IV PGI2 vs. Inhaled PGI2 in chronic lung disease

Inhaled Therapies for PAH Erika Berman Rosenzweig, MD Associate Professor of Clinical Pediatrics (in Medicine) Director, Pulmonary Hypertension Center Columbia University Medical Center Disclosures Has received grant/research support from Actelion Pharmaceuticals US, Inc., Bayer AG, Eli Lilly, Gilead Sciences, Inc., Novartis AG, Pfizer and United Therapeutics Corporation Has served as a consultant for Actelion, GIlead and United Therapeutics. Why the inhalation route for PH? Directly penetrates to target Vasodilates well ventilated areas avoiding V/Q mismatch Minimize systemic side effects (e.g. systemic hypotension) Avoid intravenous/sq route complications Potential for use in critical care settings IV PGI2 vs. Inhaled PGI2 in chronic lung disease Why the inhalation route for PH? Directly penetrates to target Vasodilates well ventilated areas avoiding V/Q mismatch Minimize systemic side effects (e.g. systemic hypotension) Avoid intravenous/sq route complications Potential for use in critical care settings Pediatric PAH in the critical care setting: Potential Target Populations for Inhaled Therapy Neonatal PAH PPHN CDH (congenital diaphragmatic hernia) BPD Pediatric PAH CHD perioperative Pre cardiac transplant with elevated PVR Acute PAH crisis 1

Inhaled Agents for Pediatric PAH Oxygen Inhaled nitric oxide (FDA approved) Inhaled iloprost (limited pediatric data) Inhaled treprostinil (no published pediatric data) Inhaled Nitric Oxide (NO) FDA approved in 1999 for use in near-term neonates with hypoxic respiratory failure Used frequently off label for many other forms of acute pulmonary hypertension Acute de-compensation in IPAH/APAH Perioperative use Acute vasodilator testing during catheterization At present not practical for long-term use in outpatient setting Not all patients respond to NO NINOS: Neonatal Inhaled Nitric Oxide Study Group (1997) Multicenter RCT to determine whether ino would reduce mortality or need for ECMO in infants with hypoxic respiratory failure ino was found to be a safe treatment which improved oxygenation and decreased the need for ECMO support. ino did not change the mortality rate 3% of infants had no significant response to ino at 2 ppm The Neonatal Inhaled NO Study Group, NEJM 1997 Response to ino: NINOS Response to ino Columbia NICU 22-27 Diagnosis Patients (N=37) Percent of Total Median Treatment Time (Days) (Range) Average Treatment Time (Days) (SD) Percent Treatment Failures Non- Responders PPHN 145 39% 4 (.2-84) 6.1 (+/- 9.5) 32% CDH 57 15% 7 (.4-12) 12.2 (+/- 19.2) 6% Cardiac 119 32% 5 (.2-29) 5.5 (+/- 4.4) N/A NINOS, NEJM 1997 Subgroup of CDH patients (n=53); no difference in survival and increased need for ECMO Prematurity 49 14% 4 (1-12) 17.7 (+/- 26.4) N/A Rosenzweig, EB, Unpublished data 2

Rationale for Study of other PAH agents in Critical Care Setting Oxygen and Nitric Oxide don t always work What about Treatment of Long-Term PAH in Children? Alternative Inhaled Agents Treatment Rationale ino not readily available for chronic use at present until delivery modes are more portable Inhaled are less invasive than IV/SQ prostanoids Avoid SQ/IV complications Which patients to consider? Suboptimal response to oral therapy (FC III) Previous complications with SQ/IV prostanoids Inhaled Agents for Pediatric PAH Oxygen Inhaled nitric oxide Inhaled iloprost (limited pediatric data) Inhaled treprostinil Inhaled : Background FDA approved for adults with FC Class III and IV group 1 PAH in 24; 25 added indication as addon for symptomatic patients despite oral therapy Longer-acting prostacyclin analogue (2- to 3-min half-life) Still requires frequent inhalations (6 to 9x/d) 2.5-5. ucg/inh 6-9 times per day Aerosolized delivery system Optimal delivery: 2.5-5um droplet size Time course of the effects of aerosolized iloprost on pulmonary vascular resistance (PVR) 4 devices EMEA app, 2 FDA app Hoeper, M. M. et al. JACC 2;35:176-182 in Pediatrics: Background Inhaled has been used worldwide in many adults with Group I PAH Outpatient data for pediatric patients are limited due to: Lack of pediatric data Difficulty in administering the medication in children < 7 years old via i-neb Frequency of inhalations; impact on quality of life Critical care setting data in children are also limited to case reports 3

AIR Study: Design AIR Study: Primary Endpoint AIR: Study Dosing Objective: Randomized, double-blind, placebocontrolled study (37 European centers in 11 countries) to assess efficacy of iloprost Duration: 12 weeks vs. Placebo monotherapy Patients: 23 patients with NYHA Class III or IV IPAH (5%) Chronic thromboembolic PH (28%) Associated with CTD (17%) Anorexigen use (4.5%) Olschewski H. N Engl J Med. 22;347:322-329 >1% Increase in 6 Minute Walk Combined Endpoint of Clinical Improvement Improvement in NYHA Functional Class (> 1 Class) Distance + + No Clinical Deterioration or Death Olschewski H. et al.,n Engl J Med. 22. 2.5 or 5 mcg per treatment dose 6 to 9 doses/day while awake 9% of patients did not use during sleeping hours Median inhaled dose, 3 mcg/day Mean inhalations/day = 7.3 Olschewski H. N Engl J Med. 22. Percent responders 1 96 (n=68) 87 Placebo (n=78) 8 6 4 2 AIR: Patient Improvement Approximately 5:1 Improvement vs. Placebo (Composite Primary Endpoint) No death or deterioration 43 26 6MWD 1% increase 3 min after inhalation 25 8 NYHA Class improvement p=.33 19 4 Composite clinical endpoint Olschewski H. N Engl J Med. 22. 28 Actelion Pharmaceuticals US, Inc. All rights reserved. Inhaled : Change From Baseline in 6MWD (AIR Trial) Mean change from baseline (m) 4 3 2 1-1 -2-3 -4 Placebo (n=12) (n=11) Week 4 Placebo corrected change at 12 weeks: 36 meters Walks performed at dose peak Week 8 Week 12 p=.4 n=23 Olschewski H et al., N Engl J Med. 22 Change from baseline (%) 2 15 1 5-5 -1-15 -2-25 -3 AIR: Improved Hemodynamic Parameters Post Inhalation -23% PVR Cardiac Output P<.1 for the difference from baseline values. P<.5 for the difference from baseline values. +9% 15% -5% Placebo -9%.4% mpap Olschewski H. et al, 28 N Engl Actelion J Pharmaceuticals Med. 22;347:322-329. US, Inc. All rights reserved. 4

AIR-Trial () Summary Improvement in composite end point of clinical improvement (p<.1) Improvement in post inhalational walking distance (36 m, p=.4) Improvement in NYHA FC class (p<.5) Improvement in post inhalational hemodynamics (PVR, CO, PAPm) Improvement in quality of life (p<.5) Olschewski, et al. NEJM, 22 : Side Effects Vasodilation (flushing) Increased cough Headache Jaw pain Insomnia Nausea, vomiting Syncope STEP Study Design: added to Bosentan Objective Primary: Evaluate safety of adding iloprost to an endothelin receptor antagonist (ERA) Secondary: Efficacy endpoints (Clinical worsening, Functional class, Hemodynamics, 6MWT) Duration: or placebo added for 12 weeks to stable monotherapy with an ERA (mean ERA duration 18 months) Patients: 67 patients with PAH 55% IPAH; 45% Associated PAH 94% NYHA class III McLaughlin VV et al. Am J Respir Crit Care Med. 26 STEP Study Design: Prospective, randomized, double-bind, placebo-controlled, parallel-group ERA 125mg BID At least 16 weeks 2.5 mcg Placebo Baseline randomization 5mcg Placebo 1 Dose 12 weeks (n=34) (n=33) 3 months McLaughlin VV et al. Am J Respir Crit Care Med. 26. STEP: Primary Endpoint (Safety) Patients treated with an ERA tolerated the addition of inhaled iloprost Up to 5 mcg 6 to 9 times per day during waking hours Dosing Mean daily inhaled dose was 27 mcg Mean number of inhalations per day was 5.6 Safety trends were consistent with those observed in the larger AIR trial McLaughlin VV et al. Am J Respir Crit Care Med. 26 Inhaled Added to Bosentan (STEP) (n=67) 7 6 5 4 3 2 1 Mean 6MWD Change from Baseline (m) Bosentan + (n=32) p=.51 Bosentan + Placebo (n=33) 1..75.5.25 *log-rank test. McLaughlin VV et al. Am J Respir Crit Care Med. 26;174:1257-1263. Proportion Free of Clinical Worsening Placebo p=.2*. 28 56 84 Time (d) 5

Pediatric : Questions Are these data applicable to children? Is there a role for iloprost in the critical care setting? Is there a role for long-term iloprost in children? Safe? Effective? How would children manage the handheld device for long-term use? Delivery and dosing? Compliance? Pediatric PAH in the critical care setting: Target Populations/Early Experience Neonatal PAH PPHN CDH (congenital diaphragmatic hernia) BPD Pediatric PAH CHD perioperative Pre cardiac transplant with elevated PVR Acute PAH crisis in Neonatal PAH: Rationale Bronchopulmonary Dysplasia (BPD) widespread and Mortality rate in BPD patients with significant pulmonary hypertension is 5% and higher in some studies Chronic lung disease may cause significant VQ mismatch Other forms of neonatal PAH (e.g. PPHN, CDH) have significant failure rate with inhaled NO Delivery: Critical Care Setting PPHN: experience Neonatal case reports (n=4) Ehlen M, et al. treated 1 neonate with severe PPHN unresponsive to ino with iloprost Decreased RVSP by echo and improved oxygenation Conchiero GA, et al. described successful use of iloprost in 1 pt with PPHN De Luca D et al, described 2 cases of neonatal iloprost use (1- CDH, 1 PPHN) CDH pt improved PAP, but died of pneumothorax PPHN pt had significant improvement of PAP and was weaned from ventilator, but died of neurologic compromise Ehlen M, et al.,cardiol. Young, 23 Conchiero GA, et al., Ann Pediatr, 25 DeLuca D, et al., Paed Anesth, 27 Inhaled in Pediatric Patients (non-neonatal): CHD (n=28) Muller M et al, describe the use of iloprost during congenital heart surgery (ASD/VSD closure) following CPB (n=1) Rimensberger P, et al, compared ino and iloprost in children with CHD (n=15) Hallioglu O, et al, compare the acute hemodynamic effects of aerosolized and IV iloprost in PAH associated with CHD (n=12) Muller M et al., Anesthesiology, 23 Rimensberger P, et al., Circulation, 21 Hallioglu O, et al., Am J Cardiol, 23 6

Individual responses from all patients in Rp/Rs to ino and aerosolized iloprost (with exception of patient 1) vs. NO in peri-operative CHD Pediatric - CHD and Selectivity: Case report N=15 Rimensberger, P. C. et al. Circulation 21 Changes in Rp/Rs (*, solid line) and intracardiac shunt (Qp/Qs; {triangle up}, dotted line) in patient 1, showing inversion of shunt with ino and under iloprost aerosolization Rimensberger, P. C. et al. Circulation 21 Comparison of aerosolized and IV infusion of iloprost in 12 children (6 mos-16yrs) with PH secondary to CHD Cardiac Catheterization Baseline Hemodynamics administration: (25ng/kg/min x 1 minutes) IV administration > return to baseline> aerosolized administration Hallioglu O, et al., Am J Cardiol, 23 Pediatric : CHD and Selectivity (n=12) Case report (cont d) Inhaled iloprost Decrease in PAPm from 59+14 to 45+15 mmhg (p<.5) Rp/Rs decreased from.62+.47 to.2+.14 (p<.1) Increased the left to right shunt (p<.5) Intravenous iloprost Decrease in PAPm from 59+14 to 4+19 mmhg However, no significant decrease in Rp/Rs ratio due to substantial fall in msap (71+12 vs. 49+13 mmhg) Did not have significant increase left to right shunt Hallioglu O, et al., Am J Cardiol, 23 : Pre- Cardiac transplant Pediatrics 17 year old patient with elevated PVR Received a combination of IV epoprostenol, dobutamine and aerosolized iloprost for 21 days while awaiting transplant Aggressive pre-treatment permitted heart vs. heart-lung transplant Underwent successful heart transplant Wittwer T, Ann Thorac Surg, 21 Short- and Long-Term Effects of Inhaled Therapy in Children With Pulmonary Arterial Hypertension Reported on the long-term experience in 22 pediatric patients Safety Dosing WHO FC, 6MW, Hemodynamics, vital stats Ivy, et al. JACC 28;51:161-169 7

Study Population (n=22: patients receiving iloprost) Patients Gender - female 1 (45%) Age (years) 11.5 (4.5-17.7) Weight (kg) 35.6 (15-73) Diagnosis IPAH 11 (5%) FPAH 1 (5%) PAH-CHD 1 (45%) Repaired (9) Unrepaired (2) Residual defect () Ivy, et al. JACC 28;51:161-169169 Study Population: PH Medications at time of iloprost initiation (19/22) IV Prostanoid 9 Epoprostenol 3 Treprostinil 6 Sildenafil 16 Bosentan 11 CCB 3 Addition of PAH therapies after iloprost initiation: 7/22 Median time 2.4 months Ivy, et al. JACC 28;51:161-169 Dosing Six to nine inhalation treatments per day Minimum of 6 treatments per day (not PRN) Can be given prior to activity Dose tolerance challenge 2.5 mcg dose given If tolerated, 5. mcg dose given at next treatment Ivy, et al. JACC 28;51:161-169 Hemodynamics Effects of Acute in Pediatric PAH Following Chronic Therapy Hemodynamics Did Not Change : WHO Functional Class Baseline n=8 ino n=8 n=8 PAPm (mmhg) 66 ± 13 58 ± 18* 57 ± 19* PVRI (units m2) 21 ± 14 18 ± 17* 17 ± 15* Cardiac Index (L/min/m2) 2.9 ± 1.3 2.8 ± 1.3 3.1 ± 1.4 PCWPm (mmhg) 8 ± 2 8 ± 2 8 ± 3 RAPm (mmhg) 6 ± 4 6 ± 3 6 ± 3 Mean ± SD *P<.5 vs BL Reactive to ino and : 2/1 Ivy, et al. JACC 28;51:161-169 Baseline Before Chronic n=12 Baseline After Chronic n=12 PAPm (mmhg) 64 ± 18 64 ± 13 PVRI (units m2) 22 ± 15 19 ± 7 Cardiac Index (L/min/m2) 3.4 ± 1.3 3.6 ± 1.4 PCWPm (mmhg) 9 ± 3 7 ± 2 RAPm (mmhg) 8 ± 3 6 ± 2 Mean ± SD Mean F/U: 1 ± 6 months 3/9 Off IV Prostanoid Ivy, et al. JACC 28;51:161-169 Patient Number 25 2 15 1 5 Baseline n = 21/23 at 6months on therapy Improved 7 / Worsened 3 p =.5 6 Months WHO 4 WHO 3 WHO 2 Ivy, et al. JACC 28;51:161-169 8

Pediatric : 6MW test change Six MinuteWalk Distance (m) 9 8 7 6 5 4 3 2 1 414 ± 172 Baseline 6 Months 438 ± 17 Ivy, et al. JACC 28;51:161-169 Acute : FEF 25-75 (Forced Expiratory Flow) FEF 25-75 (% Predicted) 14 12 1 8 6 4 2 5 of 14 showed a decrease in the FEF 25-75 of more than 15 % (range 17-53 %) p-value =.38 8 ± 25 71 ± 28* Pre Post Ivy, et al. JACC 28;51:161-169 Future Direction of Inhaled in Pediatric PAH: Goals Identify appropriate target populations Protocol design to determine proper delivery and dosing, and to assess safety and efficacy Apply to long-term treatment of pediatric PAH patients Inhaled Agents for Pediatric PAH Oxygen Inhaled nitric oxide Inhaled iloprost Inhaled treprostinil Inhaled Treprostinil:?Pediatric PAH Inhaled Treprostinil FDA approved in 29 to increase walk distance in PH Group 1 patients with NYHA FC III symptoms Treprostinil is a longer acting prostanoid available in IV and SQ formulations requiring QID dosing No published data in children (ATS 211: abstract) OptiNeb : Ultrasonic Nebulizer Battery-operated (rechargeable) Single-breath technology Each treatment completed in about 1 minute May be easier for children to administer 9

Hemodynamics of Inhaled Treprostinil vs. Inhaled (n=44) Data from 44 patients who inhaled both drugs in randomized order, shown as percent of baseline values (mean ± 95% confidence interval). Voswinckel, R. et al. J Am Coll Cardiol 26 TRIUMPH-I: Study Design Randomize N=235 Key inclusion criteria NYHA class III or IV 6MWD of 2 to 45 m Bosentan or sildenafil for 3 months Therapy period Inhaled treprostinil (n=115) Inhaled treprostinil and placebo were initiated at 3 breaths q.i.d. and up-titrated up to 9 breaths (54 µg) q.i.d. as tolerated Placebo (n=12) 6 12 Weeks McLaughlin VV et al. J Am Coll Cardiol. 21 TRIUMPH-I Study: Inhaled Treprostinil Dosing Administered via treprostinil Inhalation System Inhaled treprostinil initiated at 3 breaths (18 µg) q.i.d. Dose titration up to a target of 9 breaths (54 µg) q.i.d. Mean time to achieve target breaths was 3 weeks TRIUMPH-I study q.i.d., 4 times daily. Number of breaths per treatment session Starting dose Target dose 1 2 3 4 5 6 7 8 9 McLaughlin VV et al. J Am Coll Cardiol. 21 TRIUMPH-I: Baseline Demographics and Characteristics Characteristic Placebo (n=12) Inhaled treprostinil (n=115) Age, mean (range), y 52 (18-75) 55 (2-75) Female, n (%) 98 (82) 93 (81) PAH etiology, n (%) Idiopathic PAH CVD Other 67 (56) 37 (31) 16 (13) 64 (56) 4 (35) 11 (1) NYHA class III:IV, n 118:2 112:3 Oral PAH therapy, n (%) Bosentan Sildenafil Exposure to oral therapy, mean ± SD, weeks Bosentan Sildenafil 88 (73) 32 (27) 9 ± 75 77 ± 69 77 (67) 38 (33) 98 ± 79 65 ± 6 6MWD, mean ± SD, m 351 ± 69 346 ± 63 CVD, collagen vascular disease; 6MWD, 6-minute walk distance; NYHA, New York Heart Association; PAH, pulmonary arterial hypertension; SD, standard deviation. McLaughlin VV et al. J Am Coll Cardiol. 21 Inhaled Treprostinil: Median Change in 6MWD (TRIUMPH) 6MWD median change from baseline (m) 25 2 15 1 5 p=ns 6 p=.1 19 Day 1 Week 6 peak Hodges-Lehmann estimate of treatment effect. Peak: between 1-6 min after dose. Trough: 4 hr after dose. p=.4 2 Week 12 peak p<.7 14 Week 12 trough McLaughlin VV et al. J Am Coll Cardiol. 21 TRIUMPH-I Study Clinical Summary Inhaled treprostinil for 12 weeks added to oral monotherapy for PAH improved 6MWD 82% of patients remaining in the study assessed at 1 year remained clinically stable on inhaled treprostinil without the need for additional PAH therapy Inhaled treprostinil adverse event profile Most common AEs (inhaled treprostinil vs placebo) Cough (54% vs 29%) Headache (41% vs 23%) Cough and throat irritation were considered related to inhalation route of delivery. McLaughlin VV et al. J Am Coll Cardiol. 21 1

Inhaled Treprostinil: Future Potential in Pediatric PAH? Requires clinical safety and efficacy data in children Requires dosing data in children Device potentially more user friendly for children Longer acting with less doses per day; potential impact for school age child Case series: Abstract at ATS 211 (n=18) highlights the Columbia and Colorado Pediatric PH Centers early experience Another role of the Inhaled Therapies in Children: Possible transitions off IV/SQ prostanoids 9/22 patients were transitioned off of a parenteral prostanoid to iloprost. (Ivy DD et al., JACC, 28) 13 children were successfully transitioned from IV prostanoid therapy to inhaled/oral PH therapy. 1/13 was transitioned to iloprost/bosentan combination. (Melnick L. et al, AJC, 21) Dana Point 29 PAH Evidence-based Treatment Algorithm Oral anticoagulants (E/B) IPAH/HPAH Supportive therapy and general measures Avoid excessive physical exertion (E/A) Diuretics (E/A) Birth control (E/A) Oxygen* (E/A) Psychological and social support (E/C) Digoxin (E/C) Expert referral (E/A) Infection prevention (E/A) Supervised rehabilitation (E/B) Acute vasoreactivity test (A for IPAH) (E/C for APAH) ACUTE RESPONDER NON-RESPONDER WHO Class I-IV Strength of Recommendation WHO Class II WHO Class III WHO Class IV Amlodipine, diltiazem, nifedipine (B) Ambrisentan, Bosentan, Ambrisentan, Bosentan, Epoprostenol IV A Sildenafil Epoprostenol IV, inh, Sildenafil Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, inh B Sustained response Treprostinil SC (WHO I-II) C Beraprost Treprostinil SC IV, Treprostinil IV IV, Treprostinil IV E/B Initial combination therapy (see below) Ambrisentan, Bosentan, YES NO E/C Sildenafil, Sitaxsentan, Tadalafil Not approved Treprostinil inh+ Treprostinil inh+ Amlodipine, diltiazem, INADEQUATE CLINICAL RESPONSE nifedipine (B) Sequential combination therapy INADEQUATE CLINICAL RESPONSE Atrial septostomy (E/B) and/or + (B) Prostanoids + (B) lung transplant (E/A) PDE-5 I + (B) ERA Barst RJ et al. JACC. 29 Summary: Inhaled Therapies for PAH in children Inhaled therapies including oxygen and NO are used routinely in the critical care setting and to evaluate acute vasoreactivity in the catheterization lab The study of alternate agents such as iloprost and inhaled treprostinil may offer other options for pediatric patients in both the critical and out-patient setting Further study of these agents are necessary to provide the safety, efficacy, dosing and optimal delivery modes for children 11

2mcg/mL Drug Delivery Data Volume of solution emitted 1 mcg/ml (.5 ml chamber) 2 mcg/ml (.25 ml chamber).46 ml.25 ml Dose emitted 4.54 mcg 4.97 mcg Fine particle fraction (% < 4.7 µm) Simulated dose delivery time 95.4% 9.1% 1 min 3.8 min *Validation data based on particle sizing into an Andersen Cascade Impactor with a manually generated 28.3 L/min 15-second inhalation cycle breathing pattern (data on file, Actelion Pharmaceuticals) 12