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for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
for patients with pulmonary arterial hypertension (PAH) in a phase 2 trial.
The mean decline change in pulmonary vascular resistance (PVR) after 24 weeks of treatment was significantly greater for patients treated with sotatercept at either of two doses, compared with placebo, David B. Badesch, MD, FCCP, of the University of Colorado, Aurora, reported on behalf of coinvestigators in the PULSAR trial.
“Sotatercept has a novel mechanism of action, rebalancing pro- and antiproliferative signaling through a pathway distinct from the previously approved pulmonary arterial hypertension therapies,” he said in the American Thoracic Society’s virtual clinical trial session.
The drug is a ligand trap with high selectivity for proteins within the tumor growth factor-beta superfamily signaling pathway. Investigators propose a mechanism of action whereby sotatercept promotes a rebalancing of bone morphogenetic protein receptor–II (BMPR-II) signaling to restore vascular homeostasis.
In a preclinical study, sotatercept reduced pulmonary artery pressure, pulmonary arteriolar muscularization and occlusion, right ventricular hypertrophy, and cell proliferation in the lungs of rodent models of pulmonary hypertension (Sci Transl Med. 2020 May 13. doi: 10.1126/scitranslmed.aaz5660).
Two dose levels
The PULSAR trial (NCT03496207) was a phase 2 randomized, double-blind study conducted in the United States, Brazil, Western Europe, and Australia comparing the efficacy and safety of sotatercept vs. placebo added to the standard of care in patients with PAH.
A total of 106 patients with World Health Organization (WHO) group 1 PAH or WHO functional class II or III disease were enrolled. All patients had baseline right-heart e4rcatheterization with PVR of 5 Wood units or more, had baseline 6-minute walk distance from 150 to 550 m, and were on stable treatment with standard-of-care mono, double, or triple therapies, including an endothelin-receptor antagonist, phosphodiesterase 5 inhibitor, soluble guanylate cyclase stimulator, and/or a prostacyclin, including intravenous formulations.
The median patient age was 46 years among 32 patients in the placebo group, and 48.5 years in each sotatercept dose group: 0.3 mg/kg (32 patients) and 0.7 mg/kg (42 patients).
The primary endpoint of PVR change from baseline to week 24, the end of the placebo-controlled treatment period, showed a mean decrease of 162 dynes/cm2 in the 0.3-mg/kg sotatercept group (–20.5%), and a mean decrease of 256 dynes/cm2 in the 0.7-mg/kg group (–33.9%), compared with a mean 16 dyne/cm2 decline in the placebo group (–2,1%). Both doses were associated with significantly larger decreases, compared with placebo (P = .0027 for the 0.3-mg/kg dose, and P < .0001 for the 0.7-mg/kg dose).
Six-minute walk distance, a key secondary endpoint, improved over baseline in each active-drug arm, with a least square (LS) mean improvement of 58 m in the 0.7-mg/kg group, and 50 m in the 0.7-mg/kg group. The prespecified analysis of pooled data from the two sotatercept cohorts showed an LS-mean change of 54 m over baseline, compared with 25 m for the placebo group (nominal P = .03).
Exploratory endpoints also favoring sotatercept over placebo included a 51% reduction in amino-terminal brain natriuretic propeptide (NT-proBNP), and a 20% reduction in mean pulmonary arterial pressure.
There was no significant difference between the study arms in change in cardiac output, however.
Improvements in WHO functional class were seen in 12.5% of patients on placebo, compared with 23% of patients on sotatercept, a difference that was not statistically significant.
Two patients (6%) in the 0.3-mg/kg arm and 10 (24%) in the 0.7-mg/kg arm had a serious treatment-emergent adverse event (TEAE), as did three patients (9%) in the placebo arm. Serious TEAEs included leukopenia, neutropenia, pericardial infusion, tachycardia, chorioretinopathy, peripheral edema, pyrexia, bronchitis, influenza, respiratory tract infection, femur fracture, hypotension, device breakage, syncope, and red blood cell increase.
One patient in the 0.7-mg/kg arm died from cardiac arrest deemed unrelated to study treatment.
TEAEs of special interest included thrombocytopenia in two patients in 0.3– and five patients in the 0.7–mg/kg groups, vs. no patients in the placebo groups. Most patients had existing thrombocytopenia at baseline and all were on concomitant prostacyclin infusions. No patients had grade 3 thrombocytopenia or associated bleeding events.
One patient in the 0.3-mg/kg group and six patients in the 0.7-mg/kg group had an increase in hemoglobin.
“This was not a surprise,” Dr. Badesch said. “We were prepared to manage increases in hemoglobin with dose interruption or dose reduction if necessary, and phlebotomy was also an option if needed.”
One patient in the placebo arm, two in the 0.3-mg/kg and three patients in the 0.7-mg/kg arms had TEAEs leading to discontinuation.
TEAEs occurring in 10% or more of all patients in any arm and of any grade were headache, diarrhea, peripheral edema, dizziness, fatigue, hypokalemia, and nausea.
Why no cardiac improvement?
In the question-and-answer session following the online presentation, facilitator Steven M. Kawut MD, MS, of the University of Pennsylvania and Pennsylvania Hospital in Philadelphia, remarked on the surprising lack of an apparent cardiac benefit in the study.
“You showed pretty robust decreases in NT-proBNP, decreases in pulmonary vascular resistance and right atrial pressure, and increases in 6-minute walk distance, so it’s a bit surprising that cardiac output didn’t change,” he said.
“Unlike other medications that have been tried in this field and have had a significant pulmonary vasodilatory effect, this drug is acting largely on the structure of pulmonary blood vessels,” Dr. Badesch replied. “We have thought that its primary effect is likely remodeling of the pulmonary arteries and arterioles, decreasing pulmonary vascular resistance. Unlike other drugs that have been tested in the field, it probably has no direct inotropic effect, and that may explain why cardiac output didn’t improve.”
He said that there is some echocardiographic evidence that suggests a change in right ventricular function over time. Those data are currently being analyzed, and “it’s possible that we’ll see an effect on cardiac output later.”
As of June 22, 2020, 94 of 97 patients who opted to participate in an 18-month extension period of the trial were still enrolled, and 64 patients have now been treated with sotatercept for at least 12 months.
A phase 3 trial is in the works.
The study was supported by Acceleron Pharma. Badesch disclosed research support from and consulting/advising for the company and others. Dr. Kawut has disclosed grants from several companies and travel support from ATS and the Pulmonary Hypertension Association.
FROM ATS 2020