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Effective Asthma Recovery with Once-Daily Mometasone Furoate Administered via Dry Powder Inhaler in Subjects Previously Maintained on Twice Daily Inhaled Corticosteroids
S10 Abstracts
SATURDAY
35
Single-Dose, First-in-Human Study of AMG 317: Pharmacokinetics and Safety in Healthy and Asthmatic Adults M. Vincent1, C. Banfield1, T. Kakkar1, S. Shakib2, R. Schicchitano2, T. C. Cheah1, J. Gerson1; 1Amgen Inc., Thousand Oaks, CA, 2Royal Adelaide Hospital, Adelaide, AUSTRALIA. RATIONALE: The fully human monoclonal antibody AMG 317 is being evaluated in asthma based on its ability to bind to and inhibit IL-4Ra, which is required for IL-4 and IL-13 activity. These cytokines are strongly implicated in the pathogenesis of asthma, mediating such pathologic features as serum IgE production and airway hyperresponsiveness. METHODS: In this double-blind, placebo-controlled study, single IV doses of AMG 317 were administered to 29 healthy adults (10 to 1000 mg) and 6 adults with asthma (300 mg). Single SC doses were administered to 24 healthy adults (100 or 300 mg) and 7 adults with asthma (300 mg). Safety, tolerability, and pharmacokinetic data were obtained. Pharmacodynamic evaluation was performed using an ex-vivo whole-blood assay. RESULTS: No deaths, treatment-related serious adverse events, or study discontinuations due to adverse events were reported. The most frequent adverse events were injection site reactions (SC) and headache/myalgia (IV), occurring at similar rates for AMG 317 and placebo. AMG 317 pharmacokinetics was nonlinear over the dose range 10 to 1000 mg IV and dose-proportional between 100 and 300 mg following IV and SC administration. Overall, the pharmacokinetic profile and exposure were similar between healthy and asthmatic adults. Pharmacodynamic evaluation established inhibition of TARC, eotaxin-3, and MCP-4 production in response to IL-4 and IL-13 stimulation. CONCLUSIONS: AMG 317 was well tolerated when administered as a single IV (up to 1000 mg) or SC (up to 300 mg) dose in healthy adults and adults with asthma. Its pharmacokinetic profile was nonlinear over the dose range studied. Funding: Amgen Inc.
36
Effective Asthma Recovery with Once-Daily Mometasone Furoate Administered via Dry Powder Inhaler in Subjects Previously Maintained on Twice Daily Inhaled Corticosteroids J. P. Karpel1, A. D’Urzo2; 1Beth Thalheim Asthma Center at North Shore-LIJ, New Hyde Park, NY, 2Primary Care Asthma Clinic, Toronto, ON, CANADA. RATIONALE: To evaluate the recovery of lung function and effects on asthma control in response to treatment with mometasone furoate (MF) administered once daily in the evening (QD PM) via dry powder inhaler (DPI) compared with placebo. METHODS: In a double-blind, placebo-controlled study, enrolled patients (12 y) with persistent asthma were previously treated with inhaled corticosteroids (ICSs), mostly given twice daily (BID). After an ICS reduction period, patients were randomized to 12 weeks of double-blind treatment with MF-DPI 200 mg QD PM (n 5 78), 400 mg QD PM (1 inhalation) (n 5 80), 400 mg QD PM (2 inhalations) (n 5 78), 200 mg BID (n 5 81), or placebo (n 5 83). Asthma recovery defined as an increase of FEV1 10% and return of symptom scores, albuterol use, or nocturnal awakenings to screening values or better was a secondary efficacy variable in the study. RESULTS: 400 patients with persistent asthma were randomized to treatment. Patients were partly controlled at screening; most patients (>80%) were randomized upon worsening of asthma symptoms following reduction of previous ICS dosage. The proportions of subjects experiencing asthma recovery ranged from 53% to 69% in the MF-DPI groups and 30% in the placebo group. As many as 65% of patients treated with MFDPI were considered recovered compared to only 24% of those treated with placebo on the basis of improvements in asthma symptom scores to levels at least as low as screening values for the majority of the study period (80% of study weeks). CONCLUSIONS: QD MF-DPI effectively replaces BID ICS therapy in patients with persistent asthma. Funding: Schering-Plough Corporation
J ALLERGY CLIN IMMUNOL FEBRUARY 2008
37
Use of Fluticasone Propionate/Salmeterol In a Single Device is Associated with Higher Controller to Total Asthma Medication Ratios Compared to Inhaled Corticosteroid Therapy W. Yeh1, R. H. Stanford2, D. A. Stempel2; 1University of North Carolina, Chapel Hill, NC, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To determine controller to total asthma medication ratios, a predictive measure of asthma outcomes, in users of fluticasone propionate/salmeterol administered in a single device (FSC) compared to inhaled corticosteroid (ICS) dispensed to a population of patients with asthma. METHODS: A retrospective cross sectional analysis of total asthma medication ratios for asthma patients treated with FSC and ICS was conducted. Subjects were identified from a claims database of >45 US health plans representing 58.5M covered lives from March 1, 2002 to May 31, 2006. Study subjects included those with 12 months of continuous enrollment, with diagnosis of asthma (ICD-9, 493.xx), use of FSC or ICS (not both) in each year of observation and were 4-55 years of age. The ratio was calculated as the number of controller medications divided by the albuterol plus controller medications dispensed and were evaluated by season. An overall seasonally weighted mean ratio was then calculated. Bivariate analysis was used to determine differences in the mean ratios and proportion of subjects with ratios 0.5 across cohorts. RESULTS: The mean controller to total asthma medication ratio was significantly higher for FSC, 0.62, compared to ICS, 0.51 (p < 0.001). In addition, a significantly higher proportion of FSC subjects had a ratio 0.5 (78% vs 69%, p < 0.0001) compared to ICS subjects. CONCLUSIONS: More patients on FSC were able to achieve a controller to total asthma medication ratio that has been associated with reduced asthma events and better asthma control compared to patients on ICS.
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Curcumin Modulates LPS-Induced Inflammation in Human Dendritic Cells S. Shirley1, A. J. Montpetit1, R. F. Lockey2, S. S. Mohapatra1; 1University of South Florida, Tampa, FL, 2James A. Haley Veterans Hospital, Tampa, FL. RATIONALE: Curcumin, an ingredient of Indian curry, has anti-inflammatory properties, but its role in modulating allergy and asthma and mechanisms underlying its action are unclear. We hypothesized that dendritic cells play a critical role in mediating curcumin effects and examined its role in LPS-induced human dendritic cell (DC) maturation and function. METHODS: CD14 positive monocytes were isolated from human peripheral blood and cultured for 7 days in complete medium with GMCSF and IL-4 (20 ng/ml each). Cells were treated with curcumin for 1 hour and then exposed to LPS (1 mg/ml) overnight. Culture supernatant was collected and probed for cytokines using a multiplex bead assay, and cell viability was monitored using a flow cytometry based viability dye. DC morphology and maturation were examined by microscopy and flow cytometry, respectively. The phagocytosis assay was carried out using Alexa647-conjugated dextran and protein expression was examined by western blotting. RESULTS: Pre-treatment with curcumin causes minimal loss in cell viability and results in lower levels of IL-10, IL-12 (p40 and p70), IP-10, TNF-a and IL-1b when compared to LPS-stimulated DCs. Curcumin pretreatment does not affect the expression of surface markers CD11c, HLADR, CD83, CD80, CD86 and CD54. Furthermore, pre-treatment results in lower phagocytosis when compared to the LPS-stimulated DCs. Analysis of protein expression shows pre-treated cells have lower levels of signaling molecules IL-10Ra, SOCS3 and phosho-Stat3 when compared to LPSstimulated DCs. CONCLUSIONS: These results suggest curcumin can impair LPS mediated human DC cytokine production and the IL-10 signaling pathway without affecting phenotypic maturation. Funding: NIH and VA Merit Review
SATURDAY
35
Single-Dose, First-in-Human Study of AMG 317: Pharmacokinetics and Safety in Healthy and Asthmatic Adults M. Vincent1, C. Banfield1, T. Kakkar1, S. Shakib2, R. Schicchitano2, T. C. Cheah1, J. Gerson1; 1Amgen Inc., Thousand Oaks, CA, 2Royal Adelaide Hospital, Adelaide, AUSTRALIA. RATIONALE: The fully human monoclonal antibody AMG 317 is being evaluated in asthma based on its ability to bind to and inhibit IL-4Ra, which is required for IL-4 and IL-13 activity. These cytokines are strongly implicated in the pathogenesis of asthma, mediating such pathologic features as serum IgE production and airway hyperresponsiveness. METHODS: In this double-blind, placebo-controlled study, single IV doses of AMG 317 were administered to 29 healthy adults (10 to 1000 mg) and 6 adults with asthma (300 mg). Single SC doses were administered to 24 healthy adults (100 or 300 mg) and 7 adults with asthma (300 mg). Safety, tolerability, and pharmacokinetic data were obtained. Pharmacodynamic evaluation was performed using an ex-vivo whole-blood assay. RESULTS: No deaths, treatment-related serious adverse events, or study discontinuations due to adverse events were reported. The most frequent adverse events were injection site reactions (SC) and headache/myalgia (IV), occurring at similar rates for AMG 317 and placebo. AMG 317 pharmacokinetics was nonlinear over the dose range 10 to 1000 mg IV and dose-proportional between 100 and 300 mg following IV and SC administration. Overall, the pharmacokinetic profile and exposure were similar between healthy and asthmatic adults. Pharmacodynamic evaluation established inhibition of TARC, eotaxin-3, and MCP-4 production in response to IL-4 and IL-13 stimulation. CONCLUSIONS: AMG 317 was well tolerated when administered as a single IV (up to 1000 mg) or SC (up to 300 mg) dose in healthy adults and adults with asthma. Its pharmacokinetic profile was nonlinear over the dose range studied. Funding: Amgen Inc.
36
Effective Asthma Recovery with Once-Daily Mometasone Furoate Administered via Dry Powder Inhaler in Subjects Previously Maintained on Twice Daily Inhaled Corticosteroids J. P. Karpel1, A. D’Urzo2; 1Beth Thalheim Asthma Center at North Shore-LIJ, New Hyde Park, NY, 2Primary Care Asthma Clinic, Toronto, ON, CANADA. RATIONALE: To evaluate the recovery of lung function and effects on asthma control in response to treatment with mometasone furoate (MF) administered once daily in the evening (QD PM) via dry powder inhaler (DPI) compared with placebo. METHODS: In a double-blind, placebo-controlled study, enrolled patients (12 y) with persistent asthma were previously treated with inhaled corticosteroids (ICSs), mostly given twice daily (BID). After an ICS reduction period, patients were randomized to 12 weeks of double-blind treatment with MF-DPI 200 mg QD PM (n 5 78), 400 mg QD PM (1 inhalation) (n 5 80), 400 mg QD PM (2 inhalations) (n 5 78), 200 mg BID (n 5 81), or placebo (n 5 83). Asthma recovery defined as an increase of FEV1 10% and return of symptom scores, albuterol use, or nocturnal awakenings to screening values or better was a secondary efficacy variable in the study. RESULTS: 400 patients with persistent asthma were randomized to treatment. Patients were partly controlled at screening; most patients (>80%) were randomized upon worsening of asthma symptoms following reduction of previous ICS dosage. The proportions of subjects experiencing asthma recovery ranged from 53% to 69% in the MF-DPI groups and 30% in the placebo group. As many as 65% of patients treated with MFDPI were considered recovered compared to only 24% of those treated with placebo on the basis of improvements in asthma symptom scores to levels at least as low as screening values for the majority of the study period (80% of study weeks). CONCLUSIONS: QD MF-DPI effectively replaces BID ICS therapy in patients with persistent asthma. Funding: Schering-Plough Corporation
J ALLERGY CLIN IMMUNOL FEBRUARY 2008
37
Use of Fluticasone Propionate/Salmeterol In a Single Device is Associated with Higher Controller to Total Asthma Medication Ratios Compared to Inhaled Corticosteroid Therapy W. Yeh1, R. H. Stanford2, D. A. Stempel2; 1University of North Carolina, Chapel Hill, NC, 2GlaxoSmithKline, Research Triangle Park, NC. RATIONALE: To determine controller to total asthma medication ratios, a predictive measure of asthma outcomes, in users of fluticasone propionate/salmeterol administered in a single device (FSC) compared to inhaled corticosteroid (ICS) dispensed to a population of patients with asthma. METHODS: A retrospective cross sectional analysis of total asthma medication ratios for asthma patients treated with FSC and ICS was conducted. Subjects were identified from a claims database of >45 US health plans representing 58.5M covered lives from March 1, 2002 to May 31, 2006. Study subjects included those with 12 months of continuous enrollment, with diagnosis of asthma (ICD-9, 493.xx), use of FSC or ICS (not both) in each year of observation and were 4-55 years of age. The ratio was calculated as the number of controller medications divided by the albuterol plus controller medications dispensed and were evaluated by season. An overall seasonally weighted mean ratio was then calculated. Bivariate analysis was used to determine differences in the mean ratios and proportion of subjects with ratios 0.5 across cohorts. RESULTS: The mean controller to total asthma medication ratio was significantly higher for FSC, 0.62, compared to ICS, 0.51 (p < 0.001). In addition, a significantly higher proportion of FSC subjects had a ratio 0.5 (78% vs 69%, p < 0.0001) compared to ICS subjects. CONCLUSIONS: More patients on FSC were able to achieve a controller to total asthma medication ratio that has been associated with reduced asthma events and better asthma control compared to patients on ICS.
38
Curcumin Modulates LPS-Induced Inflammation in Human Dendritic Cells S. Shirley1, A. J. Montpetit1, R. F. Lockey2, S. S. Mohapatra1; 1University of South Florida, Tampa, FL, 2James A. Haley Veterans Hospital, Tampa, FL. RATIONALE: Curcumin, an ingredient of Indian curry, has anti-inflammatory properties, but its role in modulating allergy and asthma and mechanisms underlying its action are unclear. We hypothesized that dendritic cells play a critical role in mediating curcumin effects and examined its role in LPS-induced human dendritic cell (DC) maturation and function. METHODS: CD14 positive monocytes were isolated from human peripheral blood and cultured for 7 days in complete medium with GMCSF and IL-4 (20 ng/ml each). Cells were treated with curcumin for 1 hour and then exposed to LPS (1 mg/ml) overnight. Culture supernatant was collected and probed for cytokines using a multiplex bead assay, and cell viability was monitored using a flow cytometry based viability dye. DC morphology and maturation were examined by microscopy and flow cytometry, respectively. The phagocytosis assay was carried out using Alexa647-conjugated dextran and protein expression was examined by western blotting. RESULTS: Pre-treatment with curcumin causes minimal loss in cell viability and results in lower levels of IL-10, IL-12 (p40 and p70), IP-10, TNF-a and IL-1b when compared to LPS-stimulated DCs. Curcumin pretreatment does not affect the expression of surface markers CD11c, HLADR, CD83, CD80, CD86 and CD54. Furthermore, pre-treatment results in lower phagocytosis when compared to the LPS-stimulated DCs. Analysis of protein expression shows pre-treated cells have lower levels of signaling molecules IL-10Ra, SOCS3 and phosho-Stat3 when compared to LPSstimulated DCs. CONCLUSIONS: These results suggest curcumin can impair LPS mediated human DC cytokine production and the IL-10 signaling pathway without affecting phenotypic maturation. Funding: NIH and VA Merit Review