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Ralinepag Plasma Levels Correlate with Improvements in Functional and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension
S208
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
measures were observed for ralinepag XR tablet with low steady-state peak-to-trough ratio (≤2) upon qd dosing, approximating the ‘ideal’ continuous IV infusion-like PK profile for agents in this drug class, and minimal food effect. Females had higher mean exposure measures than males, for which such differences were not statistically significant or considered clinically meaningful. Conclusion: The ralinepag XR tablet offers improved PK performance over both ralinepag and selexipag IR formulations, with extended exposure and low peak-to-trough ratio with qd dosing, supporting its use in the ADVANCE Phase 3 program.
495 Two Polymorphic Gene Loci Associated with Treprostinil Dose in Pulmonary Arterial Hypertension M.A. Psotka,1 V. Thomeas-McEwing,2 E.R. Gamazon,3 T. Hirota,4 P.N. Friedman,5 A. Konkashbaev,3 M. Kubo,4 Y. Nakamura,6 M.J. Ratain,7 R.L. Benza,8 N.J. Cox,3 M.I. Gomberg-Maitland,1 and M.L. Maitland.2 1Inova Heart and Vascular Institute, Falls Church, VA; 2 Center for Personalized Health, Inova Schar Cancer Institute, Falls Church, VA; 3Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN; 4Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; 5Feinberg School of Medicine, Northwestern Univeristy, Chicago, IL; 6Cancer Precision Medicine Research Center, Japanese Foundation for Cancer Research, Tokyo, Japan; 7Department of Medicine, University of Chicago, Chicago, IL; and the 8Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA. Purpose: Prostacyclin infusion is an effective therapy for pulmonary arterial hypertension (PAH) but has variable clinical response and dosing requirements. We performed a genome-wide association study (GWAS) to identify biologically-based predictors of prostacyclin response heterogeneity and gene variants associated with PAH pathogenesis. Methods: Ninety-eight patients with hemodynamically-defined PAH treated at two academic centers were included. Stably dosed treprostinil therapy was the quantitative phenotype for the GWAS. Candidate genes with the largest effect sizes and strongest statistical associations were further characterized in silico and in vitro to confirm mechanistic hypotheses, and at cardiac catheterization to assess for mechanistically consistent physiological effects. Results: Three loci associated with treprostinil dose with P<10¡6; all three had clinically significant effect sizes (Table). Specific SNPs at two of the loci: rs11078738 in PFAS and rs10023113 in CAMK2D encoded sequence changes with predictable consequences. Production of the prostacyclininduced pulmonary vasodilator cyclic adenosine monophosphate was reduced in human cell lines by the missense variant rs11078738. The allele of rs10023113 in the promoter of CAMK2D associated with higher treprostinil dose, conferred a reduced affinity for the FOXP1 transcriptional repressor, was associated with increased expression of CAMKIId in ventricular tissue, and was associated with elevated right mean atrial and ventricular diastolic pressures in a separate cohort of patients at cardiac catheterization. Conclusion: The conduct of effective GWAS is challenging with small numbers of patients. However, by employing the quantitative phenotype of stable treprostinil dose we identified 2 novel loci for treatment response in PAH, gene variants associated with more severe right ventricular dysfunction and higher ultimate dose of treprostinil. Work is ongoing to further characterize these variants.
Loci Associated with Treprostinil Dose
SNP
Chromosome Gene
b
P-Value
Variant Variant Ancestral Allele Allele Allele Frequency
rs2377415 rs10023113 rs11078738 rs12951103 rs4792722
1 4 17 17 17
-17.8 26.3 20.7 20.8 20.2
2.5 £ 10-6 4.7 £ 10-6 4.6 £ 10-6 6.2 £ 10-6 7.9 £ 10-6
A G A A G
CAMK2D PFAS PFAS -
G A G G A
0.500 0.137 0..239 0.796 0.235
496 Ralinepag Plasma Levels Correlate with Improvements in Functional and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension H.W. Farber,1 N. Sood,2 I.R. Preston,1 J. Adams,3 J. Grundy,3 C. King,3 P. Klassen,3 V.F. Tapson,4 V. McLaughlin,5 and R.J. Oudiz.6 1Professor of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA; 2University of Texas Health Science Center of Houston, Houston, TX; 3Arena Pharmaceuticals, Inc, San Diego, CA; 4Cedars-Sinai Medical Center, Los Angeles, CA; 5Kim A. Eagle, MD, Endowed Professor of Cardiovascular Medicine, Director of Pulmonary Hypertension Program, University of Michigan, Ann Arbor, MI; and the 6Department of Medicine, Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrence, CA. Purpose: Ralinepag is an oral, selective, and potent prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension (PAH) that has shown efficacy in patients with PAH in a randomized, double-blind Phase 2 study. Despite evidence of a dose-effect relationship for some drugs targeting the prostacyclin pathway, the relationship between drug plasma levels and efficacy is unknown, particularly for oral therapies. This post hoc analysis of the Phase 2 study evaluated whether ralinepag plasma levels correlated with improvements in functional and/or hemodynamic parameters, including pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD). Methods: Adults with stable functional class II-IV PAH and 6MWD of 100-500 m, on background approved single or dual oral PAH treatment, were randomized 2:1 to receive ralinepag (n=40) or placebo (n=21) for 9 weeks of titration, then 13 weeks of maintenance. Treatment was initiated at 10 mg twice daily (bid) and titrated weekly to maximum tolerated dose, up to 300 mg bid. Ralinepag plasma levels were measured 4 hours postdose at Weeks 9, 10, 14, 18, and 22 (maintenance phase: Weeks 9-22), and mean levels were calculated. Right heart catheterization was performed at Baseline and at Week 22. Efficacy was assessed as percent change in functional and hemodynamic parameters from Baseline to Week 22. Correlation coefficients between mean plasma levels of ralinepag and percent change in efficacy parameters were calculated. Results: Ralinepag plasma levels correlated with ralinepag dose. Over the 22-week study period, there was a significant correlation between ralinepag plasma levels and improvements in PVR and 6MWD (Table). Conclusion: In patients with PAH, ralinepag plasma levels correlated with ralinepag dose and with improvements in PVR and 6MWD, demonstrating a correlation between plasma levels of a prostacyclin pathway oral drug and hemodynamic/functional parameters.
Parameter
Slope (% Change per ng/mL)
95% Confidence Interval
R2
P Value
6MWD PVR
2.49 −4.34
0.45 to 4.53 −6.77 to −1.71
0.10 0.18
0.018 0.0015
497 The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients with Pulmonary Hypertension Associated with HFpEF M.J. Bashline,1 T.N. Bachman,2 N.L. Helbling,3 M.T. Gladwin,4 and M.A. Simon.3 1Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Department of Bioengineering, Uinversity of Pittsburgh, Pittsburgh, PA; 3Vascular Medicine Institute, UPMC Heart and Vascular Institute, Pittsburgh, PA; and the 4Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. Purpose: The severity and clinical response of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance (PVR).
The Journal of Heart and Lung Transplantation, Vol 38, No 4S, April 2019
measures were observed for ralinepag XR tablet with low steady-state peak-to-trough ratio (≤2) upon qd dosing, approximating the ‘ideal’ continuous IV infusion-like PK profile for agents in this drug class, and minimal food effect. Females had higher mean exposure measures than males, for which such differences were not statistically significant or considered clinically meaningful. Conclusion: The ralinepag XR tablet offers improved PK performance over both ralinepag and selexipag IR formulations, with extended exposure and low peak-to-trough ratio with qd dosing, supporting its use in the ADVANCE Phase 3 program.
495 Two Polymorphic Gene Loci Associated with Treprostinil Dose in Pulmonary Arterial Hypertension M.A. Psotka,1 V. Thomeas-McEwing,2 E.R. Gamazon,3 T. Hirota,4 P.N. Friedman,5 A. Konkashbaev,3 M. Kubo,4 Y. Nakamura,6 M.J. Ratain,7 R.L. Benza,8 N.J. Cox,3 M.I. Gomberg-Maitland,1 and M.L. Maitland.2 1Inova Heart and Vascular Institute, Falls Church, VA; 2 Center for Personalized Health, Inova Schar Cancer Institute, Falls Church, VA; 3Division of Genetic Medicine, Vanderbilt University School of Medicine, Nashville, TN; 4Center for Integrative Medical Sciences, RIKEN, Tokyo, Japan; 5Feinberg School of Medicine, Northwestern Univeristy, Chicago, IL; 6Cancer Precision Medicine Research Center, Japanese Foundation for Cancer Research, Tokyo, Japan; 7Department of Medicine, University of Chicago, Chicago, IL; and the 8Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA. Purpose: Prostacyclin infusion is an effective therapy for pulmonary arterial hypertension (PAH) but has variable clinical response and dosing requirements. We performed a genome-wide association study (GWAS) to identify biologically-based predictors of prostacyclin response heterogeneity and gene variants associated with PAH pathogenesis. Methods: Ninety-eight patients with hemodynamically-defined PAH treated at two academic centers were included. Stably dosed treprostinil therapy was the quantitative phenotype for the GWAS. Candidate genes with the largest effect sizes and strongest statistical associations were further characterized in silico and in vitro to confirm mechanistic hypotheses, and at cardiac catheterization to assess for mechanistically consistent physiological effects. Results: Three loci associated with treprostinil dose with P<10¡6; all three had clinically significant effect sizes (Table). Specific SNPs at two of the loci: rs11078738 in PFAS and rs10023113 in CAMK2D encoded sequence changes with predictable consequences. Production of the prostacyclininduced pulmonary vasodilator cyclic adenosine monophosphate was reduced in human cell lines by the missense variant rs11078738. The allele of rs10023113 in the promoter of CAMK2D associated with higher treprostinil dose, conferred a reduced affinity for the FOXP1 transcriptional repressor, was associated with increased expression of CAMKIId in ventricular tissue, and was associated with elevated right mean atrial and ventricular diastolic pressures in a separate cohort of patients at cardiac catheterization. Conclusion: The conduct of effective GWAS is challenging with small numbers of patients. However, by employing the quantitative phenotype of stable treprostinil dose we identified 2 novel loci for treatment response in PAH, gene variants associated with more severe right ventricular dysfunction and higher ultimate dose of treprostinil. Work is ongoing to further characterize these variants.
Loci Associated with Treprostinil Dose
SNP
Chromosome Gene
b
P-Value
Variant Variant Ancestral Allele Allele Allele Frequency
rs2377415 rs10023113 rs11078738 rs12951103 rs4792722
1 4 17 17 17
-17.8 26.3 20.7 20.8 20.2
2.5 £ 10-6 4.7 £ 10-6 4.6 £ 10-6 6.2 £ 10-6 7.9 £ 10-6
A G A A G
CAMK2D PFAS PFAS -
G A G G A
0.500 0.137 0..239 0.796 0.235
496 Ralinepag Plasma Levels Correlate with Improvements in Functional and Hemodynamic Parameters in Patients with Pulmonary Arterial Hypertension H.W. Farber,1 N. Sood,2 I.R. Preston,1 J. Adams,3 J. Grundy,3 C. King,3 P. Klassen,3 V.F. Tapson,4 V. McLaughlin,5 and R.J. Oudiz.6 1Professor of Medicine, Pulmonary, Critical Care and Sleep Division, Tufts Medical Center, Boston, MA; 2University of Texas Health Science Center of Houston, Houston, TX; 3Arena Pharmaceuticals, Inc, San Diego, CA; 4Cedars-Sinai Medical Center, Los Angeles, CA; 5Kim A. Eagle, MD, Endowed Professor of Cardiovascular Medicine, Director of Pulmonary Hypertension Program, University of Michigan, Ann Arbor, MI; and the 6Department of Medicine, Division of Cardiology, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrence, CA. Purpose: Ralinepag is an oral, selective, and potent prostacyclin receptor agonist in development for the treatment of pulmonary arterial hypertension (PAH) that has shown efficacy in patients with PAH in a randomized, double-blind Phase 2 study. Despite evidence of a dose-effect relationship for some drugs targeting the prostacyclin pathway, the relationship between drug plasma levels and efficacy is unknown, particularly for oral therapies. This post hoc analysis of the Phase 2 study evaluated whether ralinepag plasma levels correlated with improvements in functional and/or hemodynamic parameters, including pulmonary vascular resistance (PVR) and 6-minute walk distance (6MWD). Methods: Adults with stable functional class II-IV PAH and 6MWD of 100-500 m, on background approved single or dual oral PAH treatment, were randomized 2:1 to receive ralinepag (n=40) or placebo (n=21) for 9 weeks of titration, then 13 weeks of maintenance. Treatment was initiated at 10 mg twice daily (bid) and titrated weekly to maximum tolerated dose, up to 300 mg bid. Ralinepag plasma levels were measured 4 hours postdose at Weeks 9, 10, 14, 18, and 22 (maintenance phase: Weeks 9-22), and mean levels were calculated. Right heart catheterization was performed at Baseline and at Week 22. Efficacy was assessed as percent change in functional and hemodynamic parameters from Baseline to Week 22. Correlation coefficients between mean plasma levels of ralinepag and percent change in efficacy parameters were calculated. Results: Ralinepag plasma levels correlated with ralinepag dose. Over the 22-week study period, there was a significant correlation between ralinepag plasma levels and improvements in PVR and 6MWD (Table). Conclusion: In patients with PAH, ralinepag plasma levels correlated with ralinepag dose and with improvements in PVR and 6MWD, demonstrating a correlation between plasma levels of a prostacyclin pathway oral drug and hemodynamic/functional parameters.
Parameter
Slope (% Change per ng/mL)
95% Confidence Interval
R2
P Value
6MWD PVR
2.49 −4.34
0.45 to 4.53 −6.77 to −1.71
0.10 0.18
0.018 0.0015
497 The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients with Pulmonary Hypertension Associated with HFpEF M.J. Bashline,1 T.N. Bachman,2 N.L. Helbling,3 M.T. Gladwin,4 and M.A. Simon.3 1Department of Internal Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA; 2Department of Bioengineering, Uinversity of Pittsburgh, Pittsburgh, PA; 3Vascular Medicine Institute, UPMC Heart and Vascular Institute, Pittsburgh, PA; and the 4Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA. Purpose: The severity and clinical response of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance (PVR).