Treatment of Paediatric Pulmonary Hypertension

Treatment of Paediatric Pulmonary Hypertension Dunbar Ivy, MD The Children s Hospital Heart Institute University of Colorado School of Medicine 1

Disclosures I have the following financial relationships with the manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services discussed in this CME activity: The University of Colorado contracts with Actelion, Bayer, Lilly, and United Therapeutics for which I am a consultant UC Contract: Steering Committee Actelion / Bayer / Lilly / United Therapeutics Funding from NIH / FDA I do intend to discuss an unapproved/investigative use of a commercial product/device in my presentation. 2

5 th WSPH: Screening/Diagnostic Algorithm for Suspected Pediatric PH/PAH Yes Normal Echo / CXR / ECG? PH unlikely No Echo indicates left heart etiology of PH? Yes Evaluate for left heart, valvular disease Yes but suspect sleep disordered breathing Polysomnography Selective pulmonary angiography No No PFTs normal other than low DLco? Chest CT normal? Yes V/Q scan normal or low probability? No Evaluate for parenchymal lung disease, connective tissue disease, neuromuscular disease, or chest wall/restrictive disease Adapted from: Ivy DD, et al. J Am Coll Cardiol. 2013;62:D117-D126.

Guidelines for PH Management in BPD Screening for PH by echocardiogram is recommended in infants with established BPD (class I, Level B) Evaluation and treatment of lung disease, including assessments for hypoxemia, aspiration, structural airways disease, and the need for changes in respiratory support, is recommended in infants with BPD and PH before initiation of PAH-targeted therapy (class I, Level B) Evaluation for chronic therapy for PH in infants with BPD should follow recommendations for all children with PH and include cardiac catheterization to diagnose disease severity and potential contributing factors such as LVDD, anatomic shunts, pulmonary vein stenosis, and systemic collaterals (class I, Level B) Supplemental oxygen therapy is reasonable to avoid episodic or sustained hypoxemia and with the goal of maintaining oxygen saturations between 92% and 95% in patients with established BPD and PH (class IIa, Level C) PAH-targeted therapy can be useful for infants with BPD and PH on optimal treatment of underlying respiratory and cardiac disease (class Ila, Level C) Abman SH, Hansmann G, Archer S, Ivy DD, et al. Circulation. 2015;132:2037-2099

WSPH -2013 Consensus Pediatric IPAH/HPAH Treatment Algorithm * Expert Referral General: Consider Diuretics, Oxygen, Anticoagulation, Digoxin Acute Vasoreactivity Testing Oral CCB Positive + > 1 y.o. Lower Risk Negative Higher Risk - Improved - Sustained reactivity Yes Continue CCB No Modified from J Am Coll Cardiol. 2009;53:1573-1619. ERA or PDE-5i (oral) Iloprost (inhaled) Treprostinil (inhaled/oral) Selexipag (oral) Reassess consider early combo-therapy Epoprostenol or Treprostinil (IV/SQ) Consider Early Combination ERA or PDE-5i (oral) Atrial septostomy Lung transplant *Use of all agents is considered off label in children aside from sildenafil / bosentan formulation in EU /bosentan in US

6 Pulmonary Vascular Reactivity Testing Acute response Classic (REVEAL) - Decrease in mpap of at least 20% - with the PVR decreasing 20% - with no change or an increase in cardiac output Acute response -Sitbon - Decrease in mpap of at least 10 mmhg - with the mpap decreasing 40 mmhg - with a normal or high cardiac output

Idiopathic PAH in Children: Survival and Treatment Success with Chronic Oral CCB in Acute Responders Event Free Proportion Years after Diagnosis 7 Yung D, et al. Circulation 2004;110:497-503

8 Responder Status and CCB Survival Douwes, JM, et.al. JACC 2016, Vol.67(11), p.1312-1323

Role of CCBs in PAH Patients with PAH should NOT be treated empirically with CCBs In patients with PAH with right heart failure, CCB therapy may worsen the heart failure Patients who fail to respond to acute vasodilator challenge should NOT be treated with CCBs Acute vasodilator challenge should be performed during right heart catheterization Use inhaled NO or IV epoprostenol for acute challenge

10 Safety, Efficacy and Dosing of the Following Medications is Not Yet Established in Pediatric Patients

Established vasomotor pathways targeted by current and emerging therapies in PAH ETB NO Humbert M et al. Circulation. 2014;130:2189-2208

PAH-specific Treatment Options for Adults Failing Acute Vasoreactivity Testing Oral Therapy Inhaled Therapy Continuous Parenteral Therapy ERAs PDE5 Inhibitors sgc Stimulator Prostacyclin Prostacyclins Ambrisentan Sildenafil Riociguat Treprostinil Iloprost Epoprostenol (Flolan ) Bosentan Tadalafil Treprostinil RTS epoprostenol (Veletri ) Macitentan Treprostinil (SC or IV) Note: Only bosentan is FDA approved for use in pediatric patients over 3 years of age.

WSPH 2013 - Consensus Pediatric IPAH/HPAH Treatment Algorithm Higher risk vs. Lower Risk Factors LOWER RISK DETERMINANTS OF RISK HIGHER RISK No Clinical evidence of RV failure Yes No Progression of Symptoms Yes No Syncope Yes Growth Failure to thrive I,II WHO Functional Class III,IV Minimally elevated SBNP / NTproBNP Significantly elevated Rising level Echocardiography Severe RV enlargement/dysfunction Pericardial Effusion Systemic CI > 3.0 L/min/m 2 mpap/msap < 0.75 Acute Vasoreactivity Hemodynamics Systemic CI < 2.5 L/min/m 2 mpap/msap > 0.75 RAP > 10mmHg PVRI > 20 WU*m 2 Ivy, et al. J Am Coll Cardiol. 2013;62:D117-26

Endothelin Receptor Antagonists Generic Name Bosentan Ambrisentan Macitentan Selectivity ET A /ET B ET A ET A /ET B Trade Name Tracleer Letairis Opsummit Manufacturer Actelion Gilead Actelion Approval 2001 Sep 2017 Class III, IV II, III Indications (Package Insert) PAH WHO Group I 2007 2013 PAH WHO Group I PAH WHO Group I Route Oral Oral Oral 15

FDA Approval of Bosentan in pediatric patients aged 3 years and older with idiopathic or congenital PAH to improve pulmonary vascular resistance (PVR), which is expected to result in an improvement in exercise ability

BREATHE 3 : Study Design Screening Day 1 Hemodynamics Single-dose PK Week 12 Hemodynamics Multiple-dose PK Extended Open label Weight Group* Single dose PK Dose Target dose (4 weeks) x > 40 kg 125 mg 62.5 mg bid 125 mg bid 20 < x < 40 kg 62.5 mg 31.25 mg bid 62.5 mg bid 10 < x < 20 kg 31.25 mg 31.25 mg qd 31.25 mg bid Barst, et al. Clin Pharm Ther 2003 * + Flolan

BREATHE-3: Baseline Hemodynamics N=19 Patients 10-20 kg Patients 20-40 kg Patients >40 kg All PAPm (mm Hg) 58 57 65 60 PVRI (Dyn.sec. m 2.cm -5 ) 1150 1150 1320 1210 Cardiac Index (L/min/m 2 ) 4.3 3.5 4.2 4.0 PCWPm (mm Hg) 9 7 9 8 RAPm (mm Hg) 7 6 6 6 mpap: mean pulmonary arterial pressure; PVRI: pulmonary vascular resistance index; mpcwp: mean pulmonary capillary wedge pressure; mrap: mean right atrial pressure Barst, et al. Clin Pharm Ther 2003

Table 3. Bosentan: Safety Beghetti, et al. Ped Res 2008:64:200-204 4

Pulmonary arterial hypertension in children Protocol AC-052-365 FUTURE 1 An open label, multicentre study to assess the pharmacokinetics, tolerability, and safety of a paediatric formulation of bosentan in children with idiopathic or familial pulmonary arterial hypertension

MACITENTAN VERSUS STANDARD OF CARE IN DELAYING DISEASE PROGRESSION IN CHILDREN WITH PULMONARY ARTERIAL HYPERTENSION: THE TOMORROW STUDY DESIGN

Clinical trials identifier: NCT02932410 TOMORROW study First randomized controlled pivotal study in children statistically powered to assess time to disease progression Primary objective Evaluate the efficacy of macitentan compared with standard of care in delaying disease progression in children with PAH Secondary objectives Assess safety and tolerability of macitentan in children with PAH Assess pharmacokinetics of macitentan in children with PAH

Clinical trials identifier: NCT02932410 Study design Event-driven, open-label study Randomization stratified for ERA & WHO FC Study schedule Screening 6 weeks PK visit Visits every 12 weeks EOS Follow-up 6 weeks Treatment arms Randomization (1:1) Macitentan (monotherapy or add-on to PDE-5i) SoC ( 2 PAH-specific treatments) 187 events: Study closure EOS, end of study; ERA, endothelin receptor antagonist; SoC, standard of care; WHO FC, World Health Organization functional class

Clinical trials identifier: NCT02932410 Disease progression: Composite endpoint Primary endpoint: Time to 1 st disease progression event up to EOS OR OR OR OR Death (all causes) Atrial septostomy or Pott's anastomosis Registration on lung transplant list Hospitalization due to PAH Clinical worsening of PAH Need for/initiation of new PAH-specific therapy or IV diuretics or continuous oxygen use AND Clinical worsening of PAH Characterized as: OR OR OR Worsening in WHO functional class Syncope (new/worsened) 2 PAH symptoms (new/worsened) Signs of RHF not responding to oral diuretics All events adjudicated by a blinded clinical events committee Shortness of breath/dyspnea, chest pain, cyanosis, dizziness/near syncope, or fatigue EOS, end of study

25 ETRA Interactions Contraindications: - Liver disease - Pregnancy - Cyclosporine - Risk of male infertility? Bosentan may decrease plasma sildenafil level by 60% Ambrisentan / Macitentan no effect on sildenafil or warfarin

Generic Name PDE5 Inhibitors Sildenafil Tadalafil Trade Name Revatio Cialis Manufacturer Pfizer Lilly Approval 2005 2009 Class Indications (Package Insert) II,III, IV PAH WHO Group I PAH WHO Group I Route oral oral 26

STARTS-1 and -2 A randomized, double-blind, placebo controlled, dose ranging, parallel group study of oral sildenafil in the treatment of children, aged 1-17 years, with pulmonary arterial hypertension (PAH) Barst R, Ivy DD, et al. Circulation 2012;125:324-334

STARTS-1: Placebo-adjusted Percent Change VO 2 Peak Low (n=24) Medium (n=26) High (n=27) 3.81 7.98 11.33 7.71 Low/Med/High (n=77) p = 0.056-10 -5 0 5 10 15 20 25 VO 2 Peak (% change from baseline to Week 16) Comparison to Placebo (n=29) with 95% CIs Barst R, Ivy DD, et al. Circulation 2012;125:324-334

Kaplan-Meier Estimated Survival From Start of Sildenafil Treatment in STARTS-1 and -2 94% 93% 88% Hazard ratios for mortality were 3.95 (95% CI, 1.46 10.65) H vs L Barst RJ, et al. Circulation 2014;129:1914-1923

Baseline Characteristics and Mortality 77% (30/39) of deaths were in IPAH children 77% (30/39) of the subjects who died had baseline PVRI to the median (15 Wood units x m2) 67% (26/39) had mpap to the median (62 mmhg) 72% (28/39) had RAP to the median (7.0 mmhg) Barst RJ, et al. Circulation 2014;129:1914-1923

spap (mm Hg) spap/ssbp Sildenafil in Chronic Lung Disease of Infancy 120 Change in Systolic Pulmonary Artery Pressures in Response to Sildenafil p <0.001 p <0.001; T-test (n = 13) 1.4 Change in Systolic Pulmonary/Systemic Artery Pressure in Response to Sildenafil p <0.001; T-test (n = 13) 100 1.2 80 60 40 20 1 0.8 0.6 0.4 0.2 0 Baseline After Sildenafil 0 Baseline After Sildenafil Median interval between studies: 58 days (25-334) Median interval between studies: 58 days (25-334) Mourani, Sontag, Ivy, Abman. J Peds 2009;154:379-384 31

Oxyhemoglobin saturation (%) Mean PA pressure (mmhg) Sildenafil in Failing Fontan Physiology 100 20.0 90 p=0.017 17.5 p=0.018 15.0 80 12.5 70 Pre Post 10.0 Pre Post Morchi, Ivy, Duster, et al. Congenit Heart Dis 2009;4:107-111 32

33 Tadalafil in Pediatric PH 1. Protocol H6D-MC-LVHV A Double-Blind Efficacy and Safety Study of the Phosphodiesterase Type 5 Inhibitor Tadalafil in Pediatric Patients with Pulmonary Arterial Hypertension

Prostanoids Generic Name Epoprostenol Treprostinil Iloprost Trade Name Flolan Remodulin Ventavis Manufacturer GlaxoSmithKline United Therapeutics Actelion Approval 1996 2002(SQ) 2004 (IV) INH 2009 2013 (Oral) 2004 Class III, IV II, III, IV III, IV Indications (Package Insert) PPH, SPH due to scleroderma PAH PAH WHO Group I Route Continuous IV Cont. SQ or IV Inhaled 34

Event Free Proportion Idiopathic PAH in Children: Survival and Treatment Success with Chronic IV Epoprostenol Years after Epoprostenol Initiation 35 Yung D, et al. Circulation 2004;110:497-503

IV Treprostinil Administration Requires higher dose Longer half life: 3-4 hours Stable at room temp for 48 hrs for IV and 72 hrs for SQ No Ice Packs Every other day mixing

Oral Treprostinil Laser Drilled Hole Semi-permeable Membrane

Clinical Trial: Oral Treprostinil Multi-center, open-label, safety, tolerability and pharmacokinetic study of oral treprostinil in pediatric subjects with stable PAH aged 7 to 17 years who are, (1) transitioning from parenteral Remodulin therapy; (2) transitioning from inhaled prostacyclin therapy; or (3) not currently receiving prostacyclin therapy Primary Outcome Measures: Successful transition from parenteral Remodulin to oral treprostinil Cohort 1: A successful transition is defined as a subject who is receiving oral treprostinil and no longer receiving Remodulin at Week 4 and clinically maintained on oral treprostinil treatment through Week 24 Cohort 2 and 3: A successful initiation of oral treprostinil will be defined as a subject who has been clinically maintained on oral treprostinil through Week 24 Frequency of adverse events ClinicalTrials.gov Identifier: NCT02276872

Oral Selexipag: Non-Prostanoid IP Receptor Agonist

Patent Child

Riociguat: PATENT Child 42

Event-Free (%) Ambition: Time to First Clinical Failure Event Primary Analysis Set 100 75 1 year 88.9% 2 year 79.7% 3 year 67.6% 50 1 year 75.5% 2 year 63.2% 3 year 56.1% Number at risk: 25 0 Combination therapy Pooled monotherapy Time (weeks) HR: 0.502 95% CI (0.348, 0.724) p=0.0002 0 24 48 72 96 120 144 168 192 Combination: 253 229 186 145 106 71 36 4 Pooled monotherapy: 247 209 155 108 77 49 25 5 N Engl J Med 2015;373:834-44 44

AMBITION: Initial Combination Therapy With Ambrisentan-Tadalafil Adverse Events Common Adverse Events (>=10%) Occurring with Higher Frequency in Combination Group (>=5% difference) by Etiology of PAH: Primary Analysis Set IPAH/HPAH APAH AE Term n, (%) Combination Therapy (n=134) Ambrisentan Monotherapy (n=75) Tadalafil Monotherapy (n=70) Any event 130 (97%) 71 (95%) 65 (93%) Edema peripheral 64 (48%) 23 (31%) 19 (27%) Headache 60 (45%) 24 (32%) 22 (31%) Nasal congestion 28 (21%) 12 (16%) 8 (11%) Dizziness 28 (21%) 10 (13%) 6 (9%) Nausea 23 (17%) 9 (12%) 8 (11%) AE Term n, (%) Combination Therapy (n=119) Ambrisentan Monotherapy (n=51) Tadalafil Monotherapy (n=51) Any event 117 (98%) 49 (96%) 49 (96%) Edema peripheral 51 (43%) 18 (35%) 15 (29%) Nasal congestion 26 (22%) 7 (14%) 7 (14%) Anemia 20 (17%) 2 (4%) 6 (12%) Bronchitis 15 (13%) 1 (2%) 2 (4%) Non-cardiac chest pain 13 (11%) 1 (2%) 3 (6%) Only adverse events with onset between first dose of study drug and last dose±30 days are tabulated 45

Drug Interactions 46