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ePS03.4 Improved rate of decline in percent predicted FEV1 (ppFEV1) is not associated with acute improvement in ppFEV1 in patients with cystic fibrosis (CF) treated with ivacaftor
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Oral Presentations / Journal of Cystic Fibrosis 15 (2016) S1–S50
decrease in sweat chloride). we documented the reversal of cf sinus desease, all patients have had a drastic reduction of nasal symptoms established by the improving of Lund–Kennedy score and Lund–Mackay score. We found Pseudomonas in nasal culture in 68.8% of the patients after the therapy in only the 25%. Conclusion: This study suggests that ivacaftor improves clinical findings in cystic fibrosis patients with chronic rhinosinusitis. ePS03.4 Improved rate of decline in percent predicted FEV1 (ppFEV1 ) is not associated with acute improvement in ppFEV1 in patients with cystic fibrosis (CF) treated with ivacaftor E. McKone1 , G. Sawicki2 , S. Millar3 , D. Pasta3 , J. Rubin4 , M. Konstan5 , J. Wagener6 . 1 St. Vincent’s University Hospital, Dublin, Ireland; 2 Harvard Medical School, Boston, United States; 3 ICON Clinical Research, San Francisco, United States; 4 Vertex Pharmaceuticals Incorporated, Boston, United States; 5 Case Western Reserve University, Cleveland, United States; 6 University of Colorado, Aurora, United States Objective: Ivacaftor improves lung function in patients with CF and the G551D-CFTR mutation. Previous studies have shown an acute improvement in ppFEV1 and a lower rate of ppFEV1 decline. Here we evaluate the relationship between these two treatment effects. Methods: Patients with a G551D-CTFR mutation participated in a 48week Phase 3 trial of ivacaftor and had at least 18 months of active drug during a follow-up study. Acute change was calculated as the difference between ppFEV1 on the start of ivacaftor and day 15 follow-up. The rate of decline was calculated by fitting a least squares line to all ppFEV1 values after day 30 until the end of the study (up to 3 years). The rate of decline was compared with the baseline value and both the absolute and relative acute change. A mixed model of ppFEV1 was estimated that included 3 values allowed to freely correlate: acute improvement, intercept of the rate of decline, and slope of the rate of decline. Results: Among 189 patients, no significant correlations existed between rate of decline in ppFEV1 and baseline ppFEV1 (r = −0.090; P = 0.22), absolute acute improvement (r = −0.066, P = 0.36), or relative acute improvement (r = 0.017, P = 0.82). The estimated correlation between the random effects for acute improvement and rate of decline was −0.023. Conclusions: Ivacaftor therapy produces 2 separate, uncorrelated effects on lung function in patients with CF and the G551D-CFTR mutation: an acute improvement in ppFEV1 and a reduced rate of ppFEV1 decline. The latter effect may have important implications for disease progression. Acknowledgement: Sponsored by Vertex Pharmaceuticals Incorporated ePS03.5 Inhaled cysteamine for the chronic management and symptomatic control of CF associated lung disease D. Fraser-Pitt1 , D. O’Neil1 . 1 NovaBiotics Ltd, Aberdeen, United Kingdom Objectives: We previously described the potential of orally administered cysteamine in cystic fibrosis (CF) infectious exacerbations (Devereux et al, 2015). Oral cysteamine is not however, suitable as a chronic therapy. Its poor palatability and side-effect potential from long-term use are such that its application as a high dose oral form is limited (e.g. CF exacerbations, 14 d intervention). In order to deliver cysteamine’s antimicrobial and mucolytic benefits over the longer term and to facilitate lower dosing and minise/negate systemic exposure, we have explored the application of inhaled versions of cysteamine in CF. Methods: A range of novel formulations comprising cysteamine, bulking agents and excipients were developed and those with the most promising aerosol characteristics for DPI delivery were tested in murine models of respiratory Pseudomonas aeruginosa infection; as monotherapies and with concomitant antibiotic (e.g. tobramycin) exposure. Lung tissue bacterial burden was assessed as a read-out of efficacy. Results: Potent antibiotic efficacy of the inhaled formulations was demonstrated in murine models of P. aeruginosa lung infection; both when the drug was administered alone but particularly when as an adjunct to standard of care antibiotics. The formulations were well
tolerated and a single cycle of treatment resulted in a ~6 log reduction (eradication) of lung bacterial burden. Conclusion: Inhaled cysteamine may have potential in the long-term symptomatic management and control of CF associated lung disease. From the present study we have been able to select a lead inhaled cysteamine formulation for further investigation. ePS03.7 Rosco-CF, a safety and efficacy clinical trial of (R)-roscovitine in CF patients 2,3 L. Meijer1 , G. Hery-Arnaud ´ , R. Le Berre2,4 , E. Nowak5 , L. Le Roux5 , 6 , G. Rault6 , D. Mottier5 . 1 ManRos Therapeutics, Roscoff, L. Gueganton ´ France; 2 Hˆ opital de la Cavale Blanche, CHRU Brest, Unit´e de Bact´eriologie, Brest, France; 3 Universit´e de Brest, UFR de M´edecine et des Sciences de la Sant´e, EA3882-LUBEM, Brest, France; 4 CHRU Brest, D´epartement de M´edecine Interne et Pneumologie, Brest, France; 5 Hˆ opital de la Cavale Blanche, CHRU Brest, Centre d’Investigation Clinique, INSERM CIC-1412, Brest, France; 6 Fondation Ildys, Centre de Perharidy, Roscoff, France
Objectives: Roscovitine is an orally available kinase inhibitor drug which has undergone extensive phase I and II clinical trials against various cancers. Under clinical evaluation against Cushing disease and rheumatoid arthritis, Roscovitine displays biological properties suggesting potential benefits in CF treatment [1]. The ROSCO-CF clinical study aims at evaluating this therapeutic potential [2]. Methods: A Phase 2, dose ranging, multicenter, double-blind, placebo controlled study, involving 36 CF patients, is being launched to evaluate safety and effects of (R)-roscovitine in adults CF patients, carrying two CF causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa. Results: Experimental results have shown Roscovitine acts as a proteostasis regulator that partially corrects F508del-CFTR trafficking [3]. Roscovitine stimulates the bactericidal properties of alveolar macrophages by lowering the abnormally elevated intraphagolysosomal pH of CF macrophages [4]. Roscovitine displays antiinflammatory properties due to its effects on neutrophils, on eosinophils and on the Th17/Tregs inflammatory lymphocytes balance [1]. Conclusion: Using Roscovitine for CF is a therapeutically valid proposal. We will present the clinical protocol designed to validate safety and potential beneficial effects of Roscovitine in CF patients with chronic lung P. aeruginosa infection and hopefully the first clinical results. Reference(s) [1] Meijer L et al, 2016. J Innate Immun, under revision. [2] clinicaltrials.gov: NCT02649751. [3] Norez C et al, 2014. Br J Pharmacol 171, 4831. [4] Riazanski V et al, 2015. Proc Natl Acad Sci USA 112, 6486.
ePS03.8 Therapeutic potential of inhaled ALX-009 (OSCN− /bLF) for the treatment of Achromobacter spp. infections in cystic fibrosis C. Bechetoille1 , Y. Sonmez1 , L. Jubeau1 , V. Juarez Perez1,2 . 1 Alaxia SAS, Lyon, France; 2 Stragen France, Lyon, France Recent epidemiologic studies in Europe and USA indicate that prevalence of Achromobacter spp. is increasing within the CF population. Achromobacter spp. is a gram negative bacteria able to induce severe lung infections in these patients and for which therapeutic options are limited. In previous reports, Alaxia demonstrated the therapeutic potential of the drug ALX-009 on a large collection of Burkholderia spp. clinical isolates. The present study aims at evaluating the bactericidal capacity of ALX-009 against the multi-drug resistant bacteria Achromobacter spp. Alaxia is currently assessing the inhibitory and killing activity of its drug candidate ALX-009 against 100 clinical isolates of Achromobacter spp. using standardized microbiology methods. Results observed on the 46 isolates tested so far show that ALX-009 is able to inhibit the growth of 100% of Achromobacter spp. isolates. FIC Index shows that, in most cases, OSCN− and Lactoferrin act in a synergistic or additive manner (78% of isolates). In addition, time-kill curves provide further insights on the killing pattern of the combination and demonstrate that
Oral Presentations / Journal of Cystic Fibrosis 15 (2016) S1–S50
decrease in sweat chloride). we documented the reversal of cf sinus desease, all patients have had a drastic reduction of nasal symptoms established by the improving of Lund–Kennedy score and Lund–Mackay score. We found Pseudomonas in nasal culture in 68.8% of the patients after the therapy in only the 25%. Conclusion: This study suggests that ivacaftor improves clinical findings in cystic fibrosis patients with chronic rhinosinusitis. ePS03.4 Improved rate of decline in percent predicted FEV1 (ppFEV1 ) is not associated with acute improvement in ppFEV1 in patients with cystic fibrosis (CF) treated with ivacaftor E. McKone1 , G. Sawicki2 , S. Millar3 , D. Pasta3 , J. Rubin4 , M. Konstan5 , J. Wagener6 . 1 St. Vincent’s University Hospital, Dublin, Ireland; 2 Harvard Medical School, Boston, United States; 3 ICON Clinical Research, San Francisco, United States; 4 Vertex Pharmaceuticals Incorporated, Boston, United States; 5 Case Western Reserve University, Cleveland, United States; 6 University of Colorado, Aurora, United States Objective: Ivacaftor improves lung function in patients with CF and the G551D-CFTR mutation. Previous studies have shown an acute improvement in ppFEV1 and a lower rate of ppFEV1 decline. Here we evaluate the relationship between these two treatment effects. Methods: Patients with a G551D-CTFR mutation participated in a 48week Phase 3 trial of ivacaftor and had at least 18 months of active drug during a follow-up study. Acute change was calculated as the difference between ppFEV1 on the start of ivacaftor and day 15 follow-up. The rate of decline was calculated by fitting a least squares line to all ppFEV1 values after day 30 until the end of the study (up to 3 years). The rate of decline was compared with the baseline value and both the absolute and relative acute change. A mixed model of ppFEV1 was estimated that included 3 values allowed to freely correlate: acute improvement, intercept of the rate of decline, and slope of the rate of decline. Results: Among 189 patients, no significant correlations existed between rate of decline in ppFEV1 and baseline ppFEV1 (r = −0.090; P = 0.22), absolute acute improvement (r = −0.066, P = 0.36), or relative acute improvement (r = 0.017, P = 0.82). The estimated correlation between the random effects for acute improvement and rate of decline was −0.023. Conclusions: Ivacaftor therapy produces 2 separate, uncorrelated effects on lung function in patients with CF and the G551D-CFTR mutation: an acute improvement in ppFEV1 and a reduced rate of ppFEV1 decline. The latter effect may have important implications for disease progression. Acknowledgement: Sponsored by Vertex Pharmaceuticals Incorporated ePS03.5 Inhaled cysteamine for the chronic management and symptomatic control of CF associated lung disease D. Fraser-Pitt1 , D. O’Neil1 . 1 NovaBiotics Ltd, Aberdeen, United Kingdom Objectives: We previously described the potential of orally administered cysteamine in cystic fibrosis (CF) infectious exacerbations (Devereux et al, 2015). Oral cysteamine is not however, suitable as a chronic therapy. Its poor palatability and side-effect potential from long-term use are such that its application as a high dose oral form is limited (e.g. CF exacerbations, 14 d intervention). In order to deliver cysteamine’s antimicrobial and mucolytic benefits over the longer term and to facilitate lower dosing and minise/negate systemic exposure, we have explored the application of inhaled versions of cysteamine in CF. Methods: A range of novel formulations comprising cysteamine, bulking agents and excipients were developed and those with the most promising aerosol characteristics for DPI delivery were tested in murine models of respiratory Pseudomonas aeruginosa infection; as monotherapies and with concomitant antibiotic (e.g. tobramycin) exposure. Lung tissue bacterial burden was assessed as a read-out of efficacy. Results: Potent antibiotic efficacy of the inhaled formulations was demonstrated in murine models of P. aeruginosa lung infection; both when the drug was administered alone but particularly when as an adjunct to standard of care antibiotics. The formulations were well
tolerated and a single cycle of treatment resulted in a ~6 log reduction (eradication) of lung bacterial burden. Conclusion: Inhaled cysteamine may have potential in the long-term symptomatic management and control of CF associated lung disease. From the present study we have been able to select a lead inhaled cysteamine formulation for further investigation. ePS03.7 Rosco-CF, a safety and efficacy clinical trial of (R)-roscovitine in CF patients 2,3 L. Meijer1 , G. Hery-Arnaud ´ , R. Le Berre2,4 , E. Nowak5 , L. Le Roux5 , 6 , G. Rault6 , D. Mottier5 . 1 ManRos Therapeutics, Roscoff, L. Gueganton ´ France; 2 Hˆ opital de la Cavale Blanche, CHRU Brest, Unit´e de Bact´eriologie, Brest, France; 3 Universit´e de Brest, UFR de M´edecine et des Sciences de la Sant´e, EA3882-LUBEM, Brest, France; 4 CHRU Brest, D´epartement de M´edecine Interne et Pneumologie, Brest, France; 5 Hˆ opital de la Cavale Blanche, CHRU Brest, Centre d’Investigation Clinique, INSERM CIC-1412, Brest, France; 6 Fondation Ildys, Centre de Perharidy, Roscoff, France
Objectives: Roscovitine is an orally available kinase inhibitor drug which has undergone extensive phase I and II clinical trials against various cancers. Under clinical evaluation against Cushing disease and rheumatoid arthritis, Roscovitine displays biological properties suggesting potential benefits in CF treatment [1]. The ROSCO-CF clinical study aims at evaluating this therapeutic potential [2]. Methods: A Phase 2, dose ranging, multicenter, double-blind, placebo controlled study, involving 36 CF patients, is being launched to evaluate safety and effects of (R)-roscovitine in adults CF patients, carrying two CF causing mutations with at least one F508del-CFTR mutation and chronically infected with Pseudomonas aeruginosa. Results: Experimental results have shown Roscovitine acts as a proteostasis regulator that partially corrects F508del-CFTR trafficking [3]. Roscovitine stimulates the bactericidal properties of alveolar macrophages by lowering the abnormally elevated intraphagolysosomal pH of CF macrophages [4]. Roscovitine displays antiinflammatory properties due to its effects on neutrophils, on eosinophils and on the Th17/Tregs inflammatory lymphocytes balance [1]. Conclusion: Using Roscovitine for CF is a therapeutically valid proposal. We will present the clinical protocol designed to validate safety and potential beneficial effects of Roscovitine in CF patients with chronic lung P. aeruginosa infection and hopefully the first clinical results. Reference(s) [1] Meijer L et al, 2016. J Innate Immun, under revision. [2] clinicaltrials.gov: NCT02649751. [3] Norez C et al, 2014. Br J Pharmacol 171, 4831. [4] Riazanski V et al, 2015. Proc Natl Acad Sci USA 112, 6486.
ePS03.8 Therapeutic potential of inhaled ALX-009 (OSCN− /bLF) for the treatment of Achromobacter spp. infections in cystic fibrosis C. Bechetoille1 , Y. Sonmez1 , L. Jubeau1 , V. Juarez Perez1,2 . 1 Alaxia SAS, Lyon, France; 2 Stragen France, Lyon, France Recent epidemiologic studies in Europe and USA indicate that prevalence of Achromobacter spp. is increasing within the CF population. Achromobacter spp. is a gram negative bacteria able to induce severe lung infections in these patients and for which therapeutic options are limited. In previous reports, Alaxia demonstrated the therapeutic potential of the drug ALX-009 on a large collection of Burkholderia spp. clinical isolates. The present study aims at evaluating the bactericidal capacity of ALX-009 against the multi-drug resistant bacteria Achromobacter spp. Alaxia is currently assessing the inhibitory and killing activity of its drug candidate ALX-009 against 100 clinical isolates of Achromobacter spp. using standardized microbiology methods. Results observed on the 46 isolates tested so far show that ALX-009 is able to inhibit the growth of 100% of Achromobacter spp. isolates. FIC Index shows that, in most cases, OSCN− and Lactoferrin act in a synergistic or additive manner (78% of isolates). In addition, time-kill curves provide further insights on the killing pattern of the combination and demonstrate that