Riociguat fails to improve pneumonia-associated pulmonary hypertension: RISE-IIP - Healio
Riociguat fails to improve pneumonia-associated pulmonary hypertension: RISE-IIP - Healio |
- Riociguat fails to improve pneumonia-associated pulmonary hypertension: RISE-IIP - Healio
- In PAH, RNF213 Gene Variant a Risk Factor for Poor Outcomes, Study Says - Pulmonary Hypertension News
- New drug target discovered for the lung disease PAH: In mice, blocking a key protein prevents dangerous lung artery thickening - Science Daily
| Riociguat fails to improve pneumonia-associated pulmonary hypertension: RISE-IIP - Healio Posted: 12 Sep 2019 07:11 AM PDT  Among patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, treatment with riociguat was linked to an increase in adverse events with no significant evidence of benefit, according to the RISE-IIP trial. In fact, the international, multicenter, double-blind, randomized, placebo-controlled phase 2b trial was terminated early due to a higher incidence of deaths, serious adverse events and adverse event-related drug discontinuations in patients treated with riociguat (Adempas, Bayer) vs. placebo, researchers wrote in The Lancet Respiratory Medicine. During the main study, most patients in the riociguat (65 of 73 patients) and placebo (64 of 74 patients) groups experienced an adverse event. The most common adverse events included peripheral edema (22% in the riociguat group vs. 9% in the placebo) and diarrhea (15% vs. 9%). Notably, serious adverse events were more common in the riociguat group than in the placebo group (37% vs. 23%), including worsening of interstitial lung disease (8% vs. 7%) and pneumonia (5% vs. 1%). Study discontinuation due to the frequency of adverse events was also more common in the riociguat group than in the placebo group (15% vs. 4%). During a long-term, open-label extension phase in which all patients switched to riociguat after 26 weeks, adverse events leading to study discontinuation occurred more often in patients switching from placebo to riociguat (11% vs. 3%). Also during the main study, 11 patients died, including three in the placebo group and eight in the riociguat group. During the long-term extension phase, nine patients who had received riociguat including eight in the former placebo group and one in the riociguat group died. In terms of efficacy, the researchers observed no improvements in 6-minute walk distance at 26 weeks with riociguat when compared with placebo. The study, which was terminated after a median of 157 days, enrolled patients aged 18 to 80 years who had idiopathic interstitial pneumonia, an FVC of at least 45%, a 6-minute walk distance of 150 m to 450 m, were WHO functional class II to IV and had precapillary pulmonary hypertension, systolic blood pressure of at least 95 mm Hg and no signs of hypotension. Patients in the riociguat group underwent a 10-week dose adjustment phase during which they received the drug in doses from 0.5 mg to 2.5 mg three times daily in 0.5 mg increments based on clinical signs and measurements followed by a 16-week maintenance phase. In an accompanying editorial, Keith C. Meyer, MD, from the department of medicine at the University of Wisconsin School of Medicine and Public Health in Madison, noted that the lack of efficacy and the unfavorable risk-benefit profile of riociguat may not be surprising, even after accounting for some of the study's limitations. "Although enrolling participants with differing idiopathic interstitial pneumonia diagnoses and potentially failing to exclude a substantial number of patients with combined pulmonary fibrosis and emphysema and extensive emphysema might have represented an Achilles' heel for this investigation, I suspect that benefit would not have been shown even in a population that consisted entirely of patients with idiopathic pulmonary fibrosis without a combined pulmonary fibrosis and emphysema phenotype," Meyer wrote. "Considering the track record of vasoactive agents approved for the treatment of pulmonary arterial hypertension that have been evaluated in clinical trials for fibrotic interstitial lung disease complicated by pulmonary hypertension, one could suggest that if a clinician is tempted to treat such a patient with a vasoactive agent, Hippocrates' advice, 'First do no harm,' should come to mind." – by Melissa Foster Disclosures: The study was funded by Bayer AG and Merck. Nathan reports he has received consultant fees from Bayer and Inova Fairfax Hospital received research funding for work pertaining to the RISE-IIP study. Please see the study for all other authors' relevant financial disclosures. Meyer reports he has received grants from the NIH, Genentech/Roche, InterMune, Parion, Nivalis, Promedior, Biogen and Galapagos. Editor's note: The headline of this article was updated on Sept. 17, 2019, to specify that the study evaluated the effects of riociguat in patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, not pneumonia-associated hypertension. The Editors regret the error. Among patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, treatment with riociguat was linked to an increase in adverse events with no significant evidence of benefit, according to the RISE-IIP trial. In fact, the international, multicenter, double-blind, randomized, placebo-controlled phase 2b trial was terminated early due to a higher incidence of deaths, serious adverse events and adverse event-related drug discontinuations in patients treated with riociguat (Adempas, Bayer) vs. placebo, researchers wrote in The Lancet Respiratory Medicine. During the main study, most patients in the riociguat (65 of 73 patients) and placebo (64 of 74 patients) groups experienced an adverse event. The most common adverse events included peripheral edema (22% in the riociguat group vs. 9% in the placebo) and diarrhea (15% vs. 9%). Notably, serious adverse events were more common in the riociguat group than in the placebo group (37% vs. 23%), including worsening of interstitial lung disease (8% vs. 7%) and pneumonia (5% vs. 1%). Study discontinuation due to the frequency of adverse events was also more common in the riociguat group than in the placebo group (15% vs. 4%). During a long-term, open-label extension phase in which all patients switched to riociguat after 26 weeks, adverse events leading to study discontinuation occurred more often in patients switching from placebo to riociguat (11% vs. 3%). Also during the main study, 11 patients died, including three in the placebo group and eight in the riociguat group. During the long-term extension phase, nine patients who had received riociguat including eight in the former placebo group and one in the riociguat group died. In terms of efficacy, the researchers observed no improvements in 6-minute walk distance at 26 weeks with riociguat when compared with placebo. The study, which was terminated after a median of 157 days, enrolled patients aged 18 to 80 years who had idiopathic interstitial pneumonia, an FVC of at least 45%, a 6-minute walk distance of 150 m to 450 m, were WHO functional class II to IV and had precapillary pulmonary hypertension, systolic blood pressure of at least 95 mm Hg and no signs of hypotension. Patients in the riociguat group underwent a 10-week dose adjustment phase during which they received the drug in doses from 0.5 mg to 2.5 mg three times daily in 0.5 mg increments based on clinical signs and measurements followed by a 16-week maintenance phase. PAGE BREAK In an accompanying editorial, Keith C. Meyer, MD, from the department of medicine at the University of Wisconsin School of Medicine and Public Health in Madison, noted that the lack of efficacy and the unfavorable risk-benefit profile of riociguat may not be surprising, even after accounting for some of the study's limitations. "Although enrolling participants with differing idiopathic interstitial pneumonia diagnoses and potentially failing to exclude a substantial number of patients with combined pulmonary fibrosis and emphysema and extensive emphysema might have represented an Achilles' heel for this investigation, I suspect that benefit would not have been shown even in a population that consisted entirely of patients with idiopathic pulmonary fibrosis without a combined pulmonary fibrosis and emphysema phenotype," Meyer wrote. "Considering the track record of vasoactive agents approved for the treatment of pulmonary arterial hypertension that have been evaluated in clinical trials for fibrotic interstitial lung disease complicated by pulmonary hypertension, one could suggest that if a clinician is tempted to treat such a patient with a vasoactive agent, Hippocrates' advice, 'First do no harm,' should come to mind." – by Melissa Foster Disclosures: The study was funded by Bayer AG and Merck. Nathan reports he has received consultant fees from Bayer and Inova Fairfax Hospital received research funding for work pertaining to the RISE-IIP study. Please see the study for all other authors' relevant financial disclosures. Meyer reports he has received grants from the NIH, Genentech/Roche, InterMune, Parion, Nivalis, Promedior, Biogen and Galapagos. Editor's note: The headline of this article was updated on Sept. 17, 2019, to specify that the study evaluated the effects of riociguat in patients with idiopathic interstitial pneumonia-associated pulmonary hypertension, not pneumonia-associated hypertension. The Editors regret the error.  |
| Posted: 30 Sep 2019 06:00 AM PDT Patients with pulmonary arterial hypertension (PAH) who carry a specific mutation in the RNF213 gene have poor clinical outcomes and worse response to combination treatments, according to a study from Japan. The study, "Poor outcomes in carriers of the RNF213 variant (p.Arg4810Lys) with pulmonary arterial hypertension," was published in The Journal of Heart and Lung Transplantation. A 2018 study found that approximately 10% of the patients with idiopathic PAH have a specific variant in the RNF213 gene — rs112735431, or p.Arg4810Lys — consisting of an amino acid substitution of arginine to lysine in the RNF213 protein. This gene alteration has already been associated with Moyamoya disease and peripheral pulmonary stenosis. In the current study, the scientists set out to characterize and assess the outcomes of PAH patients with this variant. A total of 139 patients with idiopathic or possibly heritable PAH were included, all treated between April 2005 and August 2018. Patients with mutations in the BMPR2 gene — with a well-known link to PAH — were included as controls. At both diagnosis and after combination treatment with prostaglandin I2 (PGI2) infusion, endothelin receptor antagonists (ERAs), and/or phosphodiesterase-5 inhibitors (PDE5i), the patients underwent assessments of their serum levels of B-type natriuretic peptide (BNP) — a marker of heart failure and other cardiac problems — World Health Organization (WHO) class, and six-minute walk distance (6MWD), a test of exercise capacity. Whole-exome sequencing, which screens the DNA bits containing information to generate a protein, found the p.Arg4810Lys variant in 11 patients (7.9% of the patients, eight women), all in only one of the gene copies (heterozygous). No patient showed cerebral involvement suggestive of Moyamoya disease. All 11 patients had clinically severe disease at diagnosis, as indicated by their BNP levels, cardiac output, mean pulmonary arterial pressure (mPAP), and pulmonary vascular resistance (PVR). Eight were treated with PGI2. Over a mean follow-up period of 30 months, both mPAP and PVR improved with combination treatment. In contrast, BNP levels, cardiac output, WHO class, and 6MWD scores did not change. Two of these patients had both the studied variant in RNF213 and BMPR2 gene mutations, and did not respond favorably to treatment. Compared with the 36 patients with BMPR2 gene mutations, the nine patients with the p.Arg4810Lys variant showed significantly inferior benefits with combination therapy, including in mPAP, cardiac output, BNP levels, and 6MWD scores. These patients also showed higher diastolic pressure gradients, suggesting worse response to treatment. Four patients died, three of whom were in the group with the RNF213 gene variant. One patient in this group and two in the group with BMPR2 mutations underwent lung transplants. The RNF213 gene variant carrier who underwent this procedure experienced clinical improvements and did not require hospital admission for five years. Event-free rates (no death or lung transplant) since diagnosis and the start of PGI2 treatment were significantly better in patients with BMPR2 mutations. Specifically, at five years after diagnosis, all patients with BMPR2 mutation survived and did not require lung transplants, compared with 60% in the RNF213 variant group. After introduction of PGI2, none of the patients with the RNF213 variant were event-free, compared with 93% of controls who avoided these outcomes. A similar difference favoring the group without the variant in RNF213 was also found in terms of heart failure. Patients with RNF213 variants other than p.Arg4810Lys showed better event-free rates after diagnosis than those with these gene alterations. A subsequent analysis showed that the p.Arg4810Lys variant was a risk factor for death, lung transplant, and heart failure. Post-mortem analysis of lung samples from two patients with the p.Arg4810Lys variant found lesions in pulmonary arteries, and marked venous wall and arterial thickness, venous occlusion, dilated capillaries, and lymph accumulation. "Patients with idiopathic PAH who have the RNF213 p.Arg4810Lys variant are associated with severe hemodynamics, poor reactivity to vasodilator drugs, and poor clinical outcomes," the scientists wrote. "Our findings may suggest the importance of genetic stratification of PAH to provide clinically relevant information for therapeutic strategies, leading to a personalized approach," they added. The researchers believe that earlier consideration of a lung transplant "might be required for RNF213 p.Arg4810Lys variant carriers who are developing PAH."  José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer's disease. × José is a science news writer with a PhD in Neuroscience from Universidade of Porto, in Portugal. He has also studied Biochemistry at Universidade do Porto and was a postdoctoral associate at Weill Cornell Medicine, in New York, and at The University of Western Ontario in London, Ontario, Canada. His work has ranged from the association of central cardiovascular and pain control to the neurobiological basis of hypertension, and the molecular pathways driving Alzheimer's disease. Latest Posts  |
| Posted: 12 Sep 2019 12:00 AM PDT Scientists have identified a molecular pathway that contributes to the development of pulmonary arterial hypertension (PAH), a severe, often fatal condition that has no cure. The discovery, published Sept. 12, 2019, in Nature Communications, suggests a new target for developing new drug therapies for PAH, according to researchers at Cincinnati Children's Hospital Medical Center. What is PAH? This progressive disease is characterized by high blood pressure in the lungs, and affects adults and children. When left untreated, PAH can lead to fatal heart damage. Scientists have long known that a process called vascular remodeling drives the thickening of lung arteries that contributes to the increased pressure. Reversing vascular remodeling could be curative. "PAH is a life-threatening disease in adults and can also complicate the repair of congenital heart disease in children," Hegde says. "While progress is being made to develop treatments, there currently is no effective cure available. The new molecular pathway described by our study could be targeted to develop effective therapeutics for the disease." Targeting the EYA3 protein may someday improve treatment The current study describes a molecular pathway involving the protein Eyes Absent 3 (EYA3). This protein promotes vascular remodeling and could be targeted in the development of PAH therapeutics, according to lead study investigator Rashmi Hegde, PhD, Division of Developmental Biology. EYA proteins have a mechanistically unique enzyme activity first identified by Hedge and her colleagues in 2003. In this study, the research team manipulated transgenic mice with CRISPR gene editing technology to inactivate EYA3, which significantly protected the lung arteries from vascular remodeling. When researchers tested pharmacological inhibition with previously identified drugs that target the EYA3 pathway, significant reversal of vascular remodeling was seen in laboratory rat models. Additional research is needed before a treatment strategy could be available for human testing. Beyond existing medications that target EYA3, the researchers want to design a treatment that even more precisely targets remodeling in PAH. Story Source: Materials provided by Cincinnati Children's Hospital Medical Center. Note: Content may be edited for style and length.  |
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