Review Article|Articles in Press

Pulmonary Hypertension Inhaled Therapies: An Updated Review.

  • Karim El-Kersh
    Corresponding Author: Karim El-Kersh, 985990 Nebraska Medical Center, Omaha, NE 68198, Telephone: 402.559.4087, Fax: 402.559.4140.
    Associate Professor of Medicine, Division of Pulmonary, Critical Care, & Sleep Medicine, Department of Medicine, University of Nebraska Medical Center, 985990 Nebraska Medical Center, Omaha, NE 68198
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  • Bilal A Jalil
    Assistant Professor of Medicine, Divisions of Cardiovascular Critical Care and Advanced Heart Failure, Heart and Vascular Institute, West Virginia University, 1 Medical Center Dr, Box 8500, Morgantown, WV, 26506
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      Treatments of pulmonary hypertension (PH) continue to evolve with approval of new therapies. The currently FDA approved inhaled PH therapies include inhaled iloprost for group 1 pulmonary arterial hypertension (PAH), inhaled treprostinil solution and treprostinil dry powder inhaler for both group 1 PAH and group 3 PH associated with interstitial lung disease (PH-ILD). Inhaled treprostinil was recently approved for group 3 PH-ILD based on the results of INCREASE trial and the newer formulation of treprostinil dry powder that comes with a new inhaler was recently approved for both group 1 PAH and group 3 PH-ILD based on BREEZE study. The pipeline for inhaled PH therapies includes several promising molecules that can enrich the current PH therapeutic era and mitigate several systemic side effects by directly delivering the drug to the target organ. In this review article we summarize the evidence for the currently approved inhaled PAH/PH therapies, discuss the available inhalation devices, present a roadmap for successful treatment strategy, and present several inhaled PAH/PH therapies in the pipeline.


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        • Chang KY
        • Duval S
        • Badesch DB
        • et al.
        Mortality in Pulmonary Arterial Hypertension in the Modern Era: Early Insights From the Pulmonary Hypertension Association Registry.
        J Am Heart Assoc. 2022; 11e024969
        • Humbert M
        • Kovacs G
        • Hoeper MM
        • et al.
        2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension.
        Eur Respir J. 2022;
        • Gomberg-Maitland M
        • Olschewski H.
        Prostacyclin therapies for the treatment of pulmonary arterial hypertension.
        Eur Respir J. 2008; 31: 891-901
        • Olschewski H
        • Rohde B
        • Behr J
        • et al.
        Pharmacodynamics and pharmacokinetics of inhaled iloprost, aerosolized by three different devices, in severe pulmonary hypertension.
        Chest. 2003; 124: 1294-1304
        • Olschewski H
        • Simonneau G
        • Galiè N
        • et al.
        Inhaled iloprost for severe pulmonary hypertension.
        N Engl J Med. 2002; 347: 322-329
        • Hoeper MM
        • Leuchte H
        • Halank M
        • et al.
        Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension.
        Eur Respir J. 2006; 28: 691-694
        • McLaughlin VV
        • Oudiz RJ
        • Frost A
        • et al.
        Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.
        Am J Respir Crit Care Med. 2006; 174: 1257-1263
        • Olschewski H
        • Hoeper MM
        • Behr J
        • et al.
        Long-term therapy with inhaled iloprost in patients with pulmonary hypertension.
        Respir Med. 2010; 104: 731-740
        • Saji T
        • Myoishi M
        • Sugimura K
        • et al.
        Efficacy and Safety of Inhaled Iloprost in Japanese Patients With Pulmonary Arterial Hypertension - Insights From the IBUKI and AIR Studies.
        Circ J. 2016; 80: 835-842
        • Yasuda K
        • Adachi S
        • Nishiyama I
        • Yoshida M
        • Nakano Y
        • Murohara T.
        Inhaled iloprost induces long-term beneficial hemodynamic changes in patients with pulmonary arterial hypertension receiving combination therapy.
        Pulm Circ. 2022; 12: e12074
        • Tello K
        • Kremer N
        • Richter MJ
        • et al.
        Inhaled Iloprost Improves Right Ventricular Load-Independent Contractility in Pulmonary Hypertension.
        Am J Respir Crit Care Med. 2022; 206: 111-114
        • Channick RN
        • Voswinckel R
        • Rubin LJ.
        Inhaled treprostinil: a therapeutic review.
        Drug Des Devel Ther. 2012; 6: 19-28
        • Sandifer BL
        • Brigham KL
        • Lawrence EC
        • Mottola D
        • Cuppels C
        • Parker RE.
        Potent effects of aerosol compared with intravenous treprostinil on the pulmonary circulation.
        J Appl Physiol. 1985; 99 (2005): 2363-2368
        • McLaughlin VV
        • Benza RL
        • Rubin LJ
        • et al.
        Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial.
        J Am Coll Cardiol. 2010; 55: 1915-1922
        • Benza RL
        • Seeger W
        • McLaughlin VV
        • et al.
        Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension.
        J Heart Lung Transplant. 2011; 30: 1327-1333
        • Tonelli AR
        • Sahay S
        • Gordon KW
        • et al.
        Impact of inhaled treprostinil on risk stratification with noninvasive parameters: a post hoc analysis of the TRIUMPH and BEAT studies.
        Pulm Circ. 2020; 102045894020977025
        • Shapiro S
        • Mandras S
        • Restrepo-Jaramillo R
        • et al.
        Survival and drug persistence in patients receiving inhaled treprostinil at doses greater than 54 µg (nine breaths) four times daily.
        Pulm Circ. 2021; 1120458940211052228
        • Waxman A
        • Restrepo-Jaramillo R
        • Thenappan T
        • et al.
        Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease.
        N Engl J Med. 2021; 384: 325-334
        • Nathan VFT S.D.
        • Levine D.
        • Rischard F.
        • Cassady S.
        • DuBrock H.M.
        • El-Kersh K.
        • Tarver III, J.
        • Smith P.
        • C.Q Deng
        • Shen E.
        • Waxman A.B.
        The importance of early treatment with inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease: a post-hoc analysis of the INCREASE open-label extension.
        in: 2022 Annual World Congress of the Pulmonary Vascular Research Institute. n/a. Pulmonary Circulation. 2022: A021
        • Nathan SD
        • Deng C
        • King CS
        • et al.
        Inhaled Treprostinil Dosage in Pulmonary Hypertension Associated With Interstitial Lung Disease and Its Effects on Clinical Outcomes.
        Chest. 2022;
        • Hoeper MM
        • Al-Hiti H
        • Benza RL
        • et al.
        Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.
        Lancet Respir Med. 2021; 9: 573-584
        • Nathan SD
        • Tapson VF
        • Elwing J
        • et al.
        Efficacy of Inhaled Treprostinil on Multiple Disease Progression Events in Patients with Pulmonary Hypertension due to Parenchymal Lung Disease in the INCREASE Trial.
        Am J Respir Crit Care Med. 2022; 205: 198-207
        • Nathan SD
        • Waxman A
        • Rajagopal S
        • et al.
        Inhaled treprostinil and forced vital capacity in patients with interstitial lung disease and associated pulmonary hypertension: a post-hoc analysis of the INCREASE study.
        Lancet Respir Med. 2021; 9: 1266-1274
        • Nathan SD
        • Behr J
        • Cottin V
        • et al.
        Study design and rationale for the TETON phase 3, randomised, controlled clinical trials of inhaled treprostinil in the treatment of idiopathic pulmonary fibrosis.
        BMJ Open Respir Res. 2022; 9
        • Kolb M
        • Orfanos SE
        • Lambers C
        • et al.
        The Antifibrotic Effects of Inhaled Treprostinil: An Emerging Option for ILD.
        Adv Ther. 2022; 39: 3881-3895
        • Spikes LA
        • Bajwa AA
        • Burger CD
        • et al.
        BREEZE: Open-label clinical study to evaluate the safety and tolerability of treprostinil inhalation powder as Tyvaso DPI™ in patients with pulmonary arterial hypertension.
        Pulm Circ. 2022; 12: e12063
        • Mehta PP.
        Dry powder inhalers: upcoming platform technologies for formulation development.
        Ther Deliv. 2019; 10: 551-554
      1. Koninklijke Philips N.V. -. I-neb AAD System - Battery Powered Drug Delivery System,

        • Dhand R.
        Intelligent nebulizers in the age of the Internet: The I-neb Adaptive Aerosol Delivery (AAD) system.
        J Aerosol Med Pulm Drug Deliv. 2010; 23 (Suppl 1): iii-iiv
        • Corporation UT
        Tyvaso Inahaltion System TD-300: Instrucions for Use.
        • Corporation UT.
        Tyvaso Inhalation System TD-100: Instructions for Use.
        • Corporation UT.
        Tyvaso Inhalation Powder DPI: Instructions for Use.
        • Jing ZC
        • Yu ZX
        • Shen JY
        • et al.
        Vardenafil in pulmonary arterial hypertension: a randomized, double-blind, placebo-controlled study.
        Am J Respir Crit Care Med. 2011; 183: 1723-1729
        • Aizawa K
        • Hanaoka T
        • Kasai H
        • et al.
        Long-term vardenafil therapy improves hemodynamics in patients with pulmonary hypertension.
        Hypertens Res. 2006; 29: 123-128
        • Ried M
        • Neu R
        • Lehle K
        • et al.
        Superior vasodilation of human pulmonary vessels by vardenafil compared with tadalafil and sildenafil: additive effects of bosentan.
        Interact Cardiovasc Thorac Surg. 2017; 25: 254-259
        • ND Anne Keogh
        • Kotlyar Eugene
        • Kaye David
        • Maurer Mari
        • Weers Jeffry
        • Parsley Ed
        Acute Hemodynamic Improvement in Chronic Pulmonary Arterial Hypertension on Dual Therapy Following RT234 Inhalation.
        CHEST. 2020; 158: A2162-A2A63
        • Gillies RN H.
        • Dake B.
        • Chakinala M.M.
        • Feldman J.P.
        • Hill N.S.
        • Hoeper M.
        • Humbert M.J.
        • Mclaughlin V.V.
        • Kankam M.
        A Phase 1 Single and Multiple Ascending Dose (SAD/MAD) Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of AV-101, a Novel Inhaled Dry Powder Formulation of Imatinib in Healthy Subjects.
        American Thoracic Society, San Francisco, CA, USA2022: A3594 (-A94)
        • Hoeper MM
        • Barst RJ
        • Bourge RC
        • et al.
        Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study.
        Circulation. 2013; 127: 1128-1138
        • Ghofrani HA
        • D'Armini AM
        • Grimminger F
        • et al.
        Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.
        N Engl J Med. 2013; 369: 319-329
        • Becker-Pelster EM
        • Hahn MG
        • Delbeck M
        • et al.
        Inhaled mosliciguat (BAY 1237592): targeting pulmonary vasculature via activating apo-sGC.
        Respir Res. 2022; 23: 272
        • Goldbart A
        • Golan-Tripto I
        • Pillar G
        • et al.
        Inhaled nitric oxide therapy in acute bronchiolitis: A multicenter randomized clinical trial.
        Sci Rep. 2020; 10: 9605
        • Gebistorf F
        • Karam O
        • Wetterslev J
        • Afshari A.
        Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults.
        Cochrane Database Syst Rev. 2016; CD002787
        • Al Sulaiman K
        • Korayem GB
        • Altebainawi AF
        • et al.
        Evaluation of inhaled nitric oxide (iNO) treatment for moderate-to-severe ARDS in critically ill patients with COVID-19: a multicenter cohort study.
        Crit Care. 2022; 26: 304
        • Nathan SD
        • Flaherty KR
        • Glassberg MK
        • et al.
        A Randomized, Double-Blind, Placebo-Controlled Study of Pulsed, Inhaled Nitric Oxide in Subjects at Risk of Pulmonary Hypertension Associated With Pulmonary Fibrosis.
        Chest. 2020; 158: 637-645
        • Sahay S.
        Risk Assessment in Pulmonary Arterial Hypertension (PAH): Insights From the INSPIRE Study With LIQ861.
        in: ISHTL 42nd Annual Meeting & Scientific Sessions, Boston, MA, USA2022
        • Plaunt AJ
        • Islam S
        • Macaluso T
        • et al.
        Development and Characterization of Treprostinil Palmitil Inhalation Aerosol for the Investigational Treatment of Pulmonary Arterial Hypertension.
        Int J Mol Sci. 2021; 22
        • K-JC Pei Kan
        • Pan Cleo
        Inhaled liposomal treprostinil (L606) shows extended release in healthy volunteer, as well as prolongs pharmacological effect in hypoxia-induced rat.
        in: ERS International Congress. 56. European Respiratory Journal, 2020 (1480)
        • Solinc J
        • Raimbault-Machado J
        • Dierick F
        • et al.
        Platelet-Derived Growth Factor Receptor Type alpha Activation Drives Pulmonary Vascular Remodeling Via Progenitor Cell Proliferation and Induces Pulmonary Hypertension.
        J Am Heart Assoc. 2022; 11e023021
        • Schermuly RT
        • Dony E
        • Ghofrani HA
        • et al.
        Reversal of experimental pulmonary hypertension by PDGF inhibition.
        J Clin Invest. 2005; 115: 2811-2821
        • Frost AE
        • Barst RJ
        • Hoeper MM
        • et al.
        Long-term safety and efficacy of imatinib in pulmonary arterial hypertension.
        J Heart Lung Transplant. 2015; 34: 1366-1375
        • MMC Hunter Gillies
        • Dake Ben
        • Feldman Jeremy P
        • Hoeper Marius M
        • Humbert Marc
        • Jing Zhi-Cheng
        • Langley Jonathan
        • Mclaughlin Vallerie
        • Niven Ralph
        • Rosenkranz Stephan H.
        • Zhang Xiaosha
        • Hill Nicholas S
        Inhaled Imatinib for Pulmonary Arterial Hypertension Clinical Trial: Design of The Impact Phase 2b/3 Study Design.
        CHEST. 2022; 162 (Nashville, TN, USA): A2325-A2A29
        • Galkin A
        • Sitapara R
        • Clemons B
        • et al.
        Inhaled Seralutinib Exhibits Potent Efficacy in Models of Pulmonary Arterial Hypertension.
        Eur Respir J. 2022;
        • Frantz RP
        • Benza RL
        • Channick RN
        • et al.
        TORREY, a Phase 2 study to evaluate the efficacy and safety of inhaled seralutinib for the treatment of pulmonary arterial hypertension.
        Pulm Circ. 2021; 1120458940211057071
        • Hoeper MM
        • Dwivedi K
        • Pausch C
        • et al.
        Phenotyping of idiopathic pulmonary arterial hypertension: a registry analysis.
        Lancet Respir Med. 2022; 10: 937-948