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Ralinepag Offers Once Daily Oral Option for PAH
Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.
Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.
“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.
The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).
The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.
Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).
Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).
Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.
Support for Early Introduction
The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.
If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.
Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.
The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.
Attention to Adverse Effects
Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.
“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.
Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.
Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.
“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.
Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.
The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.
Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.
“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.
The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).
The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.
Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).
Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).
Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.
Support for Early Introduction
The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.
If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.
Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.
The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.
Attention to Adverse Effects
Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.
“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.
Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.
Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.
“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.
Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.
The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
Treatment with ralinepag, an investigational prostacyclin receptor agonist, reduced the risk for clinical disease worsening by 55% compared to placebo in patients with pulmonary arterial hypertension (PAH), based on new data from the ADVANCE Outcomes study presented at the American Thoracic Society (ATS) 2026 International Conference.
Ralinepag works by restoring prostacyclin signaling and activating prostacyclin receptors to affect pathways that play a role in the progression of PAH. The drug was originally formulated as an immediate-release capsule but modified to the extended-release tablet used in the current study as a way to optimize once daily dosing.
“The prostacyclin pathway is foundational in the management of PAH, and advancing prostacyclin science has benefited patients over the years,” said lead author Vallerie V. McLaughlin, MD, professor of cardiovascular medicine and director of the Pulmonary Hypertension Program at the University of Michigan, Ann Arbor, Michigan, who presented the findings at the meeting. Although other oral prostacyclin pathway agents available, ralinepag has the advantages of high potency and longer half-life that could be effective and well-tolerated in a more patient-friendly once daily formulation, McLaughlin said.
The international study population included 687 adults with PAH from 30 countries across five continents. Participants were randomized to ralinepag or placebo in addition to their standard PAH background therapies. Ralinepag was orally dosed once daily and titrated for tolerability and response. The mean age of the participants was 52 years, 80% were White, and the median time since PAH diagnosis was 2.3 years. A majority of 62% had idiopathic or heritable PAH, 28.2% had PAH as a result of connective tissue disease, 4.1% had a congenital heart defect, 3.1% had drug- or toxin-induced PAH, and 2.6% had PAH as a result of HIV infection. More than two thirds were considered low risk (characterized as Functional Class II).
The primary endpoint was the time to first indication of clinical worsening, which was defined as death, hospital admission for worsening PAH, initiation of a parenteral or inhaled prostacyclin pathway agent for worsening PAH, or unsatisfactory long-term clinical response.
Overall, patients treated with ralinepag were significantly less likely to experience a clinical worsening event than placebo patients (hazard ratio [HR], 0.45; 95% CI, 0.33-0.62; P < .0001), and 47% more likely to achieve the secondary endpoint of clinical improvement (P = .015).
Patients treated with ralinepag also showed significant improvements over placebo patients in the secondary endpoints of pro-B-type natriuretic peptide levels (24.3% reduction from baseline to week 28 over placebo; P = .0013), and in the 6-minute walk test (a placebo-corrected difference of 20.4 m from baseline to week 28; P = .0033).
Although more than 90% of participants treated with ralinepag reported an adverse event related to the drug, approximately 5% experienced drug-related serious adverse events, and the overall safety profile reflected previous ralinepag studies, with a positive risk-benefit ratio, the investigators noted.
Support for Early Introduction
The researchers expected the efficacy associated with prostacyclin therapy, said McLaughlin. “We were very pleased to see such a strong treatment effect in a relatively low-risk population, primarily Functional Class II with a mean 6-minute walk of nearly 440 meters, with the majority of patients on dual oral therapy,” she said.
If approved, ralinepag could help optimized risk status in PAH, said McLaughlin. “Many patients do not get to low risk with first-line therapy, and oral and inhaled prostacyclin pathway agents are often used in addition to dual therapy with phosphodiesterase type-5 inhibitors and endothelin receptor antagonists,” she said. “The impressive treatment effect of ralinepag in patients primarily treated with dual oral therapy reflects this real-world scenario,” she added. The significant event reduction makes a case for earlier introduction of ralinepag in relatively low-risk patients; a highly effective therapy that targets the prostacyclin pathway may reduce the need for more cumbersome and invasive prostacyclin therapies, McLaughlin added.
Ralinepag remains an investigational drug, but the company plans to seek a New Drug Application from the FDA for the treatment of PAH by the second half of 2026, according to a press release.
The research team would like to continue evaluating the ADVANCE Outcomes database to learn more about dose response, tolerability, and subgroup response, said McLaughlin. At that point, real-world data would be useful, and additional research areas in that setting would include combination therapy with other agents such as sotatercept, as well as the use of ralinepag to transition patients on more complicated and invasive therapy, she said.
Attention to Adverse Effects
Prostacyclin therapies are often offered in oral, inhaled, and the most invasive intravenous/subcutaneous routes, but a gap remains between the strong efficacy seen with parenteral therapy and what many patients are willing or able to use in real-world practice, said Parth M. Rali, MD, director of the Temple University Health System Pulmonary Embolism Response Team Program, Section Temple Lung Pulmonary Vascular Disease Program, Philadelphia, who was not involved in the study.
“Ralinepag provides sustained activation of IP receptors and has very long effective half-life, giving drug exposure comparable to parenteral therapy, and offers the first daily treatment option, which is important for the patients with PAH who are often on multiple drugs therapies,” Rali said.
Given the encouraging phase 2 findings demonstrating meaningful reductions in pulmonary vascular resistance and signals toward clinical benefit, we would like to see a favorable outcome in the phase 3 program. Primary outcome studied was time to clinical worsening in the large, randomized trial that involved global populations from the US, Europe, Latin-America, and Asia Pacific Region. Ralinepag arm had 55% reduction in risk for clinical worsening (HR, ~ 0.45) compared to placebo arm. “The positive results of the trial were primarily driven by disease progression, initiation of prostacyclin therapy, and unsatisfactory long-term clinical response at 28 weeks in ralinepag group compared to placebo group,” Rali said.
Although ralinepag offers a good option for once-a-day oral prostacyclin options for the patients, the significant number of patients in the new study who discontinued because of adverse effects is notable, said Rali. “Treating clinicians will have to watch very closely, as the real-world patient population seems to be more complex than clinical trial populations,” he said. “At the same time, clinicians will have an option to weigh against growing list of inhaled prostacyclin pathway therapies that may not have systemic side effects of the oral agents,” he added.
“Given the strong scientific data in the ADVANCE trials, ralinepag may become drug of choice for oral prostacyclin pathway agents,” Rali added. However, its place in the treatment sequence, whether it is best used early in the disease course, as an add-on for patients already receiving dual oral therapy, or potentially part of upfront combination strategies, will call for some clinician judgement, Rali said. “Patient education and gradual dose titration will likely play a major role in improving adherence and limiting prostacyclin-related adverse effects,” he added.
Questions for future research include what percentage of the patients were able to tolerate the maximum dose of the drug, and whether any changes in primary or secondary outcomes occurred depending on the dose, said Rali. Other areas of interest include whether certain patient populations derive greater benefit than others, including connective tissue disease-associated PAH, idiopathic PAH, and higher-risk patient populations. “Comparative effectiveness data against currently available oral prostacyclin pathway agents and studies evaluating transition strategies from parenteral or inhaled therapies would help clinicians better understand where ralinepag ultimately fits in the PAH treatment algorithm,” Rali said. “I also would be curious to see what the authors thought of the failure to achieve the primary endpoint in cohorts of patients from Latin America and Asia Pacific regions,” he added.
The study was funded by United Therapeutics, and McLaughlin disclosed serving as a consultant for the company. Rali had no financial conflicts to disclose.
A version of this article first appeared on Medscape.com.
Ralinepag Offers Once Daily Oral Option for PAH
Ralinepag Offers Once Daily Oral Option for PAH