KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa

R. Jain, V. V. Beckett, M. W. Konstan, F. J. Accurso, J. L. Burns, N. Mayer-Hamblett, Carlos Milla, D. R. VanDevanter, J. F. Chmiel

Research output: Contribution to journalArticle

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Abstract

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 ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p =0.003). Mean changes from baseline in log10 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 FEV1 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.

Original languageEnglish (US)
JournalJournal of Cystic Fibrosis
DOIs
StateAccepted/In press - Jan 1 2017

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Cystic Fibrosis
Pseudomonas aeruginosa
Anti-Inflammatory Agents
Placebos
Sputum
Anti-Bacterial Agents
Interleukin-8
Respiratory Signs and Symptoms
Immunoglobulin Fragments
Leukocyte Elastase
Spirometry
Kaplan-Meier Estimate
Random Allocation
Pneumonia
Monoclonal Antibodies
Safety
Liver
Enzymes
Infection
Proteins

Keywords

  • Anti-inflammatory
  • Cystic fibrosis
  • Pseudomonas aeruginosa infection
  • Type III secretion system

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Pulmonary and Respiratory Medicine

Cite this

KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa. / Jain, R.; Beckett, V. V.; Konstan, M. W.; Accurso, F. J.; Burns, J. L.; Mayer-Hamblett, N.; Milla, Carlos; VanDevanter, D. R.; Chmiel, J. F.

In: Journal of Cystic Fibrosis, 01.01.2017.

Research output: Contribution to journalArticle

Jain, R. ; Beckett, V. V. ; Konstan, M. W. ; Accurso, F. J. ; Burns, J. L. ; Mayer-Hamblett, N. ; Milla, Carlos ; VanDevanter, D. R. ; Chmiel, J. F. / KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa. In: Journal of Cystic Fibrosis. 2017.
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title = "KB001-A, a novel anti-inflammatory, found to be safe and well-tolerated in cystic fibrosis patients infected with Pseudomonas aeruginosa",
abstract = "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 ppFEV1 from placebo favoring KB001-A was observed at week 16 (95{\%} CI: 1.12, 5.30, p =0.003). Mean changes from baseline in log10 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 FEV1 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.",
keywords = "Anti-inflammatory, Cystic fibrosis, Pseudomonas aeruginosa infection, Type III secretion system",
author = "R. Jain and Beckett, {V. V.} and Konstan, {M. W.} and Accurso, {F. J.} and Burns, {J. L.} and N. Mayer-Hamblett and Carlos Milla and VanDevanter, {D. R.} and Chmiel, {J. F.}",
year = "2017",
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language = "English (US)",
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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.

PY - 2017/1/1

Y1 - 2017/1/1

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 ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p =0.003). Mean changes from baseline in log10 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 FEV1 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 ppFEV1 from placebo favoring KB001-A was observed at week 16 (95% CI: 1.12, 5.30, p =0.003). Mean changes from baseline in log10 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 FEV1 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

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SN - 1569-1993

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