TY - JOUR
T1 - KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa
AU - Jain, R.
AU - Beckett, V. V.
AU - Konstan, M. W.
AU - Accurso, F. J.
AU - Burns, J. L.
AU - Mayer-Hamblett, N.
AU - Milla, Carlos
AU - VanDevanter, D. R.
AU - Chmiel, J. F.
N1 - Funding Information:
Supported by KaloBios Pharmaceuticals, Inc. and the Cystic Fibrosis Foundation Therapeutics Development Network.
Publisher Copyright:
© 2017 European Cystic Fibrosis Society
PY - 2018/7
Y1 - 2018/7
N2 - Background: Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. Methods: This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10 mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. Results: Of 182 subjects, 169 received at least one infusion of KB001-A (n = 83) or placebo (n = 86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p = 0.995). A 3.2 increase in ppFEV 1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p = 0.003). Mean changes from baseline in log 10 sputum neutrophil elastase (NE) had a non-significant decrease (− 0.27, 95% CI: − 0.58,0.04, p = 0.084) while IL-8 concentrations at week 16 were significantly lower (− 0.27, 95% CI: − 0.55,0.00, p = 0.048) among KB001-A subjects (n = 16) relative to placebo (n = 13). Conclusions: KB001-A was safe and well-tolerated and associated with a modest FEV 1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.
AB - Background: Chronic Pseudomonas aeruginosa (Pa) airways infection, exuberant local inflammation, and progressive lung function loss are hallmarks of cystic fibrosis (CF). KB001-A is an anti-PcrV PEGylated monoclonal antibody fragment to the Type III secretion system of Pa. This 16-week study evaluated KB001-A associated effect on time-to-need for antibiotics for worsening respiratory signs and symptoms, as well as safety, and treatment-associated changes in symptom scores, inflammatory markers, and spirometry. Methods: This was a randomized, double-blind, placebo-controlled, repeat-dose study in CF subjects with Pa. Intravenous 10 mg/kg KB001-A or placebo infusions were administered at baseline and weeks 2, 4, 8, and 16, with a 4-week follow-up. Sputum inflammatory markers were assessed in a sub-study. Time-to-need for antibiotics was compared between groups by Kaplan Meier analysis and Cox proportional hazards modeling adjusting for randomization strata. Results: Of 182 subjects, 169 received at least one infusion of KB001-A (n = 83) or placebo (n = 86). KB001-A was generally safe and well-tolerated as compared to placebo, with no significant emergent adverse effects other than one serious adverse event of elevated hepatic enzymes of unclear etiology. Time to need for antibiotics did not differ between groups (HR: 1.00; 95% CI: 0.69, 1.45, p = 0.995). A 3.2 increase in ppFEV 1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p = 0.003). Mean changes from baseline in log 10 sputum neutrophil elastase (NE) had a non-significant decrease (− 0.27, 95% CI: − 0.58,0.04, p = 0.084) while IL-8 concentrations at week 16 were significantly lower (− 0.27, 95% CI: − 0.55,0.00, p = 0.048) among KB001-A subjects (n = 16) relative to placebo (n = 13). Conclusions: KB001-A was safe and well-tolerated and associated with a modest FEV 1 benefit and reduction in select sputum inflammatory markers (IL-8). KB001-A was not associated with an increased time to need for antibiotics. The lack of efficacy seen with KB001-A may be due, in part, to the low levels of the type III secretion proteins previously reported in sputum of CF patients chronically infected with Pa.
KW - Anti-inflammatory
KW - Cystic fibrosis
KW - Pseudomonas aeruginosa infection
KW - Type III secretion system
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U2 - 10.1016/j.jcf.2017.12.006
DO - 10.1016/j.jcf.2017.12.006
M3 - Article
C2 - 29292092
AN - SCOPUS:85039549283
SN - 1569-1993
VL - 17
SP - 484
EP - 491
JO - Journal of Cystic Fibrosis
JF - Journal of Cystic Fibrosis
IS - 4
ER -