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Pharmacokinetics (PK) of Adenosine A1 Receptor Antagonist BG9928 in Healthy Subjects, Elderly Subjects, and Subjects with Severe Renal Insufficiency (SRI)
The 13th Annual Scientific Meeting stepwise regression analysis revealed that age, EF, and NYHA Class IV were most strongly associated with prolonged QRS duration. Use of guideline-recommended HF medications did not differ by QRS duration. Conclusions: Prolonged QRS duration was present in 38% of device-naı¨ve patients with LVSD. Prolonged QRS is a common finding in LVSD and is more frequent in older, more symptomatic patients with reduced EF who may benefit from CRT.
[CK-1827452] (ng/mL)
1-100
O100-200
O200-300
O300-400
S65
HFSA
O400-500
O500
Difference of Least Squares Means 6 SEM Stroke Volume # 50 mL at baseline (n59 pts) SET (msec) SV (mL)^ FS (%) SET (msec) SV (mL)^ FS (%)
268 18 6 7# 53 6 8& 58 6 13& 463 8 6 3* 663 16 6 5* 262 361 262 6 6 2# Stroke Volume O 50 mL at baseline (n534 pts) 064 19 6 5y 45 6 6& 57 6 7& -2 6 2 -2 6 2 6 6 3# 9 6 3* 061 161 3 6 1y 261
69 6 9& 14 6 4y 4 6 2#
88 6 8& 663 5 6 2y
53 6 8& 664 162
76 6 6& 12 6 3& 4 6 1&
^Doppler Derived, ## 0.05, *# 0.01, y# 0.001, &# 0.0001
placebo-controlled, cross-over fashion. Echocardiography was used to evaluate the CK-452 response. Results: All echos (n 5 564) were stratified by SV prior to treatment and paired with coincident plasma concentrations of CK-452. The concentration response for patients with a baseline SV # 50 mL versus O 50 mL was computed by binning data in 100 ng/mL increments and calculating the least squares mean difference for the change from baseline as compared to placebo. Increases in SET were similar regardless of baseline SV. In patients with SV # 50 mL, robust, statistically significant increases in SV and FS were observed despite the smaller subgroup size. Conclusions: The cardiac myosin activator, CK-452, increased SV and FS in patients with stable HF and a diminished stroke volume at baseline. Underlying these increases were similar concentration-dependent increases in SET, consistently the most sensitive indicator of drug effect. These findings support translation of this novel and unique mechanism into patients with more severe and acute heart failure.
214 212 Hypertension, Potentially Leading to Heart Failure, Associated with AntiVascular Endothelial Growth Factor Therapy Can Be Predicted by Baseline Risk Factors and Serial B-Type Natriuretic Peptide Levels during Treatment Aarif Khakoo, Mona Massey, Cindy Chua, Amy Chiu, Elie Mouhayer, Jean-Bernard Durand, Daniel J. Lenihan; Cardiology, UT MD Anderson Cancer Center, Houston, TX Introduction: Anti-vascular endothelial growth factor (Anti-VEGF) therapy is being widely used as anti-cancer treatment for a variety of cancers in combination or as a single agent. There have been several recent reports linking these treatments to the development of hypertension (HTN) and heart failure with serious deleterious effects. Currently, no method has reliably predicted the development of such cardiac toxicity with these anti-cancer therapies. Methods: We prospectively evaluated 31 patients undergoing Anti-VEGF therapy for cancer (52% gastrointestinal stromal, 32% thyroid, 10% renal cell and 6% others) who had no heart failure and a normal baseline left ventricular ejection fraction. All patients has clinical exams, B-type natriuretic peptide (BNP) levels and echocardiograms at baseline and at 6 months with other testing as clinically indicated during therapy. Results: 13/31 (42%) had hyperlipemia and strong family history of heart disease, 6/31 (19%) were diabetic, 14/31 (45%) were smokers and 17/31 (55%) were hypertensive at baseline. The mean BNP was 88 pg/ml and the mean ejection fraction was 56%. At six months, 9/31 developed severe HTN during treatment (O150/100 mm Hg, requiring more than 1 drug for control). 2 of these patients developed heart failure. BNP values during therapy were abnormal (O100 pg/ml) in 5/9 of these patients with HTN but only one value was abnormal in all of the remaining 22 patients. Ejection fraction did not significantly change throughout the follow up period except in one patient with HTN and an elevated BNP Conclusion: Patients undergoing Anti-VEGF therapy for cancer have a high prevalence of cardiac risk factors, are very likely to develop severe HTN, and BNP levels during treatment may detect heart failure earlier than ejection fraction measurements.
213
Pharmacokinetics (PK) of Adenosine A1 Receptor Antagonist BG9928 in Healthy Subjects, Elderly Subjects, and Subjects with Severe Renal Insufficiency (SRI) Thomas C. Marbury1, Barry Ticho2, Scott Stecher2, Ying Zhu2, Suzanne K. Swan3; 1 Orlando Clinical Research Center, Orlando, FL; 2Biogen Idec, Cambridge, MA; 3 Division of Nephrology, University of Minnesota, Minneapolis, MN Introduction: BG9928, a potent adenosine A1 receptor antagonist that has been shown to increase sodium excretion and reduce body weight while preserving renal function, is currently being developed as an IV and oral agent to treat heart failure patients with concomitant renal insufficiency. Objectives: To evaluate the PK of BG9928 in healthy subjects with normal renal function, elderly subjects, and subjects with SRI. Methods: This was an open-label, parallel-group study. Healthy subjects (age 18-75y) with normal renal function, elderly subjects (age $81y) with normal renal function (per age), and subjects with SRI (age 18-75y; GFR #30 mL/ min/1.73m2) received a single 30-minute IV infusion of BG9928 1 mg/kg. Blood samples were collected for analysis before and after BG9928 dosing. Results: A total of 24 subjects enrolled (8 per group). No clinically meaningful differences in total clearance and exposure of BG9928 were observed among the 3 groups (Table 1). Conclusion: In this study, no clinically meaningful differences were
Table 1. Mean (SD) PK Parameters Following IV BG9928 (1 mg/kg) Parameter tmax (hr) Cmax (ng/ml) AUClast (ng/hr/mL) AUCinf (ng/hr/mL) T1/2 (hr) Vz (mL/kg) Cl (mL/hr/kg)
Healthy Subjects (n58) 0.4 5131 16456 18139 19.9 1670 61.9
(0.12) (735.1) (6924.0) (7409.8) (11.8) (839.9) (20.2)
Subjects With SRI (n58) 0.5 4056 14513 15828 21.1 1931 82.6
(0.10) (586.5) (6700.8) (7956.4) (17.5) (1156.1) (46.4)
Elderly Subjects (n58) 0.5 4790 13771 14320 17.7 2090 80.9
(0.10) (828.5) (5642.6) (6186.3) (6.3) (1280.7) (30.5)
BG9928 at the doses administered was generally well tolerated in these subjects. The incidence of adverse events (AEs) was similar among the 3 groups, and no serious AEs were reported.
observed in PK parameters following single IV doses of BB9928 among healthy subjects with normal renal function, elderly subjects, and subjects with SRI. As BG9928 was well tolerated, these data support the conduct of additional studies to further define the PK, metabolism, safety and efficacy of this compound in patients with renal insufficiency.
An Analysis of the Response to CK-1827452, a Selective Cardiac Myosin Activator, in Stable Heart Failure Patients Stratified by Baseline Cardiac Function Fady I. Malik1, Khalil G. Saikali1, Michael M. Chen1, Jacqueline H. Lee1, Jonathan H. Goldman2, Andrew A. Wolff1, John R. Teerlink3; 1CY 1121 Investigators, Cytokinetics, Inc., South San Francisco, CA; 2ICON Medical Imaging, Inc., Warrington, PA; 3UCSF, San Francisco, CA
215
Introduction: CK-1827452 (CK-452) is a cardiac myosin activator that increased indices of systolic function in a clinical trial of patients with stable heart failure (HF). Overall, mean baseline stroke volume (SV) was normal (69 mL) in the study population, consistent with their compensated state. We stratified the population by baseline SV to see if the response to CK-452 was similar in the subgroup with diminished SV (# 50 mL). Methods: Patients with EF ! 40% (n545) and treated with stable HF medications were studied in a multi-center, double-blind, randomized,
In Hospital Early (Within 5 Days) Worsening HF Predicts Adverse Outcome in Patients Admitted for AHF e Results from the Pre-RELAX-AHF Study B. Davison Weatherley, G. Cotter, GM Felker, J.R. Teerlink, G. Filippatos, B. Greenberg, A. Voors, M. Metra, S.L. Teichman, E. Unemori, Momentum ResearchInc.Durham, NC; Cardiology, Duke Clinical Research Institute, Durham, NC; Section of Cardiology, Veterans Affairs Medical Center, University of California, San Francisco, CA; Athens University Hospital, Athens, Greece; Advanced Heart Failure Program, University of California, San Diego, CA;
[CK-1827452] (ng/mL)
1-100
O100-200
O200-300
O300-400
S65
HFSA
O400-500
O500
Difference of Least Squares Means 6 SEM Stroke Volume # 50 mL at baseline (n59 pts) SET (msec) SV (mL)^ FS (%) SET (msec) SV (mL)^ FS (%)
268 18 6 7# 53 6 8& 58 6 13& 463 8 6 3* 663 16 6 5* 262 361 262 6 6 2# Stroke Volume O 50 mL at baseline (n534 pts) 064 19 6 5y 45 6 6& 57 6 7& -2 6 2 -2 6 2 6 6 3# 9 6 3* 061 161 3 6 1y 261
69 6 9& 14 6 4y 4 6 2#
88 6 8& 663 5 6 2y
53 6 8& 664 162
76 6 6& 12 6 3& 4 6 1&
^Doppler Derived, ## 0.05, *# 0.01, y# 0.001, &# 0.0001
placebo-controlled, cross-over fashion. Echocardiography was used to evaluate the CK-452 response. Results: All echos (n 5 564) were stratified by SV prior to treatment and paired with coincident plasma concentrations of CK-452. The concentration response for patients with a baseline SV # 50 mL versus O 50 mL was computed by binning data in 100 ng/mL increments and calculating the least squares mean difference for the change from baseline as compared to placebo. Increases in SET were similar regardless of baseline SV. In patients with SV # 50 mL, robust, statistically significant increases in SV and FS were observed despite the smaller subgroup size. Conclusions: The cardiac myosin activator, CK-452, increased SV and FS in patients with stable HF and a diminished stroke volume at baseline. Underlying these increases were similar concentration-dependent increases in SET, consistently the most sensitive indicator of drug effect. These findings support translation of this novel and unique mechanism into patients with more severe and acute heart failure.
214 212 Hypertension, Potentially Leading to Heart Failure, Associated with AntiVascular Endothelial Growth Factor Therapy Can Be Predicted by Baseline Risk Factors and Serial B-Type Natriuretic Peptide Levels during Treatment Aarif Khakoo, Mona Massey, Cindy Chua, Amy Chiu, Elie Mouhayer, Jean-Bernard Durand, Daniel J. Lenihan; Cardiology, UT MD Anderson Cancer Center, Houston, TX Introduction: Anti-vascular endothelial growth factor (Anti-VEGF) therapy is being widely used as anti-cancer treatment for a variety of cancers in combination or as a single agent. There have been several recent reports linking these treatments to the development of hypertension (HTN) and heart failure with serious deleterious effects. Currently, no method has reliably predicted the development of such cardiac toxicity with these anti-cancer therapies. Methods: We prospectively evaluated 31 patients undergoing Anti-VEGF therapy for cancer (52% gastrointestinal stromal, 32% thyroid, 10% renal cell and 6% others) who had no heart failure and a normal baseline left ventricular ejection fraction. All patients has clinical exams, B-type natriuretic peptide (BNP) levels and echocardiograms at baseline and at 6 months with other testing as clinically indicated during therapy. Results: 13/31 (42%) had hyperlipemia and strong family history of heart disease, 6/31 (19%) were diabetic, 14/31 (45%) were smokers and 17/31 (55%) were hypertensive at baseline. The mean BNP was 88 pg/ml and the mean ejection fraction was 56%. At six months, 9/31 developed severe HTN during treatment (O150/100 mm Hg, requiring more than 1 drug for control). 2 of these patients developed heart failure. BNP values during therapy were abnormal (O100 pg/ml) in 5/9 of these patients with HTN but only one value was abnormal in all of the remaining 22 patients. Ejection fraction did not significantly change throughout the follow up period except in one patient with HTN and an elevated BNP Conclusion: Patients undergoing Anti-VEGF therapy for cancer have a high prevalence of cardiac risk factors, are very likely to develop severe HTN, and BNP levels during treatment may detect heart failure earlier than ejection fraction measurements.
213
Pharmacokinetics (PK) of Adenosine A1 Receptor Antagonist BG9928 in Healthy Subjects, Elderly Subjects, and Subjects with Severe Renal Insufficiency (SRI) Thomas C. Marbury1, Barry Ticho2, Scott Stecher2, Ying Zhu2, Suzanne K. Swan3; 1 Orlando Clinical Research Center, Orlando, FL; 2Biogen Idec, Cambridge, MA; 3 Division of Nephrology, University of Minnesota, Minneapolis, MN Introduction: BG9928, a potent adenosine A1 receptor antagonist that has been shown to increase sodium excretion and reduce body weight while preserving renal function, is currently being developed as an IV and oral agent to treat heart failure patients with concomitant renal insufficiency. Objectives: To evaluate the PK of BG9928 in healthy subjects with normal renal function, elderly subjects, and subjects with SRI. Methods: This was an open-label, parallel-group study. Healthy subjects (age 18-75y) with normal renal function, elderly subjects (age $81y) with normal renal function (per age), and subjects with SRI (age 18-75y; GFR #30 mL/ min/1.73m2) received a single 30-minute IV infusion of BG9928 1 mg/kg. Blood samples were collected for analysis before and after BG9928 dosing. Results: A total of 24 subjects enrolled (8 per group). No clinically meaningful differences in total clearance and exposure of BG9928 were observed among the 3 groups (Table 1). Conclusion: In this study, no clinically meaningful differences were
Table 1. Mean (SD) PK Parameters Following IV BG9928 (1 mg/kg) Parameter tmax (hr) Cmax (ng/ml) AUClast (ng/hr/mL) AUCinf (ng/hr/mL) T1/2 (hr) Vz (mL/kg) Cl (mL/hr/kg)
Healthy Subjects (n58) 0.4 5131 16456 18139 19.9 1670 61.9
(0.12) (735.1) (6924.0) (7409.8) (11.8) (839.9) (20.2)
Subjects With SRI (n58) 0.5 4056 14513 15828 21.1 1931 82.6
(0.10) (586.5) (6700.8) (7956.4) (17.5) (1156.1) (46.4)
Elderly Subjects (n58) 0.5 4790 13771 14320 17.7 2090 80.9
(0.10) (828.5) (5642.6) (6186.3) (6.3) (1280.7) (30.5)
BG9928 at the doses administered was generally well tolerated in these subjects. The incidence of adverse events (AEs) was similar among the 3 groups, and no serious AEs were reported.
observed in PK parameters following single IV doses of BB9928 among healthy subjects with normal renal function, elderly subjects, and subjects with SRI. As BG9928 was well tolerated, these data support the conduct of additional studies to further define the PK, metabolism, safety and efficacy of this compound in patients with renal insufficiency.
An Analysis of the Response to CK-1827452, a Selective Cardiac Myosin Activator, in Stable Heart Failure Patients Stratified by Baseline Cardiac Function Fady I. Malik1, Khalil G. Saikali1, Michael M. Chen1, Jacqueline H. Lee1, Jonathan H. Goldman2, Andrew A. Wolff1, John R. Teerlink3; 1CY 1121 Investigators, Cytokinetics, Inc., South San Francisco, CA; 2ICON Medical Imaging, Inc., Warrington, PA; 3UCSF, San Francisco, CA
215
Introduction: CK-1827452 (CK-452) is a cardiac myosin activator that increased indices of systolic function in a clinical trial of patients with stable heart failure (HF). Overall, mean baseline stroke volume (SV) was normal (69 mL) in the study population, consistent with their compensated state. We stratified the population by baseline SV to see if the response to CK-452 was similar in the subgroup with diminished SV (# 50 mL). Methods: Patients with EF ! 40% (n545) and treated with stable HF medications were studied in a multi-center, double-blind, randomized,
In Hospital Early (Within 5 Days) Worsening HF Predicts Adverse Outcome in Patients Admitted for AHF e Results from the Pre-RELAX-AHF Study B. Davison Weatherley, G. Cotter, GM Felker, J.R. Teerlink, G. Filippatos, B. Greenberg, A. Voors, M. Metra, S.L. Teichman, E. Unemori, Momentum ResearchInc.Durham, NC; Cardiology, Duke Clinical Research Institute, Durham, NC; Section of Cardiology, Veterans Affairs Medical Center, University of California, San Francisco, CA; Athens University Hospital, Athens, Greece; Advanced Heart Failure Program, University of California, San Diego, CA;