ΝΕΑ ΔΕΔΟΜΕΝΑ ΣΤΗ ΘΕΡΑΠΕΥΤΙΚΗ ΑΝΤΙΜΕΤΩΠΙΣΗ Της ΠΝΕΥΜΟΝΙΚΗς ΑΡΤΗΡΙΑΚΗς ΥΠΕΡΤΑΣΗς ΣΤΕΛΙΟΣ ΟΡΦΑΝΟΣ Β’ ΚΛΙΝΙΚΗ ΕΝΤΑΤΙΚΗΣ ΘΕΡΑΠΕΙΑΣ & ΔΙΑΚΛΙΝΙΚΟ ΙΑΤΡΕΙΟ ΠΝΕΥΜΟΝΙΚΗΣ ΥΠΕΡΤΑΣΗΣ Π.Γ.Ν. «ΑΤΤΙΚΟΝ»

Disclosures Actelion Bayer ELPEN Galenica GSK MSD Pharmaserve Lilly Funding, or sponsoring to attend scientific meetings, or honoraria from: Actelion Bayer ELPEN Galenica GSK MSD Pharmaserve Lilly Pfizer United Therapeutics

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EHJ & ERJ, 2015

EHJ & ERJ, 2015

Ενδοθηλιακή Δυσλειτουργία επί ΠΑΥ NO PGI2 ET-1 ET-1 is elevated (+) Vasoconstriction Cell proliferation / Hypertrophy NO and PGI2 are reduced (-) Vasodilation Anti-proliferation Anti-inflammation Endothelin (ET-1) is a potent vasoconstrictor which stimulates cell proliferation and hypertrophy To counteract the negative effects of ET-1, two important vasodilative, antimitogenic substances are derived from endothelium NO Prostacyclin In PAH, endothelium dysfunction refers to the imbalance of endothelium derived vasodilating, antiproliferative (NO, PGI2) and constricting (ET-1) Basically, there is an excess of ET-1 relative to NO and PGI2. Spieker LE et al. J Am Coll Cardiol. 2001;37:1493-1505. Luscher TF and Barton M. Circulation. 2000;102:2434-2440. Albrecht EW et al. J Pathol. 2003;199:8-17. Hankins SR and Horn EM. Curr Cardiol Rep. 2000;2:244-251.

Bosentan Ambrisentan Macitentan Selexipag Epoprostenol Treprostinil Iloprost Sildenafil Tadalafil Bosentan Ambrisentan Macitentan Selexipag Riociguat McLaughlin & McGoon Circulation 2006, 114:1417-1431 7

PATENT-1: Riociguat rapidly improves 6MWD vs placebo Ghofrani HA et al. N Engl J Med 2013;369:330–40.

Seraphin haemodynamic sub-study

Upfront combination therapy with ambrisentan/tadalafil reduced the risk of first event of clinical failure 50% Risk Reduction 95% CIs (using log-log transform method) are presented for each treatment group at weeks 4, 8, 16, 24, and then every 12 weeks up to week 96. N. Galiè, et al. N Engl J Med 2015;373:834-44

Upfront combination therapy with ambrisentan/tadalafil reduced TCF events in all subgroups CONFIDENTIAL N. Galiè, et al. N Engl J Med 2015;373:834-44

Patients without an event KM (%) Selexipag reduced the risk of the primary outcome composite of death or morbidity due to PH Patients without an event KM (%) 20 40 80 100 60 12 18 24 30 36 6 Months Selexipag Selexipag vs placebo: Risk reduction 40% HR = 0.60; 99% CI 0.46–0.78; p < 0.0001 Placebo Hospitalisation for PAH worsening and disease progression were the main components of the primary endpoint Speaker notes The primary endpoint was measured up to the end of treatment Here we see the selexipag in green and the placebo in grey The curves separate early on and this separation is maintained over the whole follow-up The risk reduction was 40% and was highly statistically significant Additional information: Absolute risk reduction of 14.6, therefore Number Needed to Treat (NNT) to prevent an event is 7 patients at 24 months No. at Risk Placebo 582 433 347 220 149 88 28 Selexipag 574 455 361 246 171 101 40

No. of patients/ no. of events Consistent treatment effect of selexipag on primary composite endpoint according to background therapy Selexipag Placebo Selexipag vs placebo No. of patients/ no. of events All patients 574/155 582/242 PAH specific therapy at baseline (interaction p value = 0.95) ERA + PDE-5i 179/47 197/80 ERA monotherapy 94/23 76/29 PDE-5i monotherapy 189/54 185/84 No PAH-specific therapy 112/31 124/49 Hazard ratio (99% CI) 0.1 0.2 0.4 0.6 1 1.4 2 Source: Figure FMMTGRP_F – Produced by zeeja1 on 28JUL14– Data dump of 12JUN2014 CI: confidence interval; EOT: end-of-treatment; ERAs: endothelin receptor antagonists; M/M: morbidity/mortality; PAH: pulmonary arterial hypertension, PDE-5: phosphodiesterase-5 Note 1: the vertical solid line references the overall treatment effect Favours selexipag Favours placebo

2015 ESC/ERS guidelines treatment algorithm Galiè N, et al. ESC/ERS Guidelines. Eur Respir J & Eur Heart J. 2015.

EHJ & ERJ, 2015

2015 ESC/ERS guidelines treatment algorithm Galiè N, et al. ESC/ERS Guidelines. Eur Respir J & Eur Heart J. 2015.

Evolution of combination therapy

Initial dual combination therapy data

Initial combination therapy, ERA+PDE5-i BONSAI: BOlogNa Sub-study on hAemodynamIcs Joint Bologna and Calgary study on INiTial bosENTan plus sIldenafil in pulmonary arterial hypertension. 1. Bachetti C et al. Am J Respir Crit Care Med 2015;191:A479. 2. Palazzini M et al. Am J Respir Crit Care Med 2016;193:A6317. 3. Sitbon O et al. Eur Respir J 2016;47:1727–36.

Optima study Ongoing, multi-centre, prospective, single-arm, open-label, Phase IV study This is an interim analysis Estimated Completion Date: November 2017 Aims to evaluate the efficacy, safety and tolerability of initial combination therapy with macitentan and tadalafil in newly diagnosed PAH patients Sitbon O, et al. Eur Respir J 2016; 47:1727-36.

OPTIMA study ERS 2017 – Milan, 9-13 September 2017

WHY IS THIS PLANT STILL BEING WATERED? IT’S EASY TO JUST FOLLOW THE INSTRUCTIONS, BUT TREATING TOO LONG WITHOUT RECOGNIZING FAILURE IS DANGEROUS IRREPLACEABLE TIME IS LOST BEFORE SWITCHING THERAPIES NEED EXPERIENCED FOLLOWUP …και Καλή Συνεργασία με Εξειδικευμένα Κέντρα !!!

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