Emerging pharmacotherapies for the treatment of pulmonary arterial hypertension

ABSTRACTIntroduction Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin.Areas covered Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved.Expert opinion Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.KEYWORDS: Pulmonary arterial hypertensionIdiopathic pulmonary arterial hypertensionPulmonary arterial hypertension pathogenesisClinical trialsRandomized controlled trialsNovel therapeuticsPulmonary vascular remodelingImmunomodulationSotaterceptDisclaimerAs a service to authors and researchers we are providing this version of an accepted manuscript (AM). Copyediting, typesetting, and review of the resulting proofs will be undertaken on this manuscript before final publication of the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal relate to these versions also. Abbreviations(PAH)=Pulmonary arterial hypertension(PVR)=Pulmonary vascular resistance(RHC)=Right heart catheterization(mPAP)=Mean pulmonary artery pressure(cGMP)=Cyclic guanosine monophosphate(NO)=Nitric Oxide(sGC)=Soluble guanylyl cyclase(PDE5i)=Phosphodiesterase type 5 inhibitor(sGCS)=sGC stimulators(ERA)=Endothelin receptor antagonist(PRA)=prostacyclin receptor agonist(6MWD)=Six-minute walk distance(CO)=Cardiac output(CI)=Cardiac index(FC)=World Health Organization functional class(RCT)=Randomized control trial(VO2)=Peak oxygen consumption(TEAEs)=Treatment-emergent adverse events(CTD)=connective tissue disease(ETA)=endothelin A(ETB)=endothelin BDry powder inhalers (DPIs),Cardiopulmonary exercise test (CPET):rho-associated protein kinase (ROCK):pulmonary vascular smooth muscle cell (PVSMC)right ventricular systolic pressure in rats (RVSP)platelet-derived growth factor (PDGF)tyrosine kinase inhibitors (TKI)bone morphogenic protein receptor 2 (BMPR2)transforming growth factor β (TGF-β)regulated SMADs (R-SMAD)growth and differentiation factors (GDFs)bone morphogenic proteins (BMPs)the type II activin receptor (ACTRIIA)extracellular domain to immunoglobulin G (ACTRIIA-Fc)17β-estradiol (E2)tricuspid annular plane systolic excursion (TAPSE)Dehydroepiandrosterone-sulfate (DHEA-S)right ventricular (RV)bromodomain and extra-terminal domain (BET)B-cell lymphoma-2 gene (BCL2)poly(ADP-ribose) polymerase (PARP)nod-like receptor family, pyrin domain containing inflammasome (NLRP3)Sodium-glucose cotransporter 2 inhibitor (SGLT2i)pulmonary artery (PA)interleukin-1 (IL-1)interleukin-6 (IL-6)leukotriene B4 (LTB4)Article highlightsPharmacologic therapy for treating PAH has expanded rapidly since the approval of intravenous prostacyclin less than 30 years agoAvailable therapies reduce pulmonary arterial pressures by compensating for alterations in prostacyclin, cGMP, and endothelin signalingThey do prevent disease progression because they fail to address the underlying pathogenesis that drives the diseaseRepurposing currently available PAH medications to be used at different doses or via other routes of administration may result in therapies that are easier for patients to use but are not likely to result in substantial improvements in clinical outcomesEncouraging results from recently completed phase 2 and 3 trials with sotatercept suggest that this drug may soon be approved for treating PAHAs the armamentarium for PAH treatments continues to grow, it will be essential to conduct future studies to determine which drugs most likely benefit individual patients with PAHRecent calls for studies that aim to develop a precision medicine approach to treating PAH will likely become increasingly relevant in this rapidly expanding areaDeclaration of interestsThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.Reviewer disclosuresA reviewer on this manuscript has disclosed they have served as a consultant for J and J. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Figure 1: Mechanism of Sotatercept. (A) PAH is characterized by disruption in both anti-proliferative and pro-proliferative cellular pathways. Reduced BMPR2 activity decreases BMP-mediated signaling, which reduces the activation of Smad1/5/8 and the transcription of genes that inhibit cell proliferation. This imbalance leads to increased cell death and loss of the integrity of the endothelial barrier. Consequently, pro-proliferative pathways are upregulated, driven by activin A and GDF production. These molecules bind to the activin receptor-like kinase (ALK) 4/5/7—ActRIIA/B complex and activate the pro-proliferative Smad2/3 pathway. This cascade also boosts the expression of BMP antagonists like gremlin-1 and noggin. (B) Sotatercept is a fusion protein that acts as a ligand trap by binding to activins and GDF, thus restoring the equilibrium between the pro-proliferative and anti-proliferative BMP pathways. Abbreviations: Activin receptor type IIA (ActRIIA/B), activin receptor-like kinase (ALK); bone morphogenic protein (BMP); bone morphogenic protein receptor type-2 (BMPR-II); growth differentiation factor (GDR); small mothers against decapentaplegic protein Smad; phosphorylated Smad (pSmad).Display full sizeFigure 2: Observed mean change (in meters) in 6-minute walk distance through 24 weeks of sotatercept treatment (solid triangles) and placebo (solid circles) [Citation77]. From New England Journal of Medicine, Hoeper et al, Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension, Volume No. 388;16, Page 1482. Copyright © (2023) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.Display full sizeFigure 3: Figure 3: Time to first Occurrence of Death or Nonfatal Clinical Worsening Event in sotatercept compared to placebo (Intention-to-treat Population) [Citation77]. From New England Journal of Medicine, Hoeper et al, Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension, Volume No. 388;16, Page 1482. Copyright © (2023) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.Display full sizeFigure 4: Figure 4: Absolute change from baseline 6MWD at 6 weeks and 3 months in subjects receiving anastrozole (circle) versus placebo (square) [Citation89].Display full sizeFootnote: Reprinted with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. Kawut et al. 2017. Anastrozole in Pulmonary Arterial Hypertension. A Randomized, Double-Blind, Placebo-controlled Trial. Am J Respir Crit Care Med. 195(3):360-368. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society. Figure 5: Individual changes in hemodynamic and functional parameters in patients with PAH treated with apabetalone for 16 weeks [Citation79]. Reprinted with permission of the American Thoracic Society. Copyright © 2023 American Thoracic Society. All rights reserved. Provencher et al. 2022. BET Protein Inhibition for Pulmonary Arterial Hypertension: A Pilot Clinical Trial. Am J Respir Crit Care Med. 11:1357-1360. The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.Display full sizeTable 1: Investigational doses, regimens, and routes of administration for the established PAH pathways. Sourced from Pubmed.gov and Clinicaltrial.gov between the years 2003 and 2023.Footnote: 6MWD = six-minute walk distance; bid = twice daily; ERA = endothelin receptor antagonist; mPAP = mean pulmonary artery pressure; n = number of patients enrolled; OLE = open-label extension; PCA = prostacyclin agonist; PDE5i = phosphodiesterase type 5 inhibitor; PVR = pulmonary vascular resistance; RCT = randomized controlled trial; sGCS = sGC stimulator; tid = three times dailyTableDownload CSVDisplay TableTable 2: Investigational drugs targeting altered pathways associated with pulmonary vascular remodeling. Sourced from Pubmed.gov and Clinicaltrial.gov between the years 2003 and 2023.Footnote: 6MWD = six-minute walk distance; BET = bromodomain and extra-terminal domain; BMPR2 = bone morphogenic protein receptor 2; CPET = cardiopulmonary exercise test; DHEA-S = dehydroepiandrosterone-sulfate (DHEA-S); DPI = dry powder inhaler; FC = functional class; n=number of patients enrolled; IL-1 = Interleukin-1; IL-6 = Interleukin-6; IV = Intravenous; NT-proBNP = N-terminal pro-B-type natriuretic peptide; PARP = poly(ADP-ribose) polymerase; PVR = Pulmonary vascular resistance; QoL = quality of life; RCT = randomized controlled trial; RHC = right heart catheterization; ROCK = rho-associated protein kinase; RV = right ventricular; RVSP = right ventricular systolic pressure; SLGT2i = Sodium-glucose cotransporter-2 inhibitor; TAPSE = tricuspid annular plane systolic excursion; TEAEs = treatment emergent adverse events; VIP = Vasoactive intestinal peptideTableDownload CSVDisplay TableAdditional informationFundingThis paper was not funded.