Disclosures United Therapeutics Not approved by the FDA for use - PowerPoint PPT Presentation

3/11/2017 Disclosures • United Therapeutics • Not approved by the FDA for use in children Prostanoids Stephanie Handler, MD Children’s Hospital of Wisconsin Medical College of Wisconsin Other Disclosures Definition • Limited “best practice” data in children • Prostanoids- subclass of eicosanoids √ Prostaglandins • Treatment decisions based on: √ Thromboxanes √ Adult PAH data √ Prostacyclins √ Pediatric off-label experience › predominantly retrospective case series • Synthesized from arachidonic acid by cyclooxygenase √ AHA/ATS Guidelines Thromboxane • PGH 2 Prostacyclin (PGI 2 ) 1

3/11/2017 Therapy for PAH Prostacyclin Pathway Medications Target Receptors Lang I et Gaine S. Eur Respir Rev 2015;24:630-41. Epoprostenol • Approved by FDA in 1995 for FC III/IV PAH • Rapidly hydrolyzed with very short half life (~3 min) • Requires continuous intravenous infusion • Flolan requires ice pack (unstable at room temperature) √ Newer IV formulation Veletri thermostable Yung D et al. Circulation 2004;110:660-5. 2

3/11/2017 Treprostinil • Remodulin approved by FDA in 2002 (SC) & 2004 (IV) • Longer half life (~3-4 hours) • Local site reactions have limited SC delivery in adults but seems to be better tolerated in children Ferdman et al. Pediatrics 2014. Levy M et al. J Pediatr 2011;158:584-8. Pediatric Survival EPOPROSTENOL ERA EPOPROSTENOL & TREPROSTINIL ERA Circ 2004;110:660-665. JHLT 2013;32(5):546-52. 3

3/11/2017 Pharmacokinetics Parenteral Prostacyclin Therapy • Epoprostenol – “gold standard” √ Use limited by risk of indwelling central venous catheter, short half life and complexity with delivery √ Can be used for rapid up-titration • Treprostinil – available as SC/ IV √ Similar risk of infection with indwelling central venous catheter but longer half life √ Monitor for site pain in SC route Inhaled Prostacyclin • Epoprostenol (reserved for ICU) • Iloprost √ Approved by FDA in 2004 √ Requires patient cooperation (10 minute delivery) and 6-9x/day administration limiting use in children • Treprostinil (Tyvaso) √ Approved by FDA in 2009 √ Administered 4x/day via nebulizer Bourge R et al. Chest 2016;150(1):27-35. 4

3/11/2017 Ivy D et al. JACC 2008;51:161-9. Krishnan U et al. JACC 2010;55:1915-22. Abman S et al. Circulation 2015;132. Abman S et al. Circulation 2015;132. 5

3/11/2017 Parenteral Therapy- Are we too late? FDA Reported Pediatric Mortality Farber H et al. J Heart Lung Transplant 2013;32:1114-1122. Maxey D, et al. Pediatr Cardiol 2013;34:1628-36. Oral Therapy • Selexipag (Uptravi) √ Selective IP prostacyclin receptor agonist √ Approved by FDA in 2015 √ Administered 2x/day (tablet only) • Treprostinil (Orinetram) √ Approved by FDA in 2013 √ Administered 3-4x/day (tablet only) Sitbon O et al. NEJM 2015;373:2522-33. 6

3/11/2017 Oral Treprostinil – Pediatric PAH • Multi-center, open-label, 24-week trial in pediatric patients aged 7-17 years with PAH • Primary objective √ Assess the safety and tolerability of oral treprostinil • Secondary objectives √ Assess effect of oral treprostinil √ Describe treprostinil pharmacokinetics Chest 2013;144(3):952-8. Circulation 2013;127:624-33 Oral Treprostinil Pediatric Trial Expanded Use • 32 subjects enrolled • Beyond Group 1 PAH… √ Cohort 1 (Remodulin) - 10 √ Cohort 2 (Tyvaso) - 10 • Neonatal/infant pulmonary hypertension √ Cohort 3 (de novo) – 12 • Single ventricle congenital heart disease • RESULTS… STAY TUNED!! 7

3/11/2017 Neonate/Infant Congenital Diaphragmatic Hernia Skarda D et al. Eur J Pediatr Surg 2015;25(5):454-9. Treprostinil PPHN Trial Treprostinil PPHN Trial • Randomized, placebo-controlled, multi-center clinical trial in • 23 sites participating neonates with PPHN with inadequate response to iNO • 9 subjects enrolled & dosed √ Study drug administered IV or SC for up to 28 days √ 4 CDH, 5 PPHN • Hypothesis: Remodulin will reduce rate of clinical worsening defined › 2 MAS, 1 birth hypoxia, 1 sepsis, 1 idiopathic as death, ECMO, or use of additional pulmonary vasodilator therapy √ 3 IV, 6 SC • Primary objective (assessed at day 14) √ Explore safety and treatment effect of Remodulin as add on therapy in neonates with PPHN compared to placebo • Secondary objectives √ Assess the effect of Remodulin √ Evaluate pharmacokinetics 8

3/11/2017 Summary • Pediatric use of treprostinil SC/IV de novo or in transition continues to increase (including new populations) • Inhaled/ oral agents considered in low risk patients √ Need to have caution to not delay institution of SC/IV therapy if novel agents considered • Combination with other PAH therapy not well understood Thank You 9