Current Status and New Treatment Approaches in Idiopathic Pulmonary Fibrosis

Yıl 2024, Cilt: 8 Sayı: 2, 91 - 103, 30.08.2024

Seyde Nur Uçar , Yusuf Elma , Bülent Altınsoy , Ayşegül Tomruk Erdem , Emine Yılmaz Can

https://doi.org/10.29058/mjwbs.1514437

Öz

Idiopathic pulmonary fibrosis is a progressive lung disease of unknown etiology, characterized by the replacement of normal lung tissue with connective tissue that does not allow for gas exchange. The development of fibrosis in lung tissue is a chronic process and multiple signaling pathways and mediators contribute to this process. Despite its unknown etiology, several genetic and environmental factors have been associated with idiopathic pulmonary fibrosis. The clinical presentation of idiopathic pulmonary fibrosis involves a gradual loss of lung function and patients usually die in the end-stage with respiratory failure. Therefore, it is critical to identify and implement appropriate treatment approaches.While there is no definitive cure, several treatment options are available to slow disease progression and improve quality of life. Among the current treatment approaches, the most commonly used are antifibrotic drugs such as pirfenidone and nintedanib. These medications can slow the progression of fibrosis in lung tissue and relieve symptoms. New therapeutic approaches targeting signaling pathways and mediators involved in pathophysiology are being developed for the disease, for which there is no effective treatment yet. These approaches include potential therapies such as the combination of pirfenidone and nintedanib, BI 1015550, PLN-74809, TRK-250, BMS-986278, PBI-4050, TD139, treprostinil and stem cell therapy. Through current and future studies, it is hoped that more effective treatment methods can be developed and the disease can be completely cured.

Anahtar Kelimeler

Antifibrotic drugs, clinical trials, idiopathic pulmonary fibrosis, new treatment approaches, pulmonary fibrosis

İdiopatik Pulmoner Fibroziste Mevcut Durum ve Yeni Tedavi Yaklaşımları

Öz

İdiyopatik pulmoner fibrozis normal akciğer dokusunun yerini gaz değişimine olanak vermeyen bağ dokusunun aldığı, etyolojisi bilinmeyen, ilerleyici bir akciğer hastalığıdır. Akciğer dokusunda fibrozisin gelişimi kronik bir süreçtir ve bu sürece birden fazla sinyal yolağı ve mediyatör katkıda bulunmaktadır. Bilinmeyen etiyolojisine rağmen, çeşitli genetik ve çevresel faktörler idiopatik pulmoner fibrozisle ilişkilendirilmektedir. İdiopatik pulmoner fibrozisin kliniği, akciğer fonksiyonlarının kademeli kaybını içermekte ve hastalar son evrede genellikle solunum yetmezliği ile kaybedilmektedir. Bu nedenle, uygun tedavi yaklaşımlarının belirlenmesi ve uygulanması kritik bir öneme sahiptir. Kesin bir tedavisi olmamakla birlikte, hastalığın ilerlemesini yavaşlatmak ve yaşam kalitesini artırmak için çeşitli tedavi seçenekleri bulunmaktadır. Mevcut tedavi yaklaşımları arasında en yaygın kullanılanlar, pirfenidon ve nintedanib gibi antifibrotik ilaçlardır. Bu ilaçlarla, akciğer dokusunda fibrozisin ilerleyişi yavaşlatılabilmekte ve semptomlar hafifletilebilmektedir. Henüz etkin bir tedavisi olmayan hastalık için, patofizyolojide rol oynayan sinyal yolaklarının ve mediyatörlerin hedeflendiği yeni tedavi yaklaşımları oluşturulmaktadır. Bu yaklaşımlar arasında pirfenidon ve nintedanib kombinasyonu, BI 1015550, PLN-74809, TRK-250, BMS-986278, PBI-4050, TD139, treprostinil ve kök hücre tedavisi gibi potansiyel tedaviler yer almaktadır. Şu anda yürütülen ve gelecekte gerçekleştirilecek çalışmalar sayesinde, daha etkili tedavi yöntemlerinin geliştirilmesi ve hastalığın tam anlamıyla tedavi edilebilmesi umut edilmektedir.

Anahtar Kelimeler

Antifibrotik ilaçlar, idiopatik pulmoner fibrozis, klinik çalışmalar, pulmoner fibrozis, yeni tedavi yaklaşımları

Kaynakça

• 1. Nalysnyk L, Cid-Ruzafa J, Rotella P, Esser D. Incidence and prevalence of idiopathic pulmonary fibrosis: review of the literature. Eur Respir Rev. 2012;21(126):355–361.
• 2. Wynn TA. Integrating mechanisms of pulmonary fibrosis. J Exp Med. 2011;208(7):1339–1350.
• 3. Weiskirchen R, Weiskirchen S, Tacke F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med. 2019;65:2-15
• 4. Spagnolo P, Sverzellati N, Rossi G, Cavazza A, Tzouvelekis A, Crestani B, Vancheri C. Idiopathic pulmonary fibrosis: an update. Ann Med. 2015;47(1):15–27.
• 5. Noble PW, Barkauskas CE, Jiang D. Pulmonary fibrosis: Patterns and perpetrators. J Clin Invest. 2012;122(8):2756-2762.
• 6. Wells AU. Managing diagnostic procedures in idiopathic pulmonary fibrosis. Eur Respir Rev. 2013;22(128):158–162.
• 7. Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Müller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schünemann HJ; ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788-824.
• 8. Ley B, Collard HR, King TE. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2011;183(4):431–440.
• 9. Zhu W, Liu C, Tan C, Zhang J. Predictive biomarkers of disease progression in idiopathic pulmonary fibrosis. Heliyon. 2024;10(1):e23543.
• 10. King TE Jr: Treatment of idiopathic pulmonary fibrosis. [Internet yayını]. 2024 Jun (Erişim Tarihi: 05.08.2024. Adres: https:// www.uptodate.com/contents/treatment-of-idiopathic-pulmonary- fibrosis?search=Treatment%20of%20idiopathic%20 pulmonary%20fibrosis&source=search_result&selectedTitle= 1%7E128&usage_type=default&display_rank=1.%20Treatment% 20of%20idiopathic%20pulmonary%20fibrosis.)
• 11. Ley B, Ryerson CJ, Vittinghoff E, Ryu JH, Tomassetti S, Lee JS, Poletti V, Buccioli M, Elicker BM, Jones KD, King TE Jr, Collard HR. A multidimensional index and staging system for idiopathic pulmonary fibrosis. Ann Intern Med. 2012;156(10):684-691.
• 12. Raghu G, Rochwerg B, Zhang Y, Garcia CA, Azuma A, Behr J, Brozek JL, Collard HR, Cunningham W, Homma S, Johkoh T, Martinez FJ, Myers J, Protzko SL, Richeldi L, Rind D, Selman M, Theodore A, Wells AU, Hoogsteden H, Schünemann HJ; American Thoracic Society; European Respiratory society; Japanese Respiratory Society; Latin American Thoracic Association. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med. 2015;192(2):e3-e19.
• 13. King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P, Lancaster L, Noble PW, Sahn SA, Szwarcberg J, Thomeer M, Valeyre D, du Bois RM; INSPIRE Study Group. Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial. Lancet. 2009;374(9685):222-228.
• 14. Raghu G, Brown KK, Collard HR, Cottin V, Gibson KF, Kaner RJ, Lederer DJ, Martinez FJ, Noble PW, Song JW, Wells AU, Whelan TP, Wuyts W, Moreau E, Patterson SD, Smith V, Bayly S, Chien JW, Gong Q, Zhang JJ, O’Riordan TG. Efficacy of simtuzumab versus placebo in patients with idiopathic pulmonary fibrosis: a randomised, double-blind, controlled, phase 2 trial. Lancet Respir Med. 2017;5(1):22-32.
• 15. Wright WA, Crowley LE, Parekh D, Crawshaw A, Dosanjh DP, Nightingale P, Thickett DR. Real-world retrospective observational study exploring the effectiveness and safety of antifibrotics in idiopathic pulmonary fibrosis. BMJ Open Respir Res. 2021;8(1):e000782.
• 16. Feng H, Zhao Y, Li Z, Kang J. Real-life experiences in a single center: efficacy of pirfenidone in idiopathic pulmonary fibrosis and fibrotic idiopathic non-specific interstitial pneumonia patients. Ther Adv Respir Dis. 2020;14:1753466620963015.
• 17. Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, Cottin V, Flaherty KR, Hansell DM, Inoue Y, Kim DS, Kolb M, Nicholson AG, Noble PW, Selman M, Taniguchi H, Brun M, Le Maulf F, Girard M, Stowasser S, Schlenker-Herceg R, Disse B, Collard HR; INPULSIS Trial Investigators. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071-2082.
• 18. Rodríguez-Portal JA. Efficacy and Safety of Nintedanib for the Treatment of Idiopathic Pulmonary Fibrosis: An Update. Drugs R D. 2018;18(1):19-25.
• 19. Cilli A, Uzer F. Disease progression in idiopathic pulmonary fibrosis under anti-fibrotic treatment. Sarcoidosis Vasc Diffuse Lung Dis. 2023;40(3):e2023034.
• 20. Suzuki Y, Mori K, Aono Y, Kono M, Hasegawa H, Yokomura K, Naoi H, Hozumi H, Karayama M, Furuhashi K, Enomoto N, Fujisawa T, Nakamura Y, Inui N, Nakamura H, Suda T. Switching antifibrotics in patients with idiopathic pulmonary fibrosis: a multi-center retrospective cohort study. BMC Pulm Med. 2021;21(1):221.
• 21. Martinez FJ, Collard HR, Pardo A, Raghu G, Richeldi L, Selman M, Swigris JJ, Taniguchi H, Wells AU. Idiopathic pulmonary fibrosis. Nat Rev Dis Primers. 2017;3:17074.
• 22. Kotloff RM, Keshavjee S. Lung Transplantation. In: Broaddus VC, Ernst JD, King TEJ, Lazarus SC, Sarmiento KF, Schnapp LM, Stapleton RD, editors. Murray & Nadel’s Textbook of Respiratory Medicine. 7th ed. Elsevier Health Sciences; 2021.1964–1979.
• 23. Huh JY, Lee JH, Song JW. Efficacy and safety of combination therapy with pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis. Front Pharmacol. 2023;14:1301923.
• 24. Hisata S, Bando M, Homma S, Kataoka K, Ogura T, Izumi S, Sakamoto S, Watanabe K, Saito Y, Shimizu Y, Kato M, Nishioka Y, Hara H, Waseda Y, Tanino Y, Yatera K, Hashimoto S, Mukae H, Inase N; Diffuse Lung Diseases Research Group of the Ministry of Health, Labour and Welfare, Japan. Safety and tolerability of combination therapy with pirfenidone and nintedanib for idiopathic pulmonary fibrosis: A multicenter retrospective observational study in Japan. Respir Investig. 2021;59(6):819-826.
• 25. Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, Wiebe S, Stansen W, Quaresma M, Stowasser S, Wuyts WA; INJOURNEY Trial Investigators. Nintedanib with Add-on Pirfenidone in Idiopathic Pulmonary Fibrosis. Results of the INJOURNEY Trial. Am J Respir Crit Care Med. 2018;197(3):356-363.
• 26. Herrmann FE, Hesslinger C, Wollin L, Nickolaus P. BI 1015550 is a PDE4B Inhibitor and a Clinical Drug Candidate for the Oral Treatment of Idiopathic Pulmonary Fibrosis. Front Pharmacol. 2022;13:838449.
• 27. Maher TM, Schlecker C, Luedtke D, Bossert S, Zoz DF, Schultz A. Phase I studies of BI 1015550, a preferential phosphodiesterase 4B inhibitor, in healthy males and patients with idiopathic pulmonary fibrosis. ERJ Open Res. 2022;8(4):00240.
• 28. Richeldi L, Azuma A, Cottin V, Hesslinger C, Stowasser S, Valenzuela C, Wijsenbeek MS, Zoz DF, Voss F, Maher TM; 1305- 0013 Trial Investigators. Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis. N Engl J Med. 2022;386(23):2178-2187.
• 29. Song KH, Cho SJ, Song JY. αvβ1 integrin as a novel therapeutic target for tissue fibrosis. Ann Transl Med. 2016;4(20):411.
• 30. Lancaster LH, Cottin V, Ramaswamy M, Goldin JG, Kim GHJ, Bellini J, Jurek M, Decaris M, Cosgrove GP, Lefebvre E, Flaherty KR. PLN-74809 Shows Favorable Safety and Tolerability and Indicates Antifibrotic Activity in a Phase 2a Study for the Treatment of Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2023;207:A2777.
• 31. Sgalla G, Franciosa C, Simonetti J, Richeldi L. Pamrevlumab for the treatment of idiopathic pulmonary fibrosis. Expert Opin Investig Drugs. 2020;29(8):771-777.
• 32. Mageto Y, Flaherty K, Brown K, Fong A, Raghu G. Safety and Tolerability of Human Monoclonal Antibody FG-3019, Anti-Connective Tissue Growth Factor, in Patients with Idiopathic Pulmonary Fibrosis. Chest. 2004;126(4):773S.
• 33. Richeldi L, Fernández Pérez ER, Costabel U, Albera C, Lederer DJ, Flaherty KR, Ettinger N, Perez R, Scholand MB, Goldin J, Peony Yu KH, Neff T, Porter S, Zhong M, Gorina E, Kouchakji E, Raghu G. Pamrevlumab, an anti-connective tissue growth factor therapy, for idiopathic pulmonary fibrosis (PRAISE): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Respir Med. 2020;8(1):25-33.
• 34. Raghu G, Richeldi L, Fernández Pérez ER, De Salvo MC, Silva RS, Song JW, Ogura T, Xu ZJ, Belloli EA, Zhang X, Seid LL, Poole L; ZEPHYRUS-1 Study Investigators. Pamrevlumab for Idiopathic Pulmonary Fibrosis: The ZEPHYRUS-1 Randomized Clinical Trial. JAMA. 2024;332(5):380-389.
• 35. Shibata A, Matsumoto T, Uchida M, Yamada M, Miyamoto Y, Inada H, Eguchi Y, Toriumi W. A Novel siRNA-Based Oligonucleotide, TRK-250, and Its Efficacy for Treatment of Idiopathic Pulmonary Fibrosis (IPF). Am J Respir Crit Care Med. 2019;199:A5391
• 36. Doi H, Atsumi J, Baratz D, Miyamoto Y. A Phase I Study of TRK-250, a Novel siRNA-Based Oligonucleotide, in Patients with Idiopathic Pulmonary Fibrosis. J Aerosol Med Pulm Drug Deliv. 2023;36(6):300-308.
• 37. van den Blink B, Dillingh MR, Ginns LC, Morrison LD, Moerland M, Wijsenbeek M, Trehu EG, Bartholmai BJ, Burggraaf J. Recombinant human pentraxin-2 therapy in patients with idiopathic pulmonary fibrosis: safety, pharmacokinetics and exploratory efficacy. Eur Respir J. 2016;47(3):889-897.
• 38. Richeldi L, Schiffman C, Behr J, Inoue Y, Corte TJ, Cottin V, Jenkins RG, Nathan SD, Raghu G, Walsh SLF, Jayia PK, Kamath N, Martinez FJ. Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial. Am J Respir Crit Care Med. 2024;209(9):1132-1140.
• 39. Swaney JS, Chapman C, Correa LD, Stebbins KJ, Bundey RA, Prodanovich PC, Fagan P, Baccei CS, Santini AM, Hutchinson JH, Seiders TJ, Parr TA, Prasit P, Evans JF, Lorrain DS. A novel, orally active LPA(1) receptor antagonist inhibits lung fibrosis in the mouse bleomycin model. Br J Pharmacol. 2010;160(7):1699-1713.
• 40. Cheng PTW, Kaltenbach RF 3rd, Zhang H, Shi J, Tao S, Li J, Kennedy LJ, Walker SJ, Shi Y, Wang Y, Dhanusu S, Reddigunta R, Kumaravel S, Jusuf S, Smith D, Krishnananthan S, Li J, Wang T, Heiry R, Sum CS, Kalinowski SS, Hung CP, Chu CH, Azzara AV, Ziegler M, Burns L, Zinker BA, Boehm S, Taylor J, Sapuppo J, Mosure K, Everlof G, Guarino V, Zhang L, Yang Y, Ruan Q, Xu C, Apedo A, Traeger SC, Cvijic ME, Lentz KA, Tirucherai G, Sivaraman L, Robl J, Ellsworth BA, Rosen G, Gordon DA, Soars MG, Gill M, Murphy BJ. Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases. J Med Chem. 2021;64(21):15549-15581.
• 41. Kim GHJ, Goldin JG, Hayes W, Oh A, Soule B, Du S. The value of imaging and clinical outcomes in a phase II clinical trial of a lysophosphatidic acid receptor antagonist in idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 2021;15:17534666211004238.
• 42. Tirucherai GS, Yu D, Revankar R, Klinger G, van Lier JJ, Taubel J, . BMS-986278, A Lysophosphatidic Acid 1 (LPA1) Receptor Antagonist, in Healthy Participants: A Single/Multiple Ascending Dose (SAD/MAD) and Japanese MAD (JMAD) Phase 1 Study. Am J Respir Crit Care Med 2020;201:A1492
• 43. Corte TJ, Lancaster L, Swigris JJ, Maher TM, Goldin JG, Palmer SM, Suda T, Ogura T, Minnich A, Zhan X, Tirucherai GS, Elpers B, Xiao H, Watanabe H, Smith RA, Charles ED, Fischer A. Phase 2 trial design of BMS-986278, a lysophosphatidic acid receptor 1 (LPA1) antagonist, in patients with idiopathic pulmonary fibrosis (IPF) or progressive fibrotic interstitial lung disease (PF-ILD). BMJ Open Respir Res. 2021;8(1):e001026.
• 44. Maher TM, van der Aar EM, Van de Steen O, Allamassey L, Desrivot J, Dupont S, Fagard L, Ford P, Fieuw A, Wuyts W. Safety, tolerability, pharmacokinetics, and pharmacodynamics of GLPG1690, a novel autotaxin inhibitor, to treat idiopathic pulmonary fibrosis (FLORA): a phase 2a randomised placebo- controlled trial. Lancet Respir Med. 2018;6(8):627-635.
• 45. Maher TM, Ford P, Brown KK, Costabel U, Cottin V, Danoff SK, Groenveld I, Helmer E, Jenkins RG, Milner J, Molenberghs G, Penninckx B, Randall MJ, Van Den Blink B, Fieuw A, Vandenrijn C, Rocak S, Seghers I, Shao L, Taneja A, Jentsch G, Watkins TR, Wuyts WA, Kreuter M, Verbruggen N, Prasad N, Wijsenbeek MS; ISABELA 1 and 2 Investigators. Ziritaxestat, a Novel Autotaxin Inhibitor, and Lung Function in Idiopathic Pulmonary Fibrosis: The ISABELA 1 and 2 Randomized Clinical Trials. JAMA. 2023;329(18):1567-1578.
• 46. Gagnon L, Leduc M, Thibodeau JF, Zhang MZ, Grouix B, Sarra-Bournet F, Gagnon W, Hince K, Tremblay M, Geerts L, Kennedy CRJ, Hébert RL, Gutsol A, Holterman CE, Kamto E, Gervais L, Ouboudinar J, Richard J, Felton A, Laverdure A, Simard JC, Létourneau S, Cloutier MP, Leblond FA, Abbott SD, Penney C, Duceppe JS, Zacharie B, Dupuis J, Calderone A, Nguyen QT, Harris RC, Laurin P. A Newly Discovered Antifibrotic Pathway Regulated by Two Fatty Acid Receptors: GPR40 and GPR84. Am J Pathol. 2018;188(5):1132-1148.
• 47. Khalil N, Manganas H, Ryerson CJ, Shapera S, Cantin AM, Hernandez P, Turcotte EE, Parker JM, Moran JE, Albert GR, Sawtell R, Hagerimana A, Laurin P, Gagnon L, Cesari F, Kolb M. Phase 2 clinical trial of PBI-4050 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2019;53(3):1800663.
• 48. Hirani N, MacKinnon AC, Nicol L, Ford P, Schambye H, Pedersen A, Nilsson UJ, Leffler H, Sethi T, Tantawi S, Gravelle L, Slack RJ, Mills R, Karmakar U, Humphries D, Zetterberg F, Keeling L, Paul L, Molyneaux PL, Li F, Funston W, Forrest IA, Simpson AJ, Gibbons MA, Maher TM. Target inhibition of galectin- 3 by inhaled TD139 in patients with idiopathic pulmonary fibrosis. Eur Respir J. 2021;57(5):2002559.
• 49. Maher T, Wijsenbeek M, Hirani N, Lindmark B, Phung D, Mac Kinnon A, Sethi T, Aslanis V, Mc Clinton C, Andersen E, Schambye H, Wang-Jairaj J. GALACTIC-1: Galectin-3 inhibition in idiopathic pulmonary fibrosis (IPF) – rationale, objectives and design of a 52-week, Phase IIb study of GB0139. Eur Respir J. 2022;60:2950.
• 50. Kyriakis JM, Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81(2):807-869.
• 51. Alcorn JF, van der Velden J, Brown AL, McElhinney B, Irvin CG, Janssen-Heininger YM. c-Jun N-terminal kinase 1 is required for the development of pulmonary fibrosis. Am J Respir Cell Mol Biol. 2009;40(4):422-432.
• 52. Mattos WLLD, Khalil N, Spencer LG, Bonella F, Folz RJ, Rolf JD, Mogulkoc N, Lancaster LH, Jenkins RG, Lynch DA, Noble PW, Maher TM, Cottin V, Senger S, Horan GS, Greenberg S, Popmihajlov Z. Phase 2, Double-Blind, Placebo-controlled Trial of a c-Jun N-Terminal Kinase Inhibitor in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2024;14.
• 53. Waxman A, Restrepo-Jaramillo R, Thenappan T, Ravichandran A, Engel P, Bajwa A, Allen R, Feldman J, Argula R, Smith P, Rollins K, Deng C, Peterson L, Bell H, Tapson V, Nathan SD. Inhaled Treprostinil in Pulmonary Hypertension Due to Interstitial Lung Disease. N Engl J Med. 2021;384(4):325-334.
• 54. Nathan SD, Waxman A, Rajagopal S, Case A, Johri S, DuBrock H, De La Zerda DJ, Sahay S, King C, Melendres-Groves L, Smith P, Shen E, Edwards LD, Nelsen A, Tapson VF. 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(11):1266-1274.
• 55. Kolb M, Orfanos SE, Lambers C, Flaherty K, Masters A, Lancaster L, Silverstein A, Nathan SD. The Antifibrotic Effects of Inhaled Treprostinil: An Emerging Option for ILD. Adv Ther. 2022;39(9):3881-3895.
• 56. Cheng W, Zeng Y, Wang D. Stem cell-based therapy for pulmonary fibrosis. Stem Cell Res Ther. 2022;13(1):492.
• 57. Glassberg MK, Minkiewicz J, Toonkel RL, Simonet ES, Rubio GA, DiFede D, Shafazand S, Khan A, Pujol MV, LaRussa VF, Lancaster LH, Rosen GD, Fishman J, Mageto YN, Mendizabal A, Hare JM. Allogeneic Human Mesenchymal Stem Cells in Patients With Idiopathic Pulmonary Fibrosis via Intravenous Delivery (AETHER): A Phase I Safety Clinical Trial. Chest. 2017;151(5):971-981.
• 58. Averyanov A, Koroleva I, Konoplyannikov M, Revkova V, Lesnyak V, Kalsin V, Danilevskaya O, Nikitin A, Sotnikova A, Kotova S, Baklaushev V. First-in-human high-cumulative-dose stem cell therapy in idiopathic pulmonary fibrosis with rapid lung function decline. Stem Cells Transl Med. 2020;9(1):6-16