Therapy Update: ERAs. Review of Mechanism. Disclosure Statements. Outline. Disclosure: Research support from United Therapeutics

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1 1 Therapy Update: ERAs Disclosure Statements Disclosure: Research support from United Therapeutics Most of the medications discussed in this presentation are off-label usage Nidhy Varghese, MD Pulmonary Medicine Baylor College of Medicine, Texas Children s Hospital Page 1 xxx00.#####.ppt 3/11/2017 3:48:58 PM Outline Review of endothelin pathology and drug targets Review of current endothelin receptor antagonists ERA combinations Recent literature review Review of Mechanism What is endothelin?? Page 2 xxx00.#####.ppt 3/11/2017 3:48:58 PM

2 2 Endothelin (ET) Potent vasoconstrictor, isolated 1988 Ambrisentan Sitaxsentan* Peptide released by vascular endothelial cells ET-1: changes in oxygen tension, catecholamines Elevated ET in fetal circulation Pulmonary hypertension Elevated ET levels Increased expression of ET-receptors More et al. Cochrane Database Syst Rev Aug 18;(8). Page 4 xxx00.#####.ppt 3/11/2017 3:48:58 PM Bosentan Macitentan *Sitaxsentan off market 2010 Adapted from Potoka KP, et al. Am J Physiol Lung Cell Mol Physiol 2015;308(4):L314-L324. Slide courtesy of Dr. Shelly Kim, PharmD, RPh Page 5 xxx00.#####.ppt 3/11/2017 3:48:58 PM Endothelin Receptors ET-A Vascular smooth muscle cells and cardiac myocytes Activation: vasoconstriction, smooth muscle proliferation, hypertrophy, cell migration and fibrosis Dominant receptor subtype in human lung tissue ET-B Endothelial cells, smooth muscle cells and fibroblasts Activation: stimulates release of vasodilators (NO and PGI2), clearance of endothelin Available ERA Formulations Drug Name (Trade) ERA Type Adverse Effects Special Considerations Bosentan (Tracleer) Ambrisentan (Letairis) Macitentan (Opsumit) Non-selective; ET-A and ET-B Selective for ET-A Non-selective; ET-A and ET-B Liver toxicity Fluid retention Teratogenicity Male infertility Effects on sildenafil Anemia Fluid retention Teratogenicity Male infertility Liver toxicity Fluid retention Teratogenicity Male infertility REMS, monthly liver panel monitoring + pregnancy REMS, monthly pregnancy testing and interval liver panel, hemoglobin indices REMS, pregnancy testing and interval labs More et al. Cochrane Database Syst Rev Aug 18;(8). Duo-Ji and Long. Int J Cardiol Jan 5. Page 6 xxx00.#####.ppt 3/11/2017 3:48:58 PM Page 7 xxx00.#####.ppt 3/11/2017 3:48:59 PM

3 3 3/11/2017 Oral Therapies in PAH Randomized controlled trials Drug Study Duration Primary endpoint No. of patients Bosentan Study-351 1,2 12 weeks 6-MWD 32 BREATHE weeks 6-MWD 213 EARLY 4 24 weeks PVR, 6-MWD 185 Sildenafil SUPER weeks 6-MWD 277 Tadalafil PHIRST 6 16 weeks 6-MWD 405 Ambrisentan ARIES-1 7,8 12 weeks 6-MWD 202 ARIES-2 7,9 12 weeks 6-MWD 192 AMBITION weeks Clinical failure 610 Macitentan SERAPHIN weeks Morbidity/Mortality 742 Selexipag GRIPHON weeks Morbidity/Mortality 1, l RN, et al. Lancet Badesch D, et al. Curr Ther Res Rubin LJ, et al. N Engl J Med Galiè N, et al. Lancet Galiè N, et al. N Engl J Med Galiè N, et al. Circulation Galiè N, et al. Circulation Oudiz R, et al. Chest Oudiz RJ, et al. J Am Coll Cardiol Galiè N, et al. Eur Respir J Pulido, et al. N Engl J Med Sitbon O et al. N Engl J Med Closer Look at Options Slide courtesy of Dr. Bruce Neale, PharmD Page 8 xxx00.#####.ppt 3/11/2017 3:48:59 PM Bosentan (Tracleer), 2001 Nonselective antagonist: ET-A affinity over ET-B Multiple studies in adults and children, including congenital heart disease Approved in children > 12 yo Improved 6MWD, lower mpap, lower PVR and higher survival estimates Bosentan, continued AHA/ATS Guidelines 2015 Weight (kg) Oral/Enteral Dose <10 kg 1 mg/kg BID x 4 weeks then increase to 2 mg/kg BID kg mg daily x 4 weeks then increased to mg BID >20-40 kg mg BID x 4 weeks then increase to 62.5 mg BID >40 kg 62.5 mg BID x 4 weeks then increase to 125 mg BID Required monthly labs (hepatic panel, pregnancy) Abman et al. Circulation Nov 24;132(21): Page 10 xxx00.#####.ppt 3/11/2017 3:48:59 PM Abman et al. Circulation Nov 24;132(21): Page 11 xxx00.#####.ppt 3/11/2017 3:48:59 PM

4 4 Bosentan Oral formulations Tablet 62.5 mg, 125 mg Rapid disintegration in water Do not crush Should not be mixed or dissolved in liquids with a low (acidic) ph (e.g., fruit juices) due to poor solubility Pediatric formulation Dispersible pill available in Europe Generic form available soon in US Bosentan, continued Potential drug interactions Bosentan can decrease sildenafil Cmax Sildenafil: increases serum concentration bosentan? Taguchi et al. Drug Metabolism 2011 Warfarin: levels are decreased by bosentan Spangler. Clin Ther 2010, case report Lexicomp Online, Hudson, Ohio: Lexi-Comp, Inc.; March 3, Page 12 xxx00.#####.ppt 3/11/2017 3:48:59 PM Page 13 Ambrisentan (Letairis), 2007 Selective ET-A antagonist for IPAH, PAH-CTD Once daily dosing Ambrisentan, continued AHA/ATS Guidelines 2015 Required labs: monthly pregnancy; blood count and hepatic panel at intervals Safety and efficacy data in children limited Takatski et al, Ped Pulm 2012 Adults Oral/enteral dose 5 mg daily; can increase to 10 mg daily based on tolerance Avoid use in neonates or infant because glucuronidation is not mature Page 14 Page 15

5 5 Ambrisentan, continued Oral formulations: Tablet 5 mg, 10 mg Administration Swallow tablet whole; do not split, crush, or chew tablet Advantages Once daily dosing No drug interaction with PDE-5 inhibitors or warfarin observed Improved safety profile for liver toxicity Macitentan (Opsumit), 2013 Non-selective antagonist: ET-A, ET-B FDA approval 2013 Modified bosentan structure for improved efficacy, safety profile and bioavailability Required labs: monthly pregnancy; blood count and hepatic panel at intervals Takatsuki S, et al. Pediatr Pulmonol 2013;48(1): Page 16 Page 17 Macitentan, continued Macitentan, continued AHA/ATS Guidelines: not included TOMORROW: Phase III trial in children Oral formulations: Tablet 10 mg Administration Swallow tablet whole; do not split, crush, or chew tablet Advantages Once daily dosing No drug interaction with PDE-5 inhibitors or warfarin observed Improved safety profile for liver toxicity Page 18 Page 19

6 6 Playing well with others: ERA combo therapies Does it make a difference? Combination therapy strategies tested in randomized controlled clinical trials Humbert M, Ghofrani, HA. Thorax 2016;71:73-83 Slide provided by Bruce Neale, PharmD Page 21 Bosentan Trials: STEP STEP Data RCT, double-blind trial Inhaled iloprost added to stable monotherapy with bosentan P = iloprost + bosentan group vs placebo Efficacy endpoints: 6MWD, FC, hemodynamics, time to clinical worsening McLaughlin et al. AJRCCM Page 22 McLaughlin et al. AJRCCM Page 23

7 7 Ambrisentan Trials: AMBITION Event-driven, double blind RCT Naïve PAH, WHO FC II-III to receive ambrisentan monotherapy, tadalafil monotherapy, or ambrisentan + tadalafil combination therapy; upfront combination therapy Primary endpoint: first event of clinical failure (death, hospitalization, disease progression, long-term clinical response) Combination group: improved BNP, clinical response, 6MWD Notes No significant differences in WHO FC at week 24 Are results specific to ambrisentan and tadalafil? Study did not allow for crossover in the monotherapy arms AMBITION Participants with No Event (%) Ambrisentan AND Tadalafil N=253 Ambrisentan or Tadalafil N= Galie et al. NEJM 373; (9) Aug 2015 Page 24 Slide provide by Bruce Neale, PharMD N Engl J Med 2015 Weeks Page 25 SERAPHIN Data Patients > 12 yo in RCT, double blind study for WHO Group 1, FC II-IV naïve or on oral/inhaled PH therapies Placebo, 3 mg or 10 mg dose of macitentan for naïve or add-on therapy Reduced clinical worsening compared to placebo for macitentan both doses Pulido et al. NEJM 2013 Page 26 Page 27

8 8 Therapy Meta-analysis Clinical Implications So many choices, so little time! Systematic review and network meta-analysis to examine comparative efficacy and tolerability of pharmacologic interventions for PAH Phase 2/3 RCTs, no true pediatric studies Assessed clinical worsening, hospitalizations, allcause mortality Jain et al Chest 2017 Page 29 Improved FC 25.2% of patients with ERA (RR, 1.56; 95% CI, ) 28.3% of patients with ERA + PDE5i (RR, 1.75; 95% CI, ) Improved 6MWD No combinations met criteria (increase in 33 m) ERA+PDE5i better of the lot Among oral agents, ERA, PDE5i, and ERA + PDE5i: improvement in patient morbidity (both clinical worsening and hospitalization) and functional status. Findings limited by few head-to-head trials and differences in reporting across trials. Page 30 Page 31

9 9 Network Meta-analysis of ERAs Comparison of four ERAs Network meta-analysis: comprehensive viewpoint synthesizing direct and indirect evidence Efficacy outcomes: 6MWD, clinical worsening 10 studies including 2172 patients RCTs in yo WHO Group I, NYHA FC II-IV, no concomitant PH therapies Included bosetan, ambrisentan, macitentan and sitaxsentan Acceptability outcomes: serious adverse events, all-cause discontinuation Duo Ji and Long. Int J Card Jan Page 32 Page 33 Conclusions ERAs are a powerful group of medications All ERAs significantly increased average 6MWD Bosentan and ambrisentan decreased clinical worsening Ambrisentan trended to less discontinuation Well-tolerated in children but more pediatric studies are needed ERAs should be considered as a part of combination therapy Based on current literature, bosentan and ambrisentan may be better ERA options in adults Page 34 Page 35

10 10 Acknowledgements: Dr. Shelly Kim, PharmD Page 36 xxx00.#####.ppt 3/11/2017 3:49:03 PM