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WS6.4 Long-term safety and efficacy of ivacaftor in subjects with cystic fibrosis who have the G551D-CFTR Mutation
Oral Presentations
Workshop 6. New Therapies Targetting Basic Defects
WS6.2 Anti-inflammatory pulmonal therapy of CF patients with amitriptyline and placebo − a randomised, double-blind, placebo-controlled Phase IIb multicenter cohort study C. Adams1 , J.G. Mainz2 , L. Naehrlich3 , C. Engel4 , G. Herrmann4 , V. Icheva4 , U. Graepler-Mainka4 , S. Heyder5 , M. Stern4 , G. D¨oring6 , E. Gulbins1 , J. Riethmueller4 . 1 University of Duisburg-Essen, Dept. of Molecular Biology, Essen, Germany; 2 University of Jena, Childrens Hospital, Jena, Germany; 3 University of Giessen, Childrens Hospital, Giessen, Germany; 4 University of T¨ubingen, Childrens Hospital, T¨ubingen, Germany; 5 Klinik Schillerh¨ohe, Gerlingen, Germany; 6 University of T¨ubingen, T¨ubingen, Germany Introduction: Data on cystic fibrosis mice demonstrate a change of the sphingolipid metabolism with a massive accumulation of ceramide in the lung, trachea and gut. Ceramide mediates increased cell death, release of DNA in bronchi, chronic inflammation and increased infection susceptibility to pulmonary P. aeruginosa infections. Genetic or pharmacological inhibition of ceramide formation employing Amitriptyline in lungs normalizes all of these pathologies. Amitriptyline inhibits the acid sphingomyelinase and thus, ceramide release. Methods: We initiated a phase IIb randomised, double-blind, placebo-controlled study. Fourty patients were treated with 2×25 mg Amitriptyline for 28 days. The primary endpoint was the change of the lung function parameter FEV1 . Secondary endpoints were decrease of ceramide concentration, pulmonary P. aeruginosa counts, mucus composition and pro- and anti-inflammatory cytokines in sputum. Results: Amitriptyline was well received in the patient group and only one SAE was reported in the placebo group. Two well-known AEs of Amitriptyline, i.e. xerostomia and tiredness, were different between placebo and Amitriptyline, but occurred only transiently. We found in 37 patients a FEV1 difference of 6.3±11.45% (p = 0.08) in the ITT analysis and in 29 patients a FEV1 difference of 8.5±10% (p = 0.013) in the PP analysis. Conclusion: The Intention-to-treat and per protocol analyses showed a remarkable primary endpoint difference of FEV1 after 28 days of treatment. These data confirm the findings of the previous studies. The results support the notion of a positive anti-inflammatory effect of Amitriptyline therapy in CF-patients.
WS6.3 Measures of nutritional status in two Phase 3 trials of ivacaftor in subjects with cystic fibrosis who have the G551D-CFTR mutation D. Borowitz1 , B. Ramsey2 , Q. Dong3 , K. Yen3 , J.S. Elborn4 . 1 State University of New York at Buffalo, Buffalo, United States; 2 Seattle Children’s Hospital, Seattle, United States; 3 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 4 Belfast Cystic Fibrosis Centre, Belfast, United Kingdom Objectives: Two Phase 3 studies were conducted to evaluate ivacaftor in CF subjects with a G551D mutation. Weight and BMI were evaluated in both studies. Methods: Both were randomized, double-blind, placebo-controlled studies. Subjects received placebo or ivacaftor 150 mg q12h for 48 weeks plus prescribed therapies. In STRIVE, 161 subjects with CF 12 years with FEV1 at screening of 40−90% predicted were dosed. In ENVISION, 52 subjects 6−11 years with FEV1 at screening of 40–105% predicted were dosed. BMI was adjusted for age and sex and analyzed as BMI-for-age z-scores in subjects 12 to 20 years in STRIVE and all subjects in ENVISION. Results: In STRIVE, 3 placebo and 10 ivacaftor subjects were pancreatic sufficient (PS). In ENVISION, 1 subject in both groups was PS. The treatment difference in mean weight change at Week 48 was 2.7 kg (P = 0.0001) in STRIVE and 2.8 kg (P = 0.0002) in ENVISION. At Week 48, the treatment difference in BMI was 0.9 kg/m2 (P < 0.0001) in STRIVE and 1.1 kg/m2 (P = 0.0003) in ENVISION. In STRIVE, BMI-for-age z-score in ivacaftor subjects improved to above the 50th percentile at Week 48. The placebo group worsened over the same period (treatment difference: 0.33; P = 0.0490). In ENVISION, BMI-for-age z-score improved in the ivacaftor group. The placebo group worsened to substantially below the 50th percentile at Week 48 (treatment difference: 0.45; P < 0.0001). Conclusions: Clinically meaningful improvements in weight and BMI were demonstrated. These increases were likely not due to the slight imbalance in PS subjects in STRIVE. There were improvements in BMI-for-age z-scores that achieved the recommended target in CF nutrition guidelines. Sponsored by Vertex
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WS6.4 Long-term safety and efficacy of ivacaftor in subjects with cystic fibrosis who have the G551D-CFTR Mutation E. McKone1 , H. Li2 , K. Yen2 , J.C. Davies3,4 , on behalf of the VX08–770– 105 Study Group. 1 St. Vincent’s University Hospital, Dublin, Ireland; 2 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 3 Royal Brompton Hospital, London, United Kingdom; 4 Imperial College, London, United Kingdom Objectives: Ivacaftor was evaluated in two 48-week Phase 3 studies. This 96-week open-label extension (PERSIST) will evaluate the safety and efficacy of long-term ivacaftor in subjects who completed the prior trials (STRIVE and ENVISION). Methods: All subjects in PERSIST received ivacaftor 150 mg q12h. Here we report the results of the first 12 weeks for subjects who received placebo (n = 67) or ivacaftor (n = 77) in STRIVE. Results: The most common AEs reported in PERSIST were pulmonary exacerbations, cough, productive cough, upper respiratory tract infection, hemoptysis, headache, and abdominal pain. 13 (9.0%) subjects had SAEs. The percent predicted FEV1 improvement observed in subjects treated with ivacaftor during the placebocontrolled study (STRIVE) was sustained after an additional 12 weeks of ivacaftor treatment in PERSIST (treatment difference: 9.4 percentage points). In subjects who had previously received placebo, the percent predicted FEV1 improvement on Day 15 in PERSIST (treatment difference: 10.1 percentage points) was similar to the Day 15 improvement in the ivacaftor group in STRIVE. 8 subjects who received placebo in STRIVE began PERSIST with an FEV1 <40% predicted. For this subgroup, the mean (SD) percent predicted FEV1 on Day 1 of STRIVE was 34.5% (3.7%) and the mean (SD) absolute change on Day 15 was 10.8 (8.7) percentage points and at Week 12 was 13.0 (10.5) percentage points. Conclusions: Ivacaftor-related improvements in lung function are sustained over 60 weeks. The response in subjects previously treated with placebo confirms the effect seen in STRIVE. Ivacaftor appears to have beneficial effects in patients with severe disease. Sponsored by Vertex
WS6.5 Ivacaftor in subjects 6 to 11 years of age with cystic fibrosis and the G551D-CFTR mutation J.C. Davies1,2 , H. Li3 , K. Yen3 , R. Ahrens4 , on behalf of the VX08–770–103 Study Group. 1 Royal Brompton Hospital, London, United Kingdom; 2 Imperial College, London, United Kingdom; 3 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 4 University of Iowa, Iowa City, United States Objectives: Ivacaftor improves FEV1 , respiratory symptoms, pulmonary exacerbation risk, and weight gain vs. placebo in subjects with CF 12 years with the G551D mutation. Since earlier treatment may offer the greatest potential for benefits, this study was conducted to evaluate the efficacy and safety of ivacaftor in younger subjects. Methods: This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Subjects were 6−11 years with a G551D mutation and FEV1 40–105% predicted. Subjects received ivacaftor 150 mg (n = 26) or placebo (n = 26) q12h for 48 weeks in addition to prescribed therapies. The dose had been confirmed in a single dose lead-in PK study. Results: Mean baseline FEV1 (SD) was 84.2% (18.1%). The treatment effect of ivacaftor for the primary endpoint, mean absolute change from baseline in % predicted FEV1 through Week 24, was 12.5% points (P < 0.0001) and through Week 48 was 10.0% points (P = 0.0006). Ivacaftor led to significant reduction in sweat chloride, a measure of improved CFTR activity, through Week 48 (treatment difference: −53.5 mmol/L; P < 0.0001). At Week 48, treatment with ivacaftor resulted in a significant increase in weight (treatment difference: 2.8 kg; P = 0.0002). The most commonly reported AEs in either arm were respiratory in nature. Conclusions: Compared to placebo, ivacaftor led to a substantial and statistically significant improvement in pulmonary function, CFTR activity, and weight in this group of relatively well children. The improvements in FEV1 were comparable to those seen in the previous study of older children and adults, despite significantly milder disease in this group. Sponsored by Vertex
Workshop 6. New Therapies Targetting Basic Defects
WS6.2 Anti-inflammatory pulmonal therapy of CF patients with amitriptyline and placebo − a randomised, double-blind, placebo-controlled Phase IIb multicenter cohort study C. Adams1 , J.G. Mainz2 , L. Naehrlich3 , C. Engel4 , G. Herrmann4 , V. Icheva4 , U. Graepler-Mainka4 , S. Heyder5 , M. Stern4 , G. D¨oring6 , E. Gulbins1 , J. Riethmueller4 . 1 University of Duisburg-Essen, Dept. of Molecular Biology, Essen, Germany; 2 University of Jena, Childrens Hospital, Jena, Germany; 3 University of Giessen, Childrens Hospital, Giessen, Germany; 4 University of T¨ubingen, Childrens Hospital, T¨ubingen, Germany; 5 Klinik Schillerh¨ohe, Gerlingen, Germany; 6 University of T¨ubingen, T¨ubingen, Germany Introduction: Data on cystic fibrosis mice demonstrate a change of the sphingolipid metabolism with a massive accumulation of ceramide in the lung, trachea and gut. Ceramide mediates increased cell death, release of DNA in bronchi, chronic inflammation and increased infection susceptibility to pulmonary P. aeruginosa infections. Genetic or pharmacological inhibition of ceramide formation employing Amitriptyline in lungs normalizes all of these pathologies. Amitriptyline inhibits the acid sphingomyelinase and thus, ceramide release. Methods: We initiated a phase IIb randomised, double-blind, placebo-controlled study. Fourty patients were treated with 2×25 mg Amitriptyline for 28 days. The primary endpoint was the change of the lung function parameter FEV1 . Secondary endpoints were decrease of ceramide concentration, pulmonary P. aeruginosa counts, mucus composition and pro- and anti-inflammatory cytokines in sputum. Results: Amitriptyline was well received in the patient group and only one SAE was reported in the placebo group. Two well-known AEs of Amitriptyline, i.e. xerostomia and tiredness, were different between placebo and Amitriptyline, but occurred only transiently. We found in 37 patients a FEV1 difference of 6.3±11.45% (p = 0.08) in the ITT analysis and in 29 patients a FEV1 difference of 8.5±10% (p = 0.013) in the PP analysis. Conclusion: The Intention-to-treat and per protocol analyses showed a remarkable primary endpoint difference of FEV1 after 28 days of treatment. These data confirm the findings of the previous studies. The results support the notion of a positive anti-inflammatory effect of Amitriptyline therapy in CF-patients.
WS6.3 Measures of nutritional status in two Phase 3 trials of ivacaftor in subjects with cystic fibrosis who have the G551D-CFTR mutation D. Borowitz1 , B. Ramsey2 , Q. Dong3 , K. Yen3 , J.S. Elborn4 . 1 State University of New York at Buffalo, Buffalo, United States; 2 Seattle Children’s Hospital, Seattle, United States; 3 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 4 Belfast Cystic Fibrosis Centre, Belfast, United Kingdom Objectives: Two Phase 3 studies were conducted to evaluate ivacaftor in CF subjects with a G551D mutation. Weight and BMI were evaluated in both studies. Methods: Both were randomized, double-blind, placebo-controlled studies. Subjects received placebo or ivacaftor 150 mg q12h for 48 weeks plus prescribed therapies. In STRIVE, 161 subjects with CF 12 years with FEV1 at screening of 40−90% predicted were dosed. In ENVISION, 52 subjects 6−11 years with FEV1 at screening of 40–105% predicted were dosed. BMI was adjusted for age and sex and analyzed as BMI-for-age z-scores in subjects 12 to 20 years in STRIVE and all subjects in ENVISION. Results: In STRIVE, 3 placebo and 10 ivacaftor subjects were pancreatic sufficient (PS). In ENVISION, 1 subject in both groups was PS. The treatment difference in mean weight change at Week 48 was 2.7 kg (P = 0.0001) in STRIVE and 2.8 kg (P = 0.0002) in ENVISION. At Week 48, the treatment difference in BMI was 0.9 kg/m2 (P < 0.0001) in STRIVE and 1.1 kg/m2 (P = 0.0003) in ENVISION. In STRIVE, BMI-for-age z-score in ivacaftor subjects improved to above the 50th percentile at Week 48. The placebo group worsened over the same period (treatment difference: 0.33; P = 0.0490). In ENVISION, BMI-for-age z-score improved in the ivacaftor group. The placebo group worsened to substantially below the 50th percentile at Week 48 (treatment difference: 0.45; P < 0.0001). Conclusions: Clinically meaningful improvements in weight and BMI were demonstrated. These increases were likely not due to the slight imbalance in PS subjects in STRIVE. There were improvements in BMI-for-age z-scores that achieved the recommended target in CF nutrition guidelines. Sponsored by Vertex
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WS6.4 Long-term safety and efficacy of ivacaftor in subjects with cystic fibrosis who have the G551D-CFTR Mutation E. McKone1 , H. Li2 , K. Yen2 , J.C. Davies3,4 , on behalf of the VX08–770– 105 Study Group. 1 St. Vincent’s University Hospital, Dublin, Ireland; 2 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 3 Royal Brompton Hospital, London, United Kingdom; 4 Imperial College, London, United Kingdom Objectives: Ivacaftor was evaluated in two 48-week Phase 3 studies. This 96-week open-label extension (PERSIST) will evaluate the safety and efficacy of long-term ivacaftor in subjects who completed the prior trials (STRIVE and ENVISION). Methods: All subjects in PERSIST received ivacaftor 150 mg q12h. Here we report the results of the first 12 weeks for subjects who received placebo (n = 67) or ivacaftor (n = 77) in STRIVE. Results: The most common AEs reported in PERSIST were pulmonary exacerbations, cough, productive cough, upper respiratory tract infection, hemoptysis, headache, and abdominal pain. 13 (9.0%) subjects had SAEs. The percent predicted FEV1 improvement observed in subjects treated with ivacaftor during the placebocontrolled study (STRIVE) was sustained after an additional 12 weeks of ivacaftor treatment in PERSIST (treatment difference: 9.4 percentage points). In subjects who had previously received placebo, the percent predicted FEV1 improvement on Day 15 in PERSIST (treatment difference: 10.1 percentage points) was similar to the Day 15 improvement in the ivacaftor group in STRIVE. 8 subjects who received placebo in STRIVE began PERSIST with an FEV1 <40% predicted. For this subgroup, the mean (SD) percent predicted FEV1 on Day 1 of STRIVE was 34.5% (3.7%) and the mean (SD) absolute change on Day 15 was 10.8 (8.7) percentage points and at Week 12 was 13.0 (10.5) percentage points. Conclusions: Ivacaftor-related improvements in lung function are sustained over 60 weeks. The response in subjects previously treated with placebo confirms the effect seen in STRIVE. Ivacaftor appears to have beneficial effects in patients with severe disease. Sponsored by Vertex
WS6.5 Ivacaftor in subjects 6 to 11 years of age with cystic fibrosis and the G551D-CFTR mutation J.C. Davies1,2 , H. Li3 , K. Yen3 , R. Ahrens4 , on behalf of the VX08–770–103 Study Group. 1 Royal Brompton Hospital, London, United Kingdom; 2 Imperial College, London, United Kingdom; 3 Vertex Pharmaceuticals Incorporated, Cambridge, United States; 4 University of Iowa, Iowa City, United States Objectives: Ivacaftor improves FEV1 , respiratory symptoms, pulmonary exacerbation risk, and weight gain vs. placebo in subjects with CF 12 years with the G551D mutation. Since earlier treatment may offer the greatest potential for benefits, this study was conducted to evaluate the efficacy and safety of ivacaftor in younger subjects. Methods: This was a Phase 3, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Subjects were 6−11 years with a G551D mutation and FEV1 40–105% predicted. Subjects received ivacaftor 150 mg (n = 26) or placebo (n = 26) q12h for 48 weeks in addition to prescribed therapies. The dose had been confirmed in a single dose lead-in PK study. Results: Mean baseline FEV1 (SD) was 84.2% (18.1%). The treatment effect of ivacaftor for the primary endpoint, mean absolute change from baseline in % predicted FEV1 through Week 24, was 12.5% points (P < 0.0001) and through Week 48 was 10.0% points (P = 0.0006). Ivacaftor led to significant reduction in sweat chloride, a measure of improved CFTR activity, through Week 48 (treatment difference: −53.5 mmol/L; P < 0.0001). At Week 48, treatment with ivacaftor resulted in a significant increase in weight (treatment difference: 2.8 kg; P = 0.0002). The most commonly reported AEs in either arm were respiratory in nature. Conclusions: Compared to placebo, ivacaftor led to a substantial and statistically significant improvement in pulmonary function, CFTR activity, and weight in this group of relatively well children. The improvements in FEV1 were comparable to those seen in the previous study of older children and adults, despite significantly milder disease in this group. Sponsored by Vertex