THE INCREASE STUDY INHALED TREPROSTINIL IN PULMONARY HYPERTENSION DUE TO INTERSTITIAL LUNG DISEASE (PH-ILD) Peter Smith, PharmD Senior Director Product Development, United Therapeutics Corporation
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3 WHO GROUP 3 PH WHO Classification of Pulmonary Hypertension 1-3 PULMONARY HYPERTENSION (PH) GROUP 1 Pulmonary Arterial Hypertension (PAH) GROUP 2 PH Due to Left Heart Disease GROUP 3 PH Due to Lung Disease GROUP 4 PH Due to Chronic Thromboembolism GROUP 5 PH Due to Unclear Multifactorial Mechanisms
4 INTERSTITIAL LUNG DISEASE (ILD) 1-3 GROUP 3 PH Due to Lung Disease Interstitial Lung Disease (ILD) Chronic Obstructive Pulmonary Disease (COPD)
5 INTERSTITIAL LUNG DISEASE (ILD) 1-3 GROUP 3 PH Due to Lung Disease Interstitial Lung Disease (ILD) Chronic Obstructive Pulmonary Disease (COPD) Idiopathic Interstitial Pneumonias Environmental and Occupational Diseases Multisystem Diseases Other: Rare Lung Diseases & Emphysema-Related Diseases IPF DIP LIP NSIP COP PPF RB-ILD AIP UIP Pneumoconiosis Chronic Hypersensitivity Pneumonitis Connective Tissue Disease Sarcoidosis Wegener s Granulomatosis Occupational Lung Disease Tuberose Sclerosis CPFE Pulmonary Histiocytosis Pulmonary Eosinophilia Pulmonary Histiocytosis
6 SCOPE OF THE PROBLEM 4 PREVALENCE OF ILD Patients in US ~230,000
7 SCOPE OF THE PROBLEM 4 PREVALENCE OF ILD PREVALENCE OF PH-ILD 15% Variable reports of PH in ILD prevalence Patients in US ~230,000 Patients in US ~30,000
8 NO APPROVED THERAPIES FOR WHO GROUP 3 5-13 SILDENAFIL / REVATIO STEP-IPF study did not achieve 20% change in 6MWD, but did suggest increased quality of life and decreased shortness of breath BOSENTAN / TRACLEER BUILD-1,-2,-3: Failed to improve 6MWD and the time to occurrence of lung fibrosis worsening B-PHIT: No improvement in hemodynamics, functional class, or symptoms MACITENTAN / OPSUMIT MUSIC study found no significant difference in PFTs, time to disease worsening, or death AMBRISENTAN/ LETAIRIS ARTEMIS-IPF was stopped early due to increased rate of disease progression and respiratory hospitalizations. Use Contraindicated RIOCIGUAT / ADEMPAS RISE-IIP study terminated due to risk of death and other serious adverse events as compared to placebo. Use Contraindicated in Europe
9 INCREASE STUDY WHY INCREASE?
10 THE itre STUDY RESULTS 11 6-MIN WALK DISTANCE (6MWD) 11 p = 0.022 WHO-FUNCTIONAL CLASS I & II 22 p = 0.041 Baseline Follow-up 0 Distance 243 ± 106 m +65 m 308 ± 109m IV I+ II 18% III Baseline VS III IV 41% Follow-up I+ II Data are from a retrospective analysis and should be interpreted with the appropriate caution.
11 VENTILATION (V)/PERFUSION (Q) MISMATCH WITH SYSTEMIC VASODILATORS 14-16 Ventilation (V) / Perfusion (Q) Gradient INHALED THERAPIES MAY PRESERVE V/Q AND PREVENT UNDESIRABLE EFFECTS ON PERFUSION
12 INCREASE STUDY DESIGN OVERVIEW NCT02630316 16 WEEK double blind study N=314 WHO Group 3 PH associated with ILD including CPFE RANDOMIZE 1:1 ~115 STUDY SITES IN US
13 INCREASE STUDY DESIGN OVERVIEW INHALED TREPROSTINIL NCT02630316 16 WEEK double blind study N=314 WHO Group 3 PH associated with ILD including CPFE PRIMARY ENDPOINT RANDOMIZE 1:1 6MWD at peak exposure ~115 STUDY SITES IN US PLACEBO
14 INCREASE STUDY DESIGN OVERVIEW INHALED TREPROSTINIL NCT02630316 16 WEEK double blind study N=314 WHO Group 3 PH associated with ILD including CPFE PRIMARY ENDPOINT RANDOMIZE 1:1 6MWD at peak exposure NCT02633293 Open Label Extension 2 YEARS ~115 STUDY SITES IN US PLACEBO
15 REFERENCES 1. Simonneau G, et al. J Am Coll Cardiol. 2013;62(25):D34-41. 2. Bourke SJ. Postgrad Med J. 2006;82:494-499. 3. Interstitial Lung Disease www.erswhitebook.com accessed December 2015. 4. United Therapeutics internal market research. 5. The Idiopathic Pulmonary Fibrosis Clinical Research Network, et al. N Engl J Med. 2010;363(7):620-628. 6. King TE Jr, et al. Am J Respir Crit Care Med. 2008;177(1):75-81. 7. Seibold JR, et al. Arthritis Rheum. 2010;62(7):2101-2108. 8. King TE Jr, et al. Am J Respir Crit Care Med. 2011;184(1):92-99. 9. Corte TJ, et al. Am J Respir Crit Care Med. 2014;190(2):208-217. 10. Raghu G, et al. Eur Respir J. 2013;42(6):1622-1632. 11. Faria-Urbina, M., Oliveira, R.K.F., Agarwal, M., Waxman A.B., et al. Lung (2018) 196:139. https://doi.org/10.1007/s00408-017-0081-7. 12. Raghu et al. Ann Inter Med. 2013; 158(9):641-9. 13. Nathan et al. Eur Resp Journal. 2017, 50 (suppl 61). DOI: 10.1183/1393003.congress-2017. OA1985 14. Rubin LJ. New Engl J Med. 1997;336(2):111-117. 15. Rubin LJ. Chest. 1993;104:236-250. 16. Seeger W, et al. J Am Coll Cardiol. 2013;62(25 Suppl):D109-116. AIP: Acute interstitial pneumonitis; COP: Cryptogenic organizing pneumonia; CPFE: Combined pulmonary fibrosis and emphysema DIP: Desquamative interstitial pneumonia; IPF: Idiopathic Pulmonary Fibrosis; LIP: Lymphoid interstitial pneumonia; NSIP: Nonspecific interstitial pneumonia; PPF: Pleuroparenchymal fibroelastosis; RB-ILD: Respiratory bronchiolitis-associated interstitial lung disease; UIP: Unclassifiable interstitial pneumonia;
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