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Safety and Tolerability of Repeat Doses of Serelaxin in Patients with Chronic Heart Failure: the RELAX-REPEAT Study
S10 Journal of Cardiac Failure Vol. 22 No. 8S August 2016 white patients (HR 0.81, 95% CI 0.73–0.90, P < .001) (p-for interaction 0.97). Conclusions: Black patients have different baseline characteristics and higher overall risk of subsequent CV events. The benefit of sacubitril/valsartan over enalapril was consistent in blacks and whites.
Baseline Characteristics and Outcomes in Black and White Patients Characteristics/ Outcomes Age Female Body Mass Index eGFR NYHA Class (3 or 4) Hypertension Diabetes mellitus Atrial fibrillation Hospitalization for HF Myocardial Infarction LVEF Outcomes Primary outcome CV Death HF Hospitalization
Black Patients (n = 428) 57 ± 13 133 (31.1%) 27.5[23.9, 32.0] 75.0[61.0, 93.0] 60 (14.1%) 321 (75%) 115 (26.9%) 91 (21.3%) 309 (72.2%) 74 (17.3%) 28.0[23.0, 33.0] Events (%) Incidence Rate 130 (30.4%) 17.3 per 100 yr 66 (15.4%) 7.8 per 100 yr 85 (19.9%) 11.3 per 100 yr
White patients (n = 5544)
P-value
66 ± 10 1161 (20.9%) 28.6 [25.6, 32.3] 64.0 [52.0, 77.0] 1676 (30.3%) 4263 (76.9%) 2010 (36.3%) 2532 (45.7%) 3586 (64.7%) 2678 (48.3%) 31.0 [26.0, 35.0]
<.001 <.001 <.001 <.001 <.001 .37 <.001 <.001 .002 <.001 <.001
Events (%) Incidence Rate 1315 (23.7%) 11.3 per 100 yr 762 (13.7%) 6.1 per 100 yr 819 (14.8%) 7.0 per 100 yr
<.001 .041 <.001
022 Safety and Tolerability of Repeat Doses of Serelaxin in Patients with Chronic Heart Failure: the RELAX-REPEAT Study John R. Teerlink1, Rajnish Saini2, Lars Gullestad3, Jacques Descotes4, Tomasz Masior5, Yaqin Wang2, Judy Pak2, Yinuo Pang6, Elaine Unemori7, Thomas Severin5; 1UCSF, San Francisco, CA; 2Novartis Pharmaceuticals, East Hanover, NJ; 3Oslo University Hospital Rikshospitalet, Oslo, Norway; 4ImmunoSafe© and Lyon University, Lyon, France; 5 Novartis Pharma, Basel, Switzerland; 6NIBR, Cambridge, MA; 7Unaffiliated, Oakland, CA Background: Nearly 30% of patients (pts) are rehospitalized within 60–90 days of discharge after an episode of acute heart failure (AHF). Serelaxin, currently in Phase III AHF trials, has been shown to reduce in-hospital worsening HF and mortality in AHF pts. As serelaxin may be repeatedly administered, the RELAX-REPEAT study assessed the safety and immumogenicity of repeat serelaxin doses in pts with compensated chronic HF. Methods: In this multicenter, double-blind, Phase IIb study (NCT01982292), pts received 3 sequential 48 hour IV infusions of serelaxin 30 μg/kg/day or placebo (2:1) at randomization, Week (Wk) 4, and 8, in addition to standard of care. Primary objective was to assess proportion of pts developing anti serelaxin antibodies at any time following serelaxin infusions. Secondary objectives included other assessments of possible serelaxin immunogenicity and safety and tolerability of repeat infusions. Exploratory assessments included effects on renal function and other biomarkers. Results: Of the 323 pts randomized, 320 (serelaxin, n = 212; placebo, n = 108) were included in the safety set. Twelve pts from the serelaxin group were excluded as they did not meet prespecified antibody analysis criteria. One of 200 pts (0.5%) who received serelaxin had anti serelaxin antibody positive results (non neutralizing) at Wk 2 through Wk 12 that were undetectable at Wk 16 and not associated with any AEs. There is 95% confidence that the true proportion of pts who develop antibodies following repeat serelaxin doses is less than 2.4% (upper limit of the exact 1-sided CI). There were no confirmed hypersensitivity or infusion related reactions following adjudication in either treatment groups; overall incidence of all treatment-emergent AEs was comparable. There were statistically significant decreases in cystatin-C and increases in eGFR following each serelaxin infusion compared with placebo (Figure), and decreases in plasma aldosterone that were significant after the 3rd infusion. Conclusion: Overall, data showed that repeat doses of serelaxin were safe and well tolerated in pts with chronic HF. The immunogenicity profile of serelaxin was favorable and there were no confirmed hyperensitivity or infusion related reactions. There were notable improvements in renal function following each 48 hour serelaxin infusion.
023 The Effect of Omecamtiv Mecarbil on Symptoms of Heart Failure in the Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) John R. Teerlink1, G. Michael Felker2, John J.V. McMurray3, Scott D. Solomon4, Adrian Kielhorn5, Fady I. Malik6, Narimon Honarpour5; 1San Francisco VAMC/UCSF, San Francisco, CA; 2Duke University, Durham, NC; 3University of Glasgow, Glasgow, United Kingdom; 4Harvard Medical School, Boston, MA; 5Amgen, Inc., Thousand Oaks, CA; 6 Cytokinetics, Inc., South San Francisco, CA Introduction: Improving myocardial contractile function remains an attractive therapeutic target in patients with heart failure and reduced ejection fraction (HFrEF). Hypothesis: The selective cardiac myosin activator, omecamtiv mecarbil (OM) improves heart failure symptoms after 20 weeks of treatment in patients with HFrEF. Methods: COSMIC-HF (NCT 01786512) was a Phase 2 multicenter, randomized, doubleblind, placebo-controlled trial in outpatients with a history of chronic HF, LVEF ≤40%, and NT-proBNP ≥200 pg/mL (≥1200 pg/mL with atrial fibrillation). Patients were randomized 1:1:1 to receive placebo, OM 25 mg BID, or OM 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily (PK-titration). Patients selfassessed heart failure symptoms at baseline with a Patient Global Rating of Severity (PGR-S; 6-point categorial Likert scale from “none” to “very severe”). The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure patient symptoms at baseline and week 20 (0–100 scale; best score = 100). Results: The KCCQ Total Symptom Score (TSS) was increased at Week 20 in a dose-related fashion with a 4.9 point improvement in the OM PK-titration group (Table; P = .03). This difference is similar in magnitude to the clinically relevant 5-point change identified for the TSS in recent work. In patients who were asymptomatic to mildly symptomatic at baseline (PGR-S Group 1 = none, very mild or mild symptoms), there were modest improvements in the TSS at week 20 and the increases in the OM-treated patients were only slightly larger compared to placebo. In patients who were moderately to very severely symptomatic at baseline (PGR-S Group 2 = moderate, severe, or very severe
Table. KCCQ Total Symptom Score (TSS) by Treatment Group (*P < .10; **P < .05) Placebo TSS-Overall (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI) TSS-Group 1: Asymptomatic to Mildly Sx (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI) TSS-Group 2: Moderately to Very Severely Sx (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI)
149 69.7 (21.2) 5.0 (1.6)
OM 25 mg po BID 150 70.9 (22.0) 6.6 (1.6)
OM PK-Titration 146 67.3 (21.3) 9.9 (1.6)
—
1.7 (−2.8, 6.1)
4.9 (0.5, 9.4)**
81
86
75
77.3 (16.4) 1.6 (1.8)
80.2 (18.3) 2.7 (2.0)
78.4 (17.4) 4.3 (1.6)
—
1.2 (−4.1, 6.4)
2.7 (−2.2, 7.6)
67
64
71
60.2 (22.6) 9.5 (2.7) —
58.3 (20.2) 11.3 (2.6) 1.8 (−5.7, 9.3)
55.5 (18.7) 16.0 (2.7) 6.5 (−1.0, 14.0)*
Baseline Characteristics and Outcomes in Black and White Patients Characteristics/ Outcomes Age Female Body Mass Index eGFR NYHA Class (3 or 4) Hypertension Diabetes mellitus Atrial fibrillation Hospitalization for HF Myocardial Infarction LVEF Outcomes Primary outcome CV Death HF Hospitalization
Black Patients (n = 428) 57 ± 13 133 (31.1%) 27.5[23.9, 32.0] 75.0[61.0, 93.0] 60 (14.1%) 321 (75%) 115 (26.9%) 91 (21.3%) 309 (72.2%) 74 (17.3%) 28.0[23.0, 33.0] Events (%) Incidence Rate 130 (30.4%) 17.3 per 100 yr 66 (15.4%) 7.8 per 100 yr 85 (19.9%) 11.3 per 100 yr
White patients (n = 5544)
P-value
66 ± 10 1161 (20.9%) 28.6 [25.6, 32.3] 64.0 [52.0, 77.0] 1676 (30.3%) 4263 (76.9%) 2010 (36.3%) 2532 (45.7%) 3586 (64.7%) 2678 (48.3%) 31.0 [26.0, 35.0]
<.001 <.001 <.001 <.001 <.001 .37 <.001 <.001 .002 <.001 <.001
Events (%) Incidence Rate 1315 (23.7%) 11.3 per 100 yr 762 (13.7%) 6.1 per 100 yr 819 (14.8%) 7.0 per 100 yr
<.001 .041 <.001
022 Safety and Tolerability of Repeat Doses of Serelaxin in Patients with Chronic Heart Failure: the RELAX-REPEAT Study John R. Teerlink1, Rajnish Saini2, Lars Gullestad3, Jacques Descotes4, Tomasz Masior5, Yaqin Wang2, Judy Pak2, Yinuo Pang6, Elaine Unemori7, Thomas Severin5; 1UCSF, San Francisco, CA; 2Novartis Pharmaceuticals, East Hanover, NJ; 3Oslo University Hospital Rikshospitalet, Oslo, Norway; 4ImmunoSafe© and Lyon University, Lyon, France; 5 Novartis Pharma, Basel, Switzerland; 6NIBR, Cambridge, MA; 7Unaffiliated, Oakland, CA Background: Nearly 30% of patients (pts) are rehospitalized within 60–90 days of discharge after an episode of acute heart failure (AHF). Serelaxin, currently in Phase III AHF trials, has been shown to reduce in-hospital worsening HF and mortality in AHF pts. As serelaxin may be repeatedly administered, the RELAX-REPEAT study assessed the safety and immumogenicity of repeat serelaxin doses in pts with compensated chronic HF. Methods: In this multicenter, double-blind, Phase IIb study (NCT01982292), pts received 3 sequential 48 hour IV infusions of serelaxin 30 μg/kg/day or placebo (2:1) at randomization, Week (Wk) 4, and 8, in addition to standard of care. Primary objective was to assess proportion of pts developing anti serelaxin antibodies at any time following serelaxin infusions. Secondary objectives included other assessments of possible serelaxin immunogenicity and safety and tolerability of repeat infusions. Exploratory assessments included effects on renal function and other biomarkers. Results: Of the 323 pts randomized, 320 (serelaxin, n = 212; placebo, n = 108) were included in the safety set. Twelve pts from the serelaxin group were excluded as they did not meet prespecified antibody analysis criteria. One of 200 pts (0.5%) who received serelaxin had anti serelaxin antibody positive results (non neutralizing) at Wk 2 through Wk 12 that were undetectable at Wk 16 and not associated with any AEs. There is 95% confidence that the true proportion of pts who develop antibodies following repeat serelaxin doses is less than 2.4% (upper limit of the exact 1-sided CI). There were no confirmed hypersensitivity or infusion related reactions following adjudication in either treatment groups; overall incidence of all treatment-emergent AEs was comparable. There were statistically significant decreases in cystatin-C and increases in eGFR following each serelaxin infusion compared with placebo (Figure), and decreases in plasma aldosterone that were significant after the 3rd infusion. Conclusion: Overall, data showed that repeat doses of serelaxin were safe and well tolerated in pts with chronic HF. The immunogenicity profile of serelaxin was favorable and there were no confirmed hyperensitivity or infusion related reactions. There were notable improvements in renal function following each 48 hour serelaxin infusion.
023 The Effect of Omecamtiv Mecarbil on Symptoms of Heart Failure in the Chronic Oral Study of Myosin Activation to Increase Contractility in Heart Failure (COSMIC-HF) John R. Teerlink1, G. Michael Felker2, John J.V. McMurray3, Scott D. Solomon4, Adrian Kielhorn5, Fady I. Malik6, Narimon Honarpour5; 1San Francisco VAMC/UCSF, San Francisco, CA; 2Duke University, Durham, NC; 3University of Glasgow, Glasgow, United Kingdom; 4Harvard Medical School, Boston, MA; 5Amgen, Inc., Thousand Oaks, CA; 6 Cytokinetics, Inc., South San Francisco, CA Introduction: Improving myocardial contractile function remains an attractive therapeutic target in patients with heart failure and reduced ejection fraction (HFrEF). Hypothesis: The selective cardiac myosin activator, omecamtiv mecarbil (OM) improves heart failure symptoms after 20 weeks of treatment in patients with HFrEF. Methods: COSMIC-HF (NCT 01786512) was a Phase 2 multicenter, randomized, doubleblind, placebo-controlled trial in outpatients with a history of chronic HF, LVEF ≤40%, and NT-proBNP ≥200 pg/mL (≥1200 pg/mL with atrial fibrillation). Patients were randomized 1:1:1 to receive placebo, OM 25 mg BID, or OM 25 mg twice daily with pharmacokinetic-guided uptitration to 50 mg twice daily (PK-titration). Patients selfassessed heart failure symptoms at baseline with a Patient Global Rating of Severity (PGR-S; 6-point categorial Likert scale from “none” to “very severe”). The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure patient symptoms at baseline and week 20 (0–100 scale; best score = 100). Results: The KCCQ Total Symptom Score (TSS) was increased at Week 20 in a dose-related fashion with a 4.9 point improvement in the OM PK-titration group (Table; P = .03). This difference is similar in magnitude to the clinically relevant 5-point change identified for the TSS in recent work. In patients who were asymptomatic to mildly symptomatic at baseline (PGR-S Group 1 = none, very mild or mild symptoms), there were modest improvements in the TSS at week 20 and the increases in the OM-treated patients were only slightly larger compared to placebo. In patients who were moderately to very severely symptomatic at baseline (PGR-S Group 2 = moderate, severe, or very severe
Table. KCCQ Total Symptom Score (TSS) by Treatment Group (*P < .10; **P < .05) Placebo TSS-Overall (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI) TSS-Group 1: Asymptomatic to Mildly Sx (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI) TSS-Group 2: Moderately to Very Severely Sx (n) Baseline—Mean (SD) Change from baseline at Week 20 - Mean (SD) Difference vs. Placebo—Mean (95%CI)
149 69.7 (21.2) 5.0 (1.6)
OM 25 mg po BID 150 70.9 (22.0) 6.6 (1.6)
OM PK-Titration 146 67.3 (21.3) 9.9 (1.6)
—
1.7 (−2.8, 6.1)
4.9 (0.5, 9.4)**
81
86
75
77.3 (16.4) 1.6 (1.8)
80.2 (18.3) 2.7 (2.0)
78.4 (17.4) 4.3 (1.6)
—
1.2 (−4.1, 6.4)
2.7 (−2.2, 7.6)
67
64
71
60.2 (22.6) 9.5 (2.7) —
58.3 (20.2) 11.3 (2.6) 1.8 (−5.7, 9.3)
55.5 (18.7) 16.0 (2.7) 6.5 (−1.0, 14.0)*