Objectives. Disclosures Oral Therapies for Children with Pulmonary Hypertensive Vascular Disease

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1 Disclosures Oral Therapies for Children with Pulmonary Hypertensive Vascular Disease Erika Berman Rosenzweig, MD Director, Pulmonary Hypertension Center Associate Professor of Clinical Pediatrics (in Medicine) Columbia University Medical Center Has received grant/research support from Actelion, Bayer AG, Eli Lily, Gilead Sciences, GSK, Novartis AG, Pfizer, and United Therapeutics Corporation Has served as a consultant for Actelion, GIlead and United Therapeutics. Objectives Provide a comprehensive review of available targeted oral treatment options for children with PAH Discuss when to consider the use an oral therapy for the treatment of PAH in a pediatric patient Provide a preview of potential future oral therapeutic targets PAH Treatment Goals Fewer/less severe symptoms Improved functional class Improved exercise capacity Improved hemodynamics Prevention of clinical worsening Improved quality of life Improved survival Ability to attend school Ability to participate in non-competitive activities Children 1

2 What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Sustained Response Yes Continue CCB Positive Negative No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. J Am Coll Cardiol. 29;53: Acute Vasoreactivity Testing Chronic Oral Adjuvant Therapies in PAH Managing right heart failure Digoxin Variable inotropic effect and use No long-term data; need to balance unproven benefits with known risks Diuretics Most patients need Anticoagulation Recommended in IPAH/HPAH Retrospective adult data only; Need to balance unproven benefits with known risks particularly in active children INR Badesch DB et al. Chest. 24;126:35S-62S. Badesch DB et al. Chest. 27;131: McLaughlin VV et al. J Am Coll Cardiol. 29;53: What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Positive Acute Vasoreactivity Testing Calcium Channel Blockers Only If acute vasodilator responsive Oral CCB Sustained Response Yes Continue CCB No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Negative Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated Vasodilator Response: Adult Definition Decrease in PAPm by 1 mm Hg Decrease of PAPm to < 4 mm Hg McLaughlin VV et al. J Am Coll Cardiol. 29;53: Sitbon O, et al. Circulation. 25 2

3 Survival in IPAH Long-term CCB Responders Calcium Channel Blockers Only If acute vasodilator responsive Cumulative survival Long-term CCB responders (~5% of acute responders or 6% of IPAH patients) Long-term CCB failure p=.7 Vasodilator Response Decrease in PAPm by 1 mm Hg Decrease of PAPm to < 4 mm Hg. Subjects at risk, n Sitbon O et al. Circulation Years Long-term CCB responders Long-term CCB failure Does this definition identify long term pediatric responders? What about children who start out with PAPm <4mmHg? Sitbon O, et al. Circulation. 25 AVT response in Young Children with resting PAPm < 4: Modification of historical definition Vasodilator Response Decrease in PAPm by 2% An increase or no change in CI Decrease in PVRi or no change in PVRi/SVRi ratio Barst RJ, et al. Circulation 212 REVEAL: Peds CCB patients with AVT available (n=42) Adult definition 22 Modified Peds definition Did not meet AVT criteria Met AVT criteria Barst RJ, et al. Circulation 212 3

4 Pediatric AVT: REVEAL Registry Overall Pediatric Acute response rate for IPAH/HPAH - 35% Of the 22 patients on CCB who were responsive by Barst modified definition, 5 year survival was 1% Of the general REVEAL population 162/216 had AVT available 36/12 (35%) IPAH/FPAH were responders 9/6 (15%) APAH-CHD were responders Barst RJ, et al. Circulation 212 IPAH in Children: Improved Survival with Chronic Calcium Channel Blockade Survival (n=26) (n=18) (n=11) (n=19) (n=6) p=.2 (n=5) 1 2 Years Acute responders Acute nonresponders (n=31) (n=43) Barst, et al. Circ, 1999 Kaplan-Meier curves for survival and treatment success in Acute Responders on CCB: n=31 Why not use CCB s in All Kids? Net Effect not same for all Pulmonary Vasodilation CO Systemic Vasodilation Neg Inotropy CO Yung D et al. Circulation 24;11: Highly variable Influenced by the drug and the disease Risks of getting it wrong: tachycardia, dyspnea, hypotension, syncope, death CCBs should NOT be used empirically 4

5 AVT response in Children: Suggest using modification of historical definition Vasodilator Response Decrease in PAPm by 2% An increase or no change in CI Decrease in PVRi or no change in PVRi/SVRi ratio Barst RJ, et al. Circulation 212 What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Sustained Response Yes Continue CCB Positive No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes McLaughlin VV et al. J Am Coll Cardiol. 29;53: Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Acute Vasoreactivity Testing Echocardiography Hemodynamics Negative Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated Oral Therapies: When are they indicated for children? Monotherapy? Up-front Combination therapy? Add on therapy? Transition off IV/SQ prostanoid therapy?? PAH Determinants of Risk: Where do Oral Therapies fit in? Is a child really ever Lower Risk? LOWER RISK? DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated McLaughlin VV et al. J Am Coll Cardiol. 29 5

6 French Registry: Kaplan-Meier Survival Estimates According to Baseline NYHA Functional Class Survival (%) No. at risk: NYHA I/II NYHA III NYHA IV NYHA I/II 4 NYHA III NYHA IV Time (mo) Combined idiopathic, familial, and anorexigen-associated PAH. Humbert M et al. Circulation. 21;122: French Registry: Kaplan-Meier Survival Estimates According to Baseline 6MWD Survival (%) No. at risk: m m -249 m Time (mo) Combined idiopathic, familial, and anorexigen-associated PAH. Humbert M et al. Circulation Plasma BNP as a Prognostic Indicator in Patients With IPAH Survival rate (%) Follow-up BNP BNP <18 pg/ml p.1 2 BNP 18 pg/ml p Time (mo) By multivariate analysis, higher BNP at follow-up (RR=25.88, p=.243) was an independent predictor of mortality. Nagaya N et al. Circulation. 2;12: ACCF/AHA Consensus PAH Treatment Algorithm Anticoagulate ± Diuretics ± Oxygen ± Digoxin Oral CCB Sustained Response Yes Continue CCB No Positive Lower Risk ERAs or PDE-5 Is (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC, inhaled) Reassess: consider combo-therapy Investigational Protocols Modified from McLaughlin VV et al. J Am Coll Cardiol. 29;53: Acute Vasoreactivity Testing Negative Higher Risk Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-5 Is (oral) Treprostinil (SC) Atrial septostomy Lung transplant 6

7 Approved Therapeutic Targets REVEAL: Pediatric Therapies (n=216) Endothelin receptor A Endothelinreceptor antagonists Endothelin Pathway Pre-proendothelin Endothelin-1 Proendothelin Endothelin receptor B Vasoconstriction and proliferation Endothelial cells Nitric Oxide Pathway L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Exogenous nitric oxide Vasodilation and antiproliferation Endothelial cells Prostacyclin Pathway Arachidonic acid camp Vasodilation and antiproliferation Prostaglandin I 2 Prostacyclin (prostaglandin I 2 ) Prostacyclin derivatives % Therapy Type Phosphodiesterase type 5 inhibitor Smooth muscle cells Smooth muscle cells Prostanoids PDE-5 inh ERAs CCB Humbert M et al. N Engl J Med. 24;351: Barst RJ, et al. Circulation 212 Approved Therapeutic Targets Endothelin receptor A Endothelinreceptor antagonists Endothelin Pathway Pre-proendothelin Endothelin-1 Smooth muscle cells Proendothelin Endothelin receptor B Vasoconstriction and proliferation Endothelial cells Nitric Oxide Pathway L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 inhibitor Exogenous nitric oxide Vasodilation and antiproliferation Endothelial cells Prostacyclin Pathway Arachidonic acid camp Vasodilation and antiproliferation Prostaglandin I 2 Prostacyclin (prostaglandin I 2 ) Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 24;351: ERA Therapies Bosentan (21) Dual endothelin receptor ET A /ET B blockade Pivotal trials included children > 12yrs old Indicated for twice daily administration to improve exercise capacity and reduce clinical worsening in WHO FC II-IV PAH patients Ambrisentan (28) Selective ET A receptor antagonist Pivotal trials in adults Indicated for once-daily treatment of PAH to improve exercise capacity and delay clinical worsening in patients with WHO FC II or III symptoms 7

8 Bosentan: 6-MWD (351 and BREATHE-1) Mean change from baseline (m) Study 351 Baseline Week **p<.5 vs baseline; p=.21 vs placebo. Values are mean±sem. Channick RN et al. Lancet. 21;358: Rubin LJ et al. N Engl J Med. 22;346; ** Bosentan (n=21) (n=11) BREATHE-1 Bosentan (n=144) (n=69) p=.2 Baseline Week Event-free (%) Bosentan: Time to Clinical Worsening (BREATHE-1 and EARLY) BREATHE-1 p=.38 Bosentan (n=144) 89% p=.15 Bosentan (n=35) (n=69) (n=13) Time (wk) 63% Time (wk) Adapted from Rubin LJ et al for the BREATHE Study Group. N Engl J Med. 22;346; Galiè N et al. Lancet. 28;371: Patients with no clinical worsening (%) p=.114 Bosentan EARLY Effects of Long-term Bosentan in Children with PAH Rosenzweig EB, Ivy DD, Widlitz A, Doran A, Claussen LR, Yung D, Abman SH, Morganti A, Nguyen N, Barst RJ. JACC. 25 Retrospective case review (2 US centers) 78 pts <18 years with IPAH or APAH Assessed long-term outcomes (up to 2 years) in pediatric PAH patients treated with bosentan Evaluated Adverse events/safety WHO functional class Hemodynamics Survival Hemodynamic Effects of Chronic Bosentan in Pediatric PAH (n=49) Patients on bosentan Baseline Follow-up Change (All patients) n=49 n=49 n=49 PAPm (mmhg) 64 ± 3 57 ± 3-7 ± 2* PVRI (units m2) 2 ± 2 15 ± 2-4 ± 2* Cardiac Index (L/min/m 2 ) 3.8 ± ±.2. ±.2 PCWPm (mmhg) 9 ± 9 ± 1 1 ± 1 RAPm (mmhg) 7 ± 1 7 ± 1 ± 1 p<.5 vs. baseline; paired t-test Mean ± SE Median f/u: 27 days Rosenzweig EB, et al., JACC, 25 8

9 Changes in WHO Functional Class at bosentan initiation and after at least eight weeks of treatment with bosentan Effects of Long-term Bosentan in Children with PAH Improvement in hemodynamics (PAPm, PVRi) Improvement or stabilization of WHO class in 9% patients 1- and 2-year survival: 98% and 91%, respectively Bosentan was well tolerated with efficacy/safety appearing similar in children as reported in adults Rosenzweig, EB. et al. J Am Coll Cardiol 25 Rosenzweig EB, et al., JACC, 25 Long-Term Outcomes in Children With Pulmonary Arterial Hypertension Treated With Bosentan in Real-World Clinical Settings D. Dunbar Ivy MD, Erika Berman Rosenzweig MD, Jean-Christophe Lemarié, Monika Brand, Daniel Rosenberg PhD, and Robyn J. Barst MD. Am J Cardiol 21. Patient treatment patterns throughout observation period (median observation was 39 months) Retrospective cohort study analyzed outcomes in 86 children with PAH treated with bosentan IPAH/ HPAH (n=36) and APAH (n=5) who started bosentan treatment from May 21 to April 23 in 2 Pediatric Pulmonary Hypertension centers Data collection ended August 26 Ivy DD, et al. Am J Card, 21 9

10 Long-Term Outcomes in Children With Pulmonary Arterial Hypertension Treated With Bosentan in Real-World Clinical Settings: Results Kaplan-Meier estimates of survival related to baseline PVRi <2 vs>2 Wood units Risk factors significantly associated with survival : PVRi WHO Functional Class Ivy DD, et al. Am J Card, 21 Ivy DD, et al. Am J Card, 21 At 4 years, the Kaplan-Meier estimate of disease progression in patients while on bosentan was 54% with a survival estimate of 82% Long-term efficacy of bosentan in the treatment of PAH in children Hislop AA, Moledina S, Foster H, Schulze-Neick, Haworth SG, Eur Resp Journal, % 5 year retrospective experience using bosentan in pediatric PAH (n=11; IPAH (42), APAH-CHD (59) Evaluated WHO FC,6MW, weight, height Treated for at least 6 months and followed for up to 5 years (2/2-5/9) Ivy DD, et al. Am J Card, 21 1

11 Long-term efficacy of bosentan in the treatment of PAH in children At 3 years 21% of IPAH patients remained on monotherapy Initial improvement in WHO FC and 6MW were sustained over 3 years K-M survival (n=11) 1, 2, 3 and 5 years 96%, 89%, 83%, and 6% Hislop AA, et al, Eur Resp Journal, 211 ERA Therapies Bosentan (21) Dual endothelin receptor ET A /ET B blockade Pivotal trials included children > 12yrs old Indicated for twice daily administration to improve exercise capacity and reduce clinical worsening in WHO FC II-IV PAH patients Ambrisentan (28) Selective ET A receptor antagonist Pivotal trials in adults Indicated for once-daily treatment of PAH to improve exercise capacity and delay clinical worsening in patients with WHO FC II or III symptoms Ambrisentan in PAH: 6MWD (ARIES) 6MWD (m) ARIES-1 1 mg ambrisentan 5 mg ambrisentan Time (wk) p-values are vs placebo. Galiè N et al. Circulation. 28;117: p<.1 p<.1 ARIES-2 5 mg ambrisentan 2.5 mg ambrisentan p< Time (wk) p<.1 Ambrisentan in PAH: Time to Clinical Worsening (ARIES) Event-free (%) ARIES-1 5 mg ambrisentan 2 1 mg ambrisentan 5 and 1 mg ambrisentan Time (wk) Galiè N et al. Circulation. 28;117: ARIES mg ambrisentan 5 mg ambrisentan 2.5 and 5 mg ambrisentan p< Time (wk) 11

12 Clinical safety, efficacy, and pharmacokinetics of ambrisentan therapy in children with pulmonary arterial hypertension Shinichi Takatsuki MD, Erika Berman Rosenzweig MD, Warren Zuckerman MD, Daniela Brady RN, Michelle Calderbank RN, and David Dunbar Ivy MD, Pediatric Pulmonary, 212 (in press) Change in WHO Functional Class between Baseline and treatment with Ambrisentan therapy Retrospective study of 38 pediatric pts at two PH Centers who received ambrisentan as initial (6%) or add on therapy for PAH; 4% transitioned from bosentan Evaluated clinical status (hemodynamics, WHO FC, exercise capacity) and for adverse events. Evaluated pharmacokinetics in a subset of patients (n=16) Takatsuki S, et al. Pediatric Pulmonary, 212 (in press) Ambrisentan: Changes in Clinical Variables Clinical variables N* On bosentan Transition On ambrisentan p value N* Add-on before after p value Kaplan-Meier estimates of survival at 1 year and 2, 3, and 4 years 6 minute walking distance (m) / / / / Brain natriuretic peptide (pg/ml) / / / / Tricuspid regurgitant velocity (m/s) Mean right atrial pressure (mmhg) / / / / / / / / Mean pulmonary arterial pressure (mmhg) Pulmonary vascular resistance index (unitxm 2 ) Pulmonary / systemic vascular index ratio / / / / / / / / /-.3.7+/ /-.8.8+/ Cardiac index (l/min/m 2 ) / / / / Alanine aminotransferase (unit/l) Aspartate aminotransferase (unit/l) / / / / / / / / Total bilirubin (mg/dl) 12.7+/-.9.7+/ /-.4.4+/ Takatsuki S, et al. Pediatric Pulmonary, 212 (in press) IPAH/HPAH 1%, 88%, 88%, and 85% PAH-CHD were 96%, 91%, 87%, and 87%, respectively 12

13 Ambrisentan pharmacokinetics in children appear similar to adults although T ½ is slightly shorter (n=16) mean Cmax mean Tmax mean T ½ mean AUC / ng/ml 3.2+/-2.1 hours 7.6+/-2.6 hours / ng hr/ml Endothelin Receptor Antagonists: Side Effects Nasal congestion Abnormal hepatic function reversible transaminase elevations >3X ULN may require dose adjustments or discontinuations monthly LFTs required for bosentan Edema lower extremity edema may require diuretic adjustment Use requires dual contraceptive methods (hormonal plus barrier) Takatsuki S, et al. Pediatric Pulmonary, 212 (in press) Endothelin Receptor Antagonists in Pediatric PAH ERA s have been shown to be efficacious and safe in adults with PAH In children, data is limited but supportive of similar use for children with PAH Close monitoring of response and for AE s and LFT abnormalities is suggested Approved Therapeutic Targets Endothelin receptor A Endothelinreceptor antagonists Endothelin Pathway Pre-proendothelin Endothelin-1 Smooth muscle cells Proendothelin Endothelin receptor B Vasoconstriction and proliferation Endothelial cells Nitric Oxide Pathway L-arginine Phosphodiesterase type 5 Nitric Oxide cgmp L-citrulline Phosphodiesterase type 5 inhibitor Exogenous nitric oxide Vasodilation and antiproliferation Endothelial cells Prostacyclin Pathway Arachidonic acid camp Vasodilation and antiproliferation Prostaglandin I 2 Prostacyclin (prostaglandin I 2 ) Smooth muscle cells Prostacyclin derivatives Humbert M et al. N Engl J Med. 24;351:

14 Effect of Sildenafil on 6MWD (SUPER) Change In 6MWD (m) Galiè N et al. N Engl J Med. 25;353: mg of sildenafil 4 mg of sildenafil 8 mg of sildenafil p< Week Sildenafil: Incidence of Clinical Worsening (SUPER) (n=7) 2 mg tid (n=69) Sildenafil 4 mg tid (n=67) Event Incidence, n (%) 8 mg tid (n=71) Clinical worsening 7 (1) 3 (4) 2 (3) 5 (7) death 1 (1) 1 (1) 2 (3) hospitalization for PAH 7 (1) 2 (3) 2 (3) 2 (3) initiation of prostacyclin 1 (1) initiation of bosentan 1 (1) 2 (3) p=ns. Clinical worsening defined as death, transplantation, hospitalization for PAH, or initiation of additional therapies for PAH. Galiè N et al for the Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med. 25;353: Kaplan-Meier estimates of survival by treatment group in the SUPER-1 study Rubin L J et al. Chest 211;14: Sildenafil Added to Epoprostenol (PACES) Mean 6MWD change from baseline (95% CI), m Baseline Study time (wk) Opposite order than usual practice. Different approach to epo dosing. Most pts on 8 mg TID (not approved). Simonneau G et al. Ann Intern Med. 28;149: Erratum: Ann Intern Med. 29;15:63; 29;151:435. p<.1 No. clinical worsening event (%) p=.2 Epoprostenol + sildenafil Epoprostenol + placebo Baseline Time from randomization (d) Baseline Persons at Risk (Censored), n Day Day Day Day 112 Epo + placebo (1) 116() 111(2) 7(36) Epo + sildenafil () 128(2) 125(2) 78(44) 14

15 Sildenafil in Children with PAH Clinical applications have been based on adult SUPER trials Limited data in pediatrics yet use is widespread In case series, dosing is variable and ranges from.5mg to 2mg/kg po t.i.d/q.i.d. despite lack of pharmacokinetic data Sildenafil Pediatric pharmacokinetic considerations In adults, onset of action 3-12 minutes (delay if taken with fatty foods up to 6 min) Hepatic metabolism (CYP 3A4 and CYP 2C9) Drug interactions CYP3A4 inhibitors (fluconazole, ketoconazole, itraconazole) lead to increase in plasma level CYP3A4 inducers (bosentan) lead to 63% decrease in sildenafil AUC and 5% increase in bosentan AUC Oral solution of sildenafil can be compounded Sildenafil Potential areas of use in Children with PAH To prevent rebound PH during ino weaning In place of NO when unavailable Infants with chronic lung disease Perioperative PAH (e.g. CHD repair) Long-term treatment of IPAH/APAH Including in combination with other targeted agents A Randomized, Double-Blind, -Controlled, Dose- Ranging Study of Oral Sildenafil Citrate in Treatment-Naïve Children with Pulmonary Arterial Hypertension (STARTS 1) Robyn J Barst, D. Dunbar Ivy, Guillermo Gaitan, Andras Szatmari, Andrzej Rudzinski, Alberto E Garcia, BKS Sastry, Tomas Pulido, Gary R Layton, Marjana Serdarevic-Pehar and David L. Wessel, Circulation, 212. The first double blind placebo controlled trial of a targeted PH therapy in children Enrolled 238 treatment naïve children weighing > 8kg Randomized to placebo, low, medium or high dose of sildenafil Data compared from baseline to 16 weeks. Additional data was captured in an extension study STARTS - 2 Barst RJ, et al. Circulation,

16 Sildenafil Dosing in STARTS-1 Sildenafil dose in mg Body wt (kg) Low Medium High > 8 to 2 NA 1 2 >2 to > STARTS studies Primary endpoint was percent change in peak VO2 (combined treatment groups) measured by CPET at 16 weeks All patients were treatment naïve 16 patients >7 yrs old were able to perform exercise test reliably and included in analyses Barst RJ, et al. Circulation, 212 Barst RJ, et al. Circulation, 212 Start 1: -adjusted Percent Change VO 2 Peak Low (n=24) Medium (n=26) High (n=27) Low/Med/High (n=77) p = VO 2 Peak (% change from baseline to Week 16) Comparison to (n=29) with 95% CIs Barst RJ, et al. Circulation, 212 Effects of Sildenafil on PVRI and mpap in Children PVRI Low (n=37) Medium (n=51) High (n=68) L/M/H (n=156) mpap Low (n=39) Medium (n=55) High (n=71) L/M/H (n=165) (Change from baseline to week 16) comparison to placebo (n=52) with 95% CIs (dyne s cm -5 m 2 ) (Change from baseline to week 16) comparison to placebo (n=56) with 95% CIs (mmhg) Barst RJ, et al. Circulation,

17 Sildenafil in Treatment Naïve Pediatric Patients: Results Primary endpoint: Mean % change in peak VO2 was not significant in placebo vs. treatment group (p=.56; all doses) Low dose sildenafil was not effective, but medium and high doses demonstrated improved peak VO2, FC and hemodynamics In STARTS 2 extension if appears that high dose sildenafil was associated with an increase in mortality Sildenafil in Treatment Naïve Pediatric Patients: Conclusions 16 week sildenafil monotherapy was well tolerated in pediatric PAH. Percent change in peak VO2 for the combined sildenafil doses was not significant Improvements in peak VO2, FC and hemodynamics in the medium dose and high doses suggest efficacy Barst RJ, et al. Circulation, 212 Barst RJ, et al. Circulation, 212 Sildenafil in Treatment Naïve Pediatric Patients: Conclusions Effect of Tadalafil on 6MWD (PHIRST) Combined with the STARTS 2 data, the overall profile favors medium dose sildenafil may be most effective with best safety profile Optimal dosing is yet to be determined In Europe, pediatric sildenafil is dosed at 1 mg for patients 1-2kg and 2 mg po tid for patients over 2 kg. Change in 6MWD (m) Tadalafil 2.5 mg Tadalafil 1 mg Tadalafil 2 mg Tadalafil 4 mg p<.1 p<.5 p<.5 Barst RJ, et al. Circulation, Weeks Galiè N et al. Circulation. 29;119;

18 Effect of Tadalafil on Time to Clinical Worsening (PHIRST) Proportion of patients with no clinical worsening Day Week Patients at risk: Tadalafil 2.5 mg Tadalafil 1 mg Tadalafil 2 mg Tadalafil 4 mg Tadalafil 2.5 mg Tadalafil 1 mg Tadalafil 2 mg Tadalafil 4 mg Galiè N et al. Circulation. 29;119; p=.41 PDE-5 Side Effects Nose bleed Headache Dyspepsia Flushing Diarrhea Visual changes Contraindicated with use of nitrates What Is the Optimal Treatment Strategy? Anticoagulate ± Diuretics ± Oxygen ± Digoxin Positive Acute Vasoreactivity Testing ACCF/AHA Consensus PAH Treatment Algorithm Anticoagulate ± Diuretics ± Oxygen ± Digoxin Acute Vasoreactivity Testing Oral CCB Sustained Response Yes Continue CCB Negative No LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes Gradual Progression of symptoms Rapid II, III WHO class IV Longer (>4 m) 6MWD Shorter (<3 m) Peak VO 2 >1.4 ml/kg/min CPET Peak VO 2 <1.4 ml/kg/min Minimal RV dysfunction RAP <1 mm Hg; CI >2.5 L/min/m 2 Echocardiography Hemodynamics Pericardial effusion, significant RV enlargement/dysfunction; RA enlargement RAP >2 mm Hg; CI <2. L/min/m 2 Minimally elevated BNP Significantly elevated Oral CCB Sustained Response Yes Continue CCB No Positive Lower Risk ERAs or PDE-5 Is (oral) Epoprostenol or Treprostinil (IV) Iloprost (inhaled) Treprostinil (SC, inhaled) Reassess: consider combo-therapy Investigational Protocols Negative Higher Risk Epoprostenol or Treprostinil (IV) Iloprost (inhaled) ERAs or PDE-5 Is (oral) Treprostinil (SC) Atrial septostomy Lung transplant McLaughlin VV et al. J Am Coll Cardiol. 29;53: Modified from McLaughlin VV et al. J Am Coll Cardiol. 29;53:

19 Initial Therapy: Making the Right Decision Determine the severity of disease Patient preference/ability Try to weigh the data When comparing trials, examine objective baseline characteristics (6MWD, hemodynamics) Low threshold for escalation given the natural history in children Ongoing or Recently Completed Adult Clinical Trials: Novel Oral Therapies FREEDOM-C SERAPHIN Current therapy Added therapy Patients (n) Study duration Primary end point Bosentan and/ or sildenafil Naïve/PDE- 5/PGI/combo Treprostinil oral 3 16 weeks 6MWD Macitentan 742 Event-driven Morbidity/mortality event PATENT Naïve/PGI/ERA Riociguat weeks 6MWD IMPRES 2 current therapies Imatinib 2 24 weeks 6MWD Gilead Stable PAH therapy Cicletanine weeks 6MWD GRIPHON ERA, PDE5 or both Selexipag 67 Event-driven Morbidity/mortality event Novartis Stable PAH therapy Nilotinib 66 6 months PVR Pediatric Oral PAH Therapies: Summary Patients with PAH now have several oral treatment options CCB (only when indicated) ERAs PDE-5 inhibitors Determining when an oral agent is appropriate is still not evidence based and caution and close surveillance is needed New oral treatments are on the horizon and may shape the future of pediatric PAH treatment 19

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