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PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.
Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.1 While associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.1 The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.2
Pathways for current therapies
Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.
The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.
For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.
TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
TGF-signaling pathway
A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).
A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
Denervation technique
Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.
Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
References
1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.
2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.
PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.
Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.1 While associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.1 The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.2
Pathways for current therapies
Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.
The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.
For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.
TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
TGF-signaling pathway
A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).
A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
Denervation technique
Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.
Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
References
1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.
2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.
PHILADELPHIA — Promise that the unmet need for more effective pulmonary artery hypertension treatments may soon be met was in strong evidence in research into three strategies presented at this year’s recent American Heart Association scientific sessions; one was based on an ancient Chinese herb epimedium (yin yang huo or horny goat weed) commonly used for treating sexual dysfunction and directly related to the phosphodiesterase inhibitors sildenafil, vardenafil, and tadalafil (sold as Viagra, Levitra, and Cialis). A second studied sotatercept, an investigational, potential first-in-class activin signaling inhibitor biologic, and a third evaluated physically ablating the baroreceptor nerves that stimulate vasoconstriction of the pulmonary artery via catheter-based techniques.
Until as recently as the late 1970s, a pulmonary arterial hypertension diagnosis was a uniformly fatal one.1 While associated with pulmonary and right ventricle remodeling, and leads toward heart failure and death. The complex underlying pathogenesis was divided into six groups by the 6th World Symposium on Pulmonary Hypertension (WSPH) in 2018, and includes as its most common features pulmonary artery endothelial cell dysfunction, pulmonary artery smooth muscle cell proliferation and migration, and dysregulated fibroblast activity leading to dysregulated vasoconstriction, micro and in-situ vascular thrombosis, vascular fibrosis and pathogenic remodeling of pulmonary vessels.1 The threshold mean arterial pressure (mPAP) for pulmonary arterial hypertension was defined by the 6th [WSPH] at mPAP ≥ 20 mm Hg, twice the upper limit of a normal mPAP of 14.0 ± 3.3 mm Hg as reported by Kovacs et al. in 2018.2
Pathways for current therapies
Current drugs for pulmonary arterial hypertension focus on three signaling pathways, including the endothelin receptor, prostacyclin and nitric oxide pathways, stated Zhi-Cheng Jing, MD, professor of medicine, head of the cardiology department at Peking Union Medical College Hospital, Peking, China. While the phosphodiesterase 5 inhibitors sildenafil and tadalafil, which target the nitric oxide pathway, came into wide use after Food and Drug Administration approval, the need for higher PDE5-selectivity remains, Dr. Jing said. Structurally modified from the active ingredient in epimedium, TPN171H is an investigational PDE5 inhibitor which has shown several favorable features: a greater PDE5 selectivity than both sildenafil and tadalafil in vitro, an ability to decrease right ventricular systolic pressure and alleviate arterial remodeling in animal studies, and safety and tolerability in healthy human subjects.
The current randomized, double-blind, placebo-and active-controlled phase IIa study assessed the hemodynamic impact of a single oral dose of TPN171H in 60 pulmonary arterial hypertension patients (mean age ~34 years, 83.3% female), all with negative vasodilation test results and in WHO class 2 or 3. Only patients aged 18-75 years with group 1 pulmonary arterial hypertension of idiopathic, connective tissue disorder, or repaired congenital heart defects etiology were included. Patients were divided into six groups: placebo, TPN171H at 2.5, 5, and 10 milligrams, and tadalafil at 20 and 40 milligrams.
For the primary endpoint of maximum decrease in pulmonary vascular resistance (PVR), significant reductions vs. placebo were found only for the TPN171H 5-mg group (–41.2% vs. –24.4%; P = .008) and for the 20-mg (–39.8%) and 40-mg (–37.6%) tadalafil groups (both P < .05). What was not seen in the tadalafil groups, but was evident in the TPN171H 5-mg group, was a significant reduction in the secondary endpoint of PVR/SVR (systolic vascular resistance) at 2, 3, and 5 hours (all P < .05). “As we know,” Dr. Jing said in an interview, “the PDE5 inhibitor functions as a vasodilator, having an impact on both pulmonary circulation and systemic circulation. So, to evaluate the selectivity for pulmonary circulation is crucial when exploring a novel drug for pulmonary arterial hypertension. The change of PVR/SVR ratio from baseline is an indicator for selectivity for pulmonary circulation and implies that TPN171H has good PDE5 selectivity in the pulmonary vasculature,” Dr. Jing said.
TPN171H was well tolerated with no serious adverse effects (vomiting 10% and headache 10% were most common with no discontinuations).
TGF-signaling pathway
A meta-analysis of randomized controlled trials of sotatercept, an investigational fusion protein under priority FDA review that modulates the TGF-beta superfamily signaling pathway, looked at PVR, pulmonary arterial pressure (PAP), right arterial pressure (RAP) and N-terminal pro-brain natriuretic peptide (NT-proBNP). A literature search by corresponding author Vamsikalyan Borra, MD, Knapp Medical Center, Weslaco, Texas, and colleagues identified two trials (STELLAR and PULSAR) comprising 429 patients with pulmonary arterial hypertension. The experimental arms (sotatercept) had 237 patients (mean age ~49 years, ~82% female) and the placebo arm had 192 patients (mean age ~47 years, ~80% female).
A pooled analysis showed significant reductions with sotatercept in PVR (standardization mean difference [SMD] = –1.00, 95% confidence interval [CI] = –1.2, –.79, P < .001), PAP (SMD = –1.34, 95% CI = 1.6, –1.08, P < .001), RAP (SMD = –0.66, 95% CI = –0.93, –0.39, P < .001), and the levels of NT-proBNP (SMD = –0.64, 95% CI = –1.01, –0.27, P < .001) at 24 weeks from baseline. The sotatercept safety profile was favorable, with lower overall incidence of adverse events (84.8% vs. 87.5%) and fewer adverse events leading to death (0.4% vs. 3.1%) compared with placebo. Further investigation is needed, however, according to Dr. Borra, into the higher frequency of reported thrombocytopenia (71.7% vs. 20.8%) with sotatercept. “Our findings,” Dr. Borra said in a poster session, “suggest that sotatercept is an effective treatment option for pulmonary arterial hypertension, with the potential to improve both pulmonary and cardiac function.”
Denervation technique
Catheter-based ablation techniques, most commonly using thermal energy, target the afferent and efferent fibers of the baroreceptor reflex in the main pulmonary artery trunk and bifurcation involved in elevated pulmonary artery pressure. Mounica Vorla, MD, Carle Foundation Hospital, Urbana, Illinois, and colleagues conducted an updated systematic review and meta-analysis of the safety and efficacy of pulmonary artery denervation (PADN) for pulmonary arterial hypertension in seven clinical trials with 506 patients with moderate-severe pulmonary arterial hypertension conducted from 2013 to 2022.
Compared with placebo, PADN treatment was associated with a significant reduction in mean pulmonary artery pressure (weighted mean difference [WMD] = –6.9 mm Hg; 95% CI = –9.7, –4.1; P < .01; I2 = 61) and pulmonary vascular resistance (WMD = –3.2; 95% CI = –5.4, –0.9; P = .005). PADN improvements in cardiac output were also statistically significant (WMD = 0.3; 95% CI = 0.07, 0.6; P = .012), with numerical improvement in 6-minute walking distance (WMD = 67.7; 95% CI = –3.73, 139.2; P = .06) in the PADN group. Side effects were less common in the PADN group as compared with the placebo group, Dr. Vorla reported. She concluded, “This updated meta-analysis supports PADN as a safe and efficacious therapy for severe pulmonary arterial hypertension.” The authors noted limitations imposed by the small sample size, large data heterogeneity, and medium-quality literature. Larger randomized, controlled trials with clinical endpoints comparing PADN with optimal medical therapy are needed, they stated.
References
1. Shah AJ et al. New Drugs and Therapies in Pulmonary Arterial Hypertension. Int J Mol Sci. 2023 Mar 19;24(6):5850. doi: 10.3390/ijms24065850. PMID: 36982922; PMCID: PMC10058689.
2. Kovacs G et al. Pulmonary Vascular Involvement in Chronic Obstructive Pulmonary Disease. Is There a Pulmonary Vascular Phenotype? Am J Respir Crit Care Med. 2018 Oct 15;198(8):1000-11. doi: 10.1164/rccm.201801-0095PP. PMID: 29746142.
FROM AHA 2023