The evolving landscape of pulmonary arterial hypertension clinical trials

Weatherald, Jason; Boucly, Athénaïs; Peters, Anthony; Montani, David; Prasad, Krishna; Psotka, Mitchell A.; Zannad, Faı̈ez; Gomberg‐Maitland, Mardi; McLaughlin, Vallerie V.; Simonneau, Gérald; Humbert, Marc

doi:10.1016/s0140-6736(22)01601-4

Cited by 43 publications

(37 citation statements)

References 135 publications

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“…Validated risk stratification instruments combine clinical, exercise, biomarker, imaging, and hemodynamic variables to obtain a multidimensional estimate of prognosis. [25][26][27][28][29][30] The most recent updates of these methods underscore the value of simplified approaches using noninvasive measures to predict survival during follow-up, including 6MWD, NYHA-FC, and BNP or NT-proBNP. [31][32][33] Of note, these biomarkers are closely linked to right ventricular dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension

et al. 2023

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BACKGROUND: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers. METHODS: Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues. RESULTS: Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50–81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000–1.001]; P =0.037 and 1.263 [95% CI, 1.049–1.520]; P =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001–1.005]; P =0.001 and 1.365 [95% CI, 1.185–1.573]; P <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03–0.61; P =0.009) and 0.17 (95% CI, 0.06–0.45; P <0.001), and for follow-up measures, 0.23 (95% CI, 0.07–0.78; P =0.019) and 0.27 (95% CI, 0.09–0.78, P =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin. CONCLUSIONS: These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.

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Section: Discussionmentioning

confidence: 99%

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension

et al. 2023

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“…46 CS1 with its multitargeted mechanism of action has the potential to be a diseasemodifying therapy for PAH and should be evaluated in a well-designed clinical trial. 17 Here we present the design of a Phase 2 randomized clinical trial that will primarily evaluate the safety, tolerability, and exploratory efficacy of CS1 in patients with PAH. This trial utilizes a broad spectrum of contemporary and novel clinical assessments coupled with implantable PA pressure monitoring using the CardioMEMS HF System.…”

Section: Epigenetic Modification As a Treatment Modality For Pahmentioning

confidence: 99%

“…57,58 Time to clinical worsening (TTCW) is now a more widely used measure; however, there is no universal definition of TTCW, which makes comparisons between different clinical trials challenging. 17 The use of composite endpoints also poses a further question regarding weighting of the individual components according to clinical importance and the frequency at which they occur. 59 Further research is required to fully establish TTCW as a validated surrogate outcome for mortality in trials evaluating treatments.…”

Section: Adult Congenital Heart Disease (Achd)mentioning

confidence: 99%

CS1, a controlled‐release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial

Benza,

Adamson,

Bhatt

et al. 2024

Pulm. circ.

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Although rare, pulmonary arterial hypertension (PAH) is associated with substantial morbidity and a median survival of approximately 7 years, even with treatment. Current medical therapies have a primarily vasodilatory effect and do not modify the underlying pathology of the disease. CS1 is a novel oral, controlled‐release formulation of valproic acid, which exhibits a multi‐targeted mode of action (pulmonary pressure reduction, reversal of vascular remodeling, anti‐inflammatory, anti‐fibrotic, and anti‐thrombotic) and therefore potential for disease modification and right ventricular modeling in patients with PAH. A Phase 1 study conducted in healthy volunteers indicated favorable safety and tolerability, with no increased risk of bleeding and significant reduction of plasminogen activator inhibitor 1. In an ongoing randomized Phase 2 clinical trial, three doses of open‐label CS1 administered for 12 weeks is evaluating the use of multiple outcome measures. The primary endpoint is safety and tolerability, as measured by the occurrence of adverse events. Secondary outcome measures include the use of the CardioMEMS™ HF System, which provides a noninvasive method of monitoring pulmonary artery pressure, as well as cardiac magnetic resonance imaging and echocardiography. Other outcomes include changes in risk stratification (using the REVEAL 2.0 and REVEAL Lite 2 tools), patient reported outcomes, functional capacity, 6‐min walk distance, actigraphy, and biomarkers. The pharmacokinetic profile of CS1 will also be evaluated. Overall, the novel design and unique, extensive clinical phenotyping of participants in this trial will provide ample evidence to inform the design of any future Phase 3 studies with CS1.

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“…[6][7][8] Therapeutics targeting ion channels or the inflammatory, hyperproliferative, metabolic, and genetic pathways involved in PAH are under evaluation, but none are currently approved for clinical use. 9 Phosphodiesterase Type-5 Inhibitors…”

Section: Pharmacologic Treatment Of Pulmonary Arterial Hypertensionmentioning

confidence: 99%

Management of Pulmonary Arterial Hypertension

Weatherald

Varughese

Liu

et al. 2023

Semin Respir Crit Care Med

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Pulmonary arterial hypertension (PAH) is a rare pulmonary vascular disease characterized by progressive pulmonary arterial remodeling, increased pulmonary vascular resistance, right ventricular dysfunction, and reduced survival. Effective therapies have been developed that target three pathobiologic pathways in PAH: nitric oxide, endothelin-1, and prostacyclin. Approved therapies for PAH include phosphodiesterase type-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclin analogs, and prostacyclin receptor agonists. Management of PAH in the modern era incorporates multidimensional risk assessment to guide the use of these medications. For patients with PAH and without significant comorbidities, current guidelines recommend two oral medications (phosphodiesterase type-5 inhibitor and endothelin receptor antagonist) for low- and intermediate-risk patients, with triple therapy including a parenteral prostacyclin to be considered in those at high or intermediate-high risk. Combination therapy may be poorly tolerated and less effective in patients with PAH and cardiopulmonary comorbidities. Thus, a single-agent approach with individualized decisions to add-on other PAH therapies is recommended in older patients and those with significant comorbid conditions. Management of PAH is best performed in multidisciplinary teams located in experienced centers. Other core pillars of PAH management include supportive and adjunctive treatments including oxygen, diuretics, rehabilitation, and anticoagulation in certain patients. Patients with PAH who progress despite optimal treatment or who are refractory to best medical care should be referred for lung transplantation, if eligible. Despite considerable progress, PAH is often fatal and new therapies that reverse the disease and improve outcomes are desperately needed.

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The evolving landscape of pulmonary arterial hypertension clinical trials

Cited by 43 publications

References 135 publications

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension

Serum and Pulmonary Expression Profiles of the Activin Signaling System in Pulmonary Arterial Hypertension

CS1, a controlled‐release formulation of valproic acid, for the treatment of patients with pulmonary arterial hypertension: Rationale and design of a Phase 2 clinical trial

Management of Pulmonary Arterial Hypertension

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