunol, Dartmouth School of Medicine, Lebanon, NH, United States, 8Vanderbilt University, Nashville, TN, United States, 9Brigham and Women's Hospital, Boston, MA, United States, 10Baylor College of Medicine, Houston, TX, United States, 11Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston, MA, United States, 12Department of Medicine, Yale School of Medicine, New Haven, CT, United States, 13Brighams Women's Hospital, Boston, MA, United States, 14Pneumology, Medical School of Hannover, Hannover, Germany, 15Biogen, Cambridge, WA, United States, 16Biogen, Boston, MA, United States, 17Univiversity of Pittsburgh School of Medicine, Pittsburgh, PA, United States.
Background: αvβ6 is upregulated on alveolar epithelial cells in IPF patients and drives local activation of TGF-β and fibrosis. BG00011 is a first in class, humanized anti-αvβ6 IgG1 monoclonal antibody. Data from primates receiving BG00011 demonstrated a dose responsive decrease in active TGF-β signaling as evidenced by marked reduction in gene expression and pSMAD2 in bronchoalveolar lavage (BAL) cells between the 0.3 mg/kg and 1 mg/kg doses. Near-maximal pSMAD2 inhibition of 70% was detected at 1 mg/kg, a dose which previously demonstrated robust anti-fibrotic activity in multiple disease models. A phase 2A study with BG00011 was conducted in patients with IPF to evaluate safety, tolerability and exposure response of TGF-β suppression.
Methods: A phase 2A randomized, placebo controlled, dose-escalating trial was conducted in IPF patients with mild to moderate impairment on pulmonary function testing. Subjects were dosed weekly for eight weeks with subcutaneous (s/c) BG00011 or placebo in 5 cohorts ranging from 0.015 to 3 mg/kg (8 patients per cohort; randomized 6 active: 2 placebo). Safety and pharmacokinetics were assessed throughout dosing and follow up. BAL cells isolated before and after treatment were evaluated for changes in pSMAD2 and 7 pre-specified genes. A dose-response relationship was generated using the percent change from baseline of pSMAD2 and the prespecified genes. An exposure response relationship was generated using BG00011 AUC at steady state (AUCss) and the percent change from the baseline of pSMAD2.
Results: Forty-one IPF patients were dosed with either BG00011 (n=31) or placebo (n= 10). Twenty-seven patients who received BG00011 (87%) and 7 patients who received placebo (70%) reported a treatment emergent adverse event (TEAE). Eight serious AEs were reported in 4 patients dosed with BG00011 and were assessed as not related to study treatment. Dosing was stopped in the 3mg/ kg cohort based on prespecified stopping criteria. Patients treated with ≥ 0.3 mg/kg BG00011 showed significant inhibition of BAL pSMAD2 levels. A near-maximal inhibition of 70% was detected at 1 mg/kg with additional changes in gene expression noted (figure 1). The drug exposure levels and steep biomarker dose-response replicated the results of the pre-clinical primate studies.
Conclusions: The Ph2A study demonstrated a decrease in active TGF-β signaling as evidenced by dose dependent reductions in pSMAD 2 and gene expression in BAL cells from patients. The combined safety, tolerability and exposure response data enabled dose selection for the upcoming 52 week global Ph2B study of BG00011 in patients with IPF.