Oral Therapies for Pulmonary Arterial Hypertension

Oral Therapies for Pulmonary Arterial Hypertension Leslie Wooten, PharmD PGY2 Internal Medicine Pharmacy Resident University of Cincinnati Medical Center April 30 th, 2018

Objectives Pharmacist Objectives Describe the classification and pathophysiology of pulmonary hypertension and pulmonary arterial hypertension Compare the pharmacokinetics and pharmacodynamics of phosphodiesterase type 5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, prostacyclins, and prostacyclin receptor agonists Analyze the primary literature supporting the use of the oral agents. Assess the place in therapy of the oral agents in the treatment of pulmonary arterial hypertension Technician Objectives Identify brand and generic names of oral therapy for pulmonary arterial hypertension Recognize oral therapy for pulmonary arterial hypertension that can be compounded into a suspension

Pulmonary Hypertension Mean pulmonary arterial pressure greater than 25 mmhg at rest as assessed by right heart catheterization Group 1 Group 2 Group 3 Group 4 Group 5 World Health Organization (WHO) Classification of Pulmonary Hypertension Primary pulmonary arterial hypertension (PAH) Left ventricular systolic or diastolic failure Pulmonary disease or hypoxia Chronic thromboembolism (CTEPH) Multifactorial National Heart Lung and Blood Institute. Pulmonary Hypertension. Accessed on Dec 2017. Galie N, et al. Eur Heart J. 2016;37:67-119

Class I Class II Class III Class IV World Health Organization (WHO) Functional Classes Ordinary physical activity does not cause undue dyspnea or fatigue, chest pain, or near syncope Comfortable at rest Ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope Comfortable at rest Less than ordinary activity causes undue dyspnea or fatigue, chest pain, or near syncope Signs of right heart failure Dyspnea and/or fatigue may even be present at rest Discomfort is increased by any physical activity Galie N, et al. Eur Heart J. 2016;37:67-119

Dysregulation of Vasodilatory System Humbert M. Eur Respir Rev. 2010;19(115):59-63 Lai YC, et al. Circ Res. 2014;115:115-130.

Treatment Targets Humbert M. Eur Respir Rev. 2010;19(115):59-63 Lai YC, et al. Circ Res. 2014;115:115-130.

Morbidity and Mortality Survival markers Exercise capacity: 6 minute walk distance Decrease in probability of a clinical event with increase of 41.8 meters WHO Functional Class Cardiac markers: NT-proBNP, CO/CI, mpap Clinical worsening Hospitalization due to PH, start of new therapy, decrease in 6MWD, persistent worsening of WHO functional class, death Quality of life NT-proBNP: N-terminal pro brain natriuretic peptide mpap: mean pulmonary arterial pressure CO/CI: cardiac output/cardiac index Gabler N, et al. Circulation. 2012;126(3):349-356. Bonner N, et al. Health Qual Life Outcomes. 2013;11(161):1-16.

Initial Treatment Selection Galie N, et al. Eur Heart J. 2016;37:67-119

Initial Monotherapy Drug Class Drugs WHO-FC II WHO-FC III WHO-FC IV Endothelin receptor antagonist PDE-5 inhibitor Bosentan Macitentan Ambrisentan Sildenafil Tadalafil ++ ++ + ++ ++ + Prostacyclin analogues Treprostinil (oral) + IP receptor antagonists Guanylate cyclase stimulator Selexipag ++ ++ Riociguat ++ ++ + Modified from European Society of Cardiology and European Respiratory Society Pulmonary Hypertension Guidelines Galie N, et al. Eur Heart J. 2016;37:67-119 Taichman DB, et al. CHEST. 2014:146(2):449-475.

Mechanism Dosing Phosphodiesterase Type 5 Inhibitors Sildenafil (Revatio ) Tadalafil (Adcirca ) Inhibits cgmp specific phosphodiesterase type-5 Initial: 5-10 mg TID Maximum: 20-40 mg TID Initial: 20 mg daily Maximum: 40 mg daily Pharmacokinetics CYP3A4 metabolism CYP3A4 metabolism Requires renal dose adjustment Clinical Pearls Often used first line due to ease of access to the medication Requires prior authorization Avoid use with riociguat or nitrates Can crush or formulate into oral suspension Sildenafil [package insert]. New York, NY: Pfizer Inc; 2017. Galie N, et al. N Engl J Med. 2005;353(20):2148-2157. Tadalafil [package insert]. Indianapolis, IN: Eli Lilly and Company; 2017. Galie N, et al. Circulation. 2009;119:2894-2903.

Phosphodiesterase Type 5 Inhibitors Clinical Trials SUPER: Sildenafil PHIRST: Tadalafil Design Monotherapy Monotherapy Background ERA: 53% Patient Characteristics Primary Outcome Secondary Outcomes Adverse Events 75% female Average age: 49 years WHO FC II: 39% WHO FC III: 58% 6MWD at 12 weeks Increased 45-50 meters Reduced mpap and PVR Improved WHO FC Headache Flushing Dyspepsia Diarrhea 63% female Average age: 54 years WHO FC II: 32% WHO FC III: 65% 6MWD at 16 weeks Increased 33-44 meters Reduced time to clinical worsening Reduced mpap and PVR Headache Flushing Dyspepsia Myalgias WHO FC: World Health Organization Functional Class ERA: endothelin receptor antagonist 6MWD: six minute walk distance mpap: mean pulmonary arterial pressure PVR: pulmonary vascular resistance Galie N, et al. Circulation. 2009;119):2894-2903. Galie N, et al. N Engl J Med. 2005;353(20):2148-2157.

Mechanism Endothelin Receptor Antagonists Bosentan (Tracleer ) ET A and ET B receptor antagonist Macitentan (Opsumit ) ET A and ET B receptor antagonist Ambrisentan (Letaris ) ET A receptor antagonist Dosing Pharmacokinetics Initial: 62.5 mg BID Maximum: 125 mg BID Metabolized by CYP3A4 and 2C9 Active metabolite Autoinduction of CYP 3A4 and 2C9 10 mg daily Initial: 5 mg daily Maximum: 10 mg daily Metabolized by CYP3A4 Active metabolite Metabolized by CYP3A4 and 2C19 Clinical Pearls REMS program for female patients due to embryo-fetal toxicity Risk for hepatotoxicity (bosentan) Causes fluid retention Cannot crush or chew tablets Can be extemporaneously compounded into oral solution Actelion Pathways patient assistance program (macitentan) ET-1: endothelin type 1 ET A/B : endothelin receptor A/B Macitentan [package insert]. San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2017. Bosentan [package insert]. San Francisco, CA: Actelion Pharmaceuticals US, Inc; 2017. Letaris [package insert]. Foster City, CA: Gilead Sciences, Inc: 2015

Endothelin Receptor Antagonists Clinical Trials Bosentan: BREATHE1 Macitentan: SERAPHIN Ambrisentan: ARIES 1 and 2 Design Monotherapy Monotherapy Background PDE-5: 61% Background oral or inhaled prostacyclin: 5% Patient Characteristics Primary Outcome Secondary Outcomes 79% female Average age: 48 years WHO FC III: 92% WHO FC IV: 8% 6MWD at 16 weeks Increased 44 meters Improved WHO FC Increased time to clinical worsening 77% female Average age: 46 years WHO FC II: 52% WHO FC III: 46% Decrease in composite: death, atrial septostomy, lung transplant, initiation of IV or subcut prostacyclin, worsening of PAH 6MWD at 24 weeks Increased 22 meters Improved WHO FC Adverse Events Hepatotoxicity Headache Anemia Peripheral edema Monotherapy 79% female Average age: 50 years WHO FC II: 38% WHO FC III: 55% 6MWD at 12 weeks Increased 51-59 meters Improved WHO FC (AIRES-1) Increased time to clinical worsening (AIRES-2) Headache Peripheral edema WHO FC: World Health Organization Functional Class PDE-5: phosphodiesterase type 5 6MWD: six minute walk distance Pulido T, et al. N Engl J Med. 2013;369:809.818. Galie N, et al. Circulation. 2008;117:3010-3019. Rubin LJ, et al. N Engl J Med. 2002;346:896-903.

Macitentan Clinical Outcomes Pulido T, et al. N Engl J Med. 2013;369:809.818.

Mechanism Indication Dosing Pharmacokinetics Riociguat (Adempas ) Stimulates soluble guanylate cyclase PAH and CTEPH Initial: 1 mg TID (0.5 mg TID if hypotensive) Maximum: 2.5 mg TID PGP substrate Active metabolite Clinical Pearls Avoid use with PDE-5 inhibitors or nitrates REMS program for female patients due to embryofetal toxicity Can crush Must re-titrate if interrupted for greater than 72 hours Aim Financial Assistance program PGP: P-glycoprotein PDE-5: phosphodiesterase type 5 Riociguat [package insert]. Whippary, NJ: Bayer HealthCare Pharmaceuticals Inc; 2017.

Design Patient Characteristics Primary Outcome Secondary Outcomes Adverse Events Riociguat Clinical Trials PATENT-1 Monotherapy or background ERA, or oral/inhaled prostacyclin 79% female Average age: 51 years WHO FC II: 42% WHO FC III: 53% 6MWD at 12 weeks Increased 36 meters Reduced mpap and PVR Reduced clinical worsening Headache Dyspepsia Peripheral edema Hypotension CHEST-1 Monotherapy 66% female Average age: 59 years WHO FC II: 31% WHO FC III: 64% 6MWD at 16 weeks Increased 49 meters Reduced mpap and PVR Improved or stabilized WHO FC Headache Dizziness Dyspepsia Hypotension Extension Trial PATENT-2 CHEST-2 Primary Outcome Sustained improvement in 6MWD Sustained improvement in 6MWD WHO FC: World Health Organization Functional Class ERA: endothelin receptor antagonist 6MWD: six minute walk distance mpap: mean pulmonary arterial pressure PVR: pulmonary vascular resistance Ghofrani HA, et al. N Engl J Med. 2013;369:330-340. Ghofrani HA, et al. N Engl J Med. 2013;369:319-329. Rubin LJ, et al. Eur Respir J. 2015;45:1303-1313. Simonneau G, et al. Eur Respir J. 2015;45:1293-1302.

Initial Oral Combination Treatment WHO-FC II WHO-FC III WHO-FC IV Ambrisentan + tadalafil ++ ++ + ERA + PDE-5 inhibitor + + + Other combinations with IV prostacyclins + + Modified from European Society of Cardiology and European Respiratory Society Pulmonary Hypertension Guidelines Galie N, et al. Eur Heart J. 2016;37:67-119. Taichman DB, et al. CHEST. 2014:146(2):449-475.

Design Patient Characteristics Primary Outcome AMBITION Trial Initiation of tadalafil 40 mg and ambrisentan 10 mg simultaneously 78% female Average age: 54 years WHO FC II: 31% WHO FC III: 69% Clinical failure Tadalafil monotherapy: 28% Ambrisentan monotherapy: 34% Tadalafil + ambrisentan: 18% P < 0.001 Secondary Outcomes Combination therapy had greater increase in 6MWD at 24 weeks 48.9 meters vs 23.8 meters Adverse Events All adverse effects were those known to be associated with PDE-5 inhibitors or ERAs WHO FC: World Health Organization Functional Class ERA: endothelin receptor antagonist PDE-5: phosphodiesterase type 5 6MWD: six minute walk distance Galie N, et al. N Engl J Med. 2015;373:834-844.

Initial Oral Combination Therapy Galie N, et al. N Engl J Med. 2015;373:834-844.

Treatment Selection for Advanced Stage PAH Galie N, et al. Eur Heart J. 2016;37:67-119

Sequential Therapy Treatment WHO-FC II WHO-FC III WHO-FC IV Macitentan added to sildenafil ++ ++ + Selexipag added to ERA and/or PDE-5 ++ ++ + Riociguat added to bosentan ++ ++ + Tadalafil added to bosentan + + + Ambrisentan/Bosentan added to sildenafil + + + Modified from European Society of Cardiology and European Respiratory Society Pulmonary Hypertension Guidelines Guidelines include recommendations for combination therapy with IV, inhaled, or subcutaneous products Galie N, et al. Eur Heart J. 2016;37:67-119 Taichman DB, et al. CHEST. 2014:146(2):449-475.

Treatment Selection for Advanced Stage PAH Galie N, et al. Eur Heart J. 2016;37:67-119

Design The Primary Pulmonary Hypertension Trial Patient Characteristics Primary Outcome Secondary Outcomes Epoprostenol IV + conventional therapy vs. conventional therapy 73% female Average age: 54 years WHO FC III: 74% WHO FC IV: 26% Exercise capacity (6MWD) Conventional therapy: decrease 29 meters Epoprostenol: increase 31 meters P < 0.002 Epoprostenol treatment Increased survival Improved QOL Improved or stabilized functional class Improved hemodynamic measurements: mpap, CI, PVR Conventional therapy: anticoagulants, calcium channel blockers, digoxin, diuretics, supplemental oxygen Barst RJ, et al. N Engl J Med. 1996;334:296-301.

Survival Benefit with IV Prostacyclins P=0.003 Barst RJ, et al. N Engl J Med. 1996;334:296-301.

Mechanism Dosage Forms Place in therapy Prostacyclins Direct pulmonary vasodilation via binding to the prostacyclin receptor Inhaled IV or subcutaneous Oral Combination therapy for WHO class III and IV Clinical Pearls IV and subcutaneous require at home continuous infusion Risk of infection with IV and subcutaneous products Conversion between dosage forms possible IV and subcutaneous more potent than oral Adverse effects are often the dose limiting factor Survival benefit with IV and subcutaneous prostacyclins Barst RJ, et al. N Engl J Med. 1996;334:296-301. Treprostinil [package insert]. Triangle Park, NC: United Therapeutics Corp; 2017.

Mechanism Indication Dosing Pharmacokinetics Oral Treprostinil (Orenitram ) Direct pulmonary vasodilation via binding to the prostacyclin receptor PAH Initial: 0.25 mg BID or 0.125 mg TID Maximum: highest tolerated dose Increased AUC and Cmax with high fat and high calorie meal Metabolized by CYP2C8 Elimination effected by hepatic impairment Clinical Pearls Must titrate up and down every 3 to 4 days Restart titration if two or more doses misses Cannot crush or chew tablets Equations to convert from IV or subcutaneous to PO ASSIST patient assistance program AUC: area under the curve Cmax: maximum concentration Treprostinil [package insert]. Triangle Park, NC: United Therapeutics Corp; 2017.

Oral Treprostinil Clinical Trials FREEDOM-C Design Background ERA: 30% Background PDE-5 inhibitor: 25% Triple therapy: 45% Patient Characteristics Primary Outcome Secondary Outcomes Adverse Events 82% female Average age: 51 years WHO FC II: 21% WHO FC III: 76% 6MWD at 16 weeks Increased 11 meters No change in WHO FC No change in clinical worsening FREEDOM-C2 Background ERA: 17% Background PDE-5 inhibitor: 43% Triple therapy: 40% 78% female Average age: 51 years WHO FC II: 26% WHO FC III: 73% 6MWD at 16 weeks Increased 10 meters No change in WHO FC No change in clinical worsening Headache, nausea, diarrhea, jaw pain, flushing, pain in extremity WHO FC: World Health Organization Functional Class ERA: endothelin receptor antagonist 6MWD: six minute walk distance Jing ZC, et al. Circulation. 2013;127:624-633. Tapson VF, et al. CHEST. 2012;142(6):1383-1390. Tapson VF, et al. CHEST. 2013; 144(3):952-958.

Background Therapy Effect on Six Minute Walk Test FREEDOM-C FREEDOM-C2 Background ERA 15 meters 7.7 meters Background PDE-5 inhibitor 17 meters 15 meters Triple therapy 10 meters 4 meters Tapson VF, et al. CHEST. 2012;142(6):1383-1390. Tapson VF, et al. CHEST. 2013; 144(3):952-958.

Mechanism Indication Dosing Pharmacokinetics Selexipag (Uptravi ) Prostacyclin receptor agonist PAH Initial: 200 mg BID Maximum: 1600 mg BID Metabolized by CYP2C8 Elimination effected by hepatic impairment Clinical Pearls Titrate up weekly Cannot crush or chew tablets Must re-titrate if interrupted for greater than 72 hours Actelion Pathways patient assistance program Selexipag [package insert]. San Francisco, CA: Actelion Pharmaceuticals US Inc; 2017.

GRIPHON Trial Design Monotherapy: 20% Background ERA: 15% Background PDE-5 inhibitor: 32% Triple therapy: 33% Patient Characteristics Primary Outcome Secondary Outcomes Adverse Events 80% female Average age: 48 years WHO FC II: 46% WHO FC III: 53% Decreased composite: death from any cause or a complication related to PAH 6MWD at 26 weeks: increased 12 meters No change WHO FC Headache, nausea, diarrhea, jaw pain, flushing, pain in extremity WHO FC: World Health Organization Functional Class ERA: endothelin receptor antagonist 6MWD: six minute walk distance Sitbon O, et al. N Engl J Med. 2015;373:2522-2533.

Selexipag Clinical Outcomes Sitbon O, et al. N Engl J Med. 2015;373:2522-2533.

Background Therapy Effect on Clinical Outcomes Sitbon O, et al. N Engl J Med. 2015;373:2522-2533.

Efficacy Comparison Outcome 6 minute walk distance Clinical worsening n (%) FREEDOM-C n=174 Treprostinil Combination therapy FREEDOM-C2 n=157 Treprostinil Combination therapy GRIPHON n=575 Selexipag Combination and Monotherapy Increase 11 m* Increase 10 m* Increase 12 m 8 (5) 11 (7) 78 (13.6) Hospitalization - 4 (3) 86 (15) Death n (%) 0 6 (4) 28 (4.9) Duration of therapy 16 weeks 16 weeks 70.7 weeks *primary outcome Jing ZC, et al. Circulation. 2013;127:624-633. Tapson VF, et al. CHEST. 2012;142(6):1383-1390. Tapson VF, et al. CHEST. 2013; 144(3):952-958. Sitbon O, et al. N Engl J Med. 2015;373:2522-2533.

Adverse Event Comparison Adverse events: n (%) FREEDOM-C n=174 Treprostinil Combination therapy FREEDOM-C2 n=157 Treprostinil Combination therapy GRIPHON n=575 Selexipag Combination and Monotherapy Headache 150 (86) 112 (71) 375 (65) Diarrhea 106 (61) 87 (55) 244 (42) Nausea 112 (64) 73 (46) 193 (34) Jaw pain 74 (43) 398 (25) 148 (26) Vomiting 76 (43) 33 (21) 104 (18) Pain in extremity 54 (31) 27 (17) 97 (17) Flushing 85 (49) 55 (35) 70 (12) Jing ZC, et al. Circulation. 2013;127:624-633. Tapson VF, et al. CHEST. 2012;142(6):1383-1390. Tapson VF, et al. CHEST. 2013; 144(3):952-958. Sitbon O, et al. N Engl J Med. 2015;373:2522-2533.

PDE-5 inhibitors Start WHO FC II and III Disease progression Endothelin receptor antagonists Selexipag (or oral treprostinil) Galie N, et al. Eur Heart J. 2016;37:67-119 Taichman DB, et al. CHEST. 2014:146(2):449-475.

Conclusions Pulmonary arterial hypertension is associated with high morbidity and mortality There are four major drug classes that target the pathophysiologic changes of PAH No oral medications have shown a direct reduction in mortality but do show improvements in functional status and morbidity Management includes the initiation of medications from different drug classes to balance the functional status with drug related adverse events

Oral Therapies for Pulmonary Arterial Hypertension Leslie Wooten, PharmD PGY2 Internal Medicine Pharmacy Resident University of Cincinnati Medical Center May 1, 2018