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1 THE GREAT DEBATE Oral Prostacyclins Disclosures • Kelly Chin, MD • Participant discloses the following financial or non-financial relationships: • Participated in clinical trials supported by Actelion, Bayer, Gilead, GlaxoSmithKline, Novartis, United Therapeutics, GeNO and the NIH • Advisory Boards or consulting: Actelion and Bayer • Steering committee for GRIPHON • Participant has indicated the following discussion of unapproved drug or product uses: • Will discuss medications not yet approved for use • R. James White, MD, PhD • Participant discloses the following financial or non-financial relationships: • United Therapeutics: Investigator, Consultant, Steering Committee (no personal financial renumeration -- support only to University of Rochester) • Gilead Sciences: Investigator, Consultant (personal renumeration, no equity) • Bayer: Consultant (personal renumeration, no equity) • Participant has indicated the following discussion of unapproved drug or product uses: • broad use of oral treprostinil for PAH; similar to my use of other drugs for PAH, my use of oral treprostinil is broader than that indicated on the label • Melisa Wilson, ARNP, ACNP-BC • Participant has no financial or non-financial arrangements or affiliations to disclose. • Participant has indicated no discussion of unapproved drug or product uses. Disclosures This continuing education activity is managed and accredited by Professional Education Services Group in cooperation with the Pulmonary Hypertension Association. Neither PESG, nor PHA, nor any accrediting organization support or endorse any product or service mentioned in the is activity. PESG and PHA staff has no financial interest to disclose. Commercial Support was not received for this activity. Learning Objectives • To understand the study results for the oral prostacyclin registration trials (FREEDOM M, C and C2 and GRIPHON) including both primary and secondary endpoints. • To understand the most common oral prostacyclin side effects and to list options for reducing side effect severity. • To identify patients who are appropriate (and especially those not appropriate) to consider using oral treprostinil in place of parenteral prostacyclin therapy (the Freedom-205 study). 5 Disclaimers • The views of the expressed in this debate are not those of PHA or any affiliates of the PHA. They are the views of the debaters who are experts in the field of PAH. 6 How many patients or research subjects have you started on oral prostacyclin? A. 0 B. 1-10 C. 11-20 D. 20-30 E. > 30 7 Is your center currently participating in a research study utilizing oral prostacyclin? A. Yes B. No What is the max total daily dose of your current patients on oral treprostinil? A. I don't have any patients on oral treprostinil B. 0.025 - 3mg C. 3.125 - 9mg D. 9.125 - 15mg E. 15.125 - 21 mg F. > 21 mg daily Jim White, MD 9 Prostacyclin in PAH: a brief history • 1976 Moncada…Vane: an unstable “PGX” compound could relax vessel preparations and inhibit platelet aggregation (Nature) • 1982 Rubin, Groves, Reeves: acute pulmonary vasodilation in 7 severe PPH patients with 50% reduction in PVR (Circ) • 1984 Higenbottam: chronic therapy in a “bedbound” woman (Lancet) • 1995 FDA approval of synthetic prostacyclin for chronic use in the US • 1996 Barst et al: 12 weeks of randomized, open-label epoprostenol therapy with robustly improved 6MWT, hemodynamics, quality of life (NEJM) • 2002 FDA approval of subcutaneous treprostinil • 2004 FDA approval of intravenous treprostinil and inhaled iloprost • 2008 FDA approval of thermostable epoprostenol (Veletri) • 2013 FDA approval of oral treprostinil • 2015 Likely introduction of oral selexipag Consistent results: data and experience Pulmonary Vascular Resistance (Woods units) 30 25 20 15 10 5 0 At Baseline After Adenosine Challenge After Epoprostenol Therapy McLaughlin VV, et al. N Engl J Med. 1998;338:273-277. Consistent challenge for our patients • IV: indwelling catheter care; thrombosis; catheter infection; sepsis; endocarditis; • SQ: Moderate-severe site pain at the time of new infusions sites is pretty much the rule; anxiety about site dislodgement • For everyone: sex, showering, sleep, and swimming will never be the same C and C2: important mistakes • Dose matters, and we didn’t get anywhere close: suggests that this behaves similarly to parenteral prostacyclins that we already know/love • BID and TID: might as well be different drugs – AE tolerance – Dose titration • If you only have experience with BID, then you don’t know TID oral TRE C: Median Change in 6MWD by Dose Achieved at Week 16 6MWD Median Change from Baseline (m) 40. UT-15C SR 34 30. 20. 18 10. 3.8 0. N (active) AE D/C or dose < or = 1 mg 1.25 mg to 3.25 mg 58 Tapson, VF… Galie, N. Chest 142: 1383-1390 (2012) 49 3.5 mg to 16 mg 52 C2: Median Change in 6MWD by Dose Achieved at Week 16 6MWD Median Change from Baseline (m) 50 UT-15C SR 44 40 30 20 12 10 0 8 AE D/C or dose < or = 1 mg N (active) UT Unpublished Data on File 33 1.25 mg to 3.25 mg 73 3.5 mg to 16 mg 41 BID TID @ U of R • Initial conversion instructions were to divide the total daily BID dose by 3 (a dose reduction for each individual dose) • Titration continued over 2-6 weeks based on tolerability • Average time from 2nd PK visit to exit from open label study was 9 months (range 6 to 12 months) Regimen Average Total Daily Dose (mg) 16 Range (mg) 4 to 35 TID (PK visit) 19 4 to 43 TID (exit from OL study) 24 3 to 60 BID Pharmacokinetic Profile 10 mg BID AUC 32 Cmin .3.5 10 mg TID AUC 56 Cmin 1.5 55 yo, 130 kg IPAH male 15/16 AE impression of change (much improved) Pharmacokinetic Parameters Parameter BID TID Total Daily Dose mg mean (range) 16 (4-35) 19 (3.75-43) Cmax ng/mL mean (SD) 8.6 (4.2) 8.9 (4.2) AUC h*ng/mL mean (SD) 47.8 (21.2) 58.0 (29.4) Pharmacokinetics – Trough Increases p = 0.013, paired t p = 0.013, paired t • Cmin increased by ~2-fold with TID dosing • Peak/trough ratio reduced by ~ 2-fold with TID dosing • AE profile improved in 12/13 Oral Treprostinil: we are learning how to give our patients a new choice… and CHOICES are GOOD. • Freedom EV: a longer trial to determine meaningful doses (> 12 mg daily) and demonstrate meaningful outcomes – Reduction in clinical events – Improvement in exercise tolerance • Developing better post-trial experience with new drugs (especially prostacyclins) has always been the rule in PAH – Site pain with SQ – High output failure with EPO Oral Prostanoids as Add-on Therapy in the Treatment of PAH Presented by Kelly Chin, MD Director, PH Program UT Southwestern Oral Prostanoids should NOT routinely be used in the treatment of PAH • Evidence for benefit too limited • Dosing issues are prohibitive ▫ Peak / trough and po admin limit dose ▫ Dose response suggests lower dose ineffective (hemodynamics and sc tre data) ▫ Peak / trough effects not fully explored – walk data • Strong evidence iv/ sc and inhaled PGI2 work ▫ Why not just try po? Delays may causes clinical worsening and death Unless very cautious - will be used in the wrong patients Prostacyclin – IV / SC FC: functional class, QOL: quality of life, CW: clinical worsening. = primary endpoint Prostacyclin Meds: Half Lives • Epo: IV only, 3-5 min • Iloprost: 20-30 min; inh vasodil for 1-2 hr • Beraprost: 0.5 to 1 hr • Treprostinil: 2-4 hrs • Selexipag: 8-14 hours Barst RJ et al. NEJM 1996;334:296 Badesch DB Annals of IM 2000;132:425 Simonneau G. AJRCCM 2002;165:800 McLaughlin VV et al. Circulation. 2002;106:1477-1482. Sitbon O et al. Upfront triple combination therapy in PAH: a pilot study. Eur Respir J 2014;43:1691 Beraprost: 12 week and 12 month studies 12 Week (ALPHABET) Study • 6MWD: 24 m, p=0.04 • Cath – no improvement ▫ Beraprost -6% PVR ▫ Placebo +1% PVR 12 Month (Barst) Study; stopped early • 1: no improvement disease progression (p=0.25) • 2: no improvement 6MWD, peak VO2, QOL, hemodynamics (PVR +1% vs + 2.5%) Galie et al. Effects of beraprost, an oral prostacyclin analog… JACC 2002;39:1496-1502. Barst RJ et al. Beraprost Therapy for PAH. JACC 2003; 41: 2119-2125 Beraprost Modified Release: Open label bid dosing - BPS-314d / BPS-MR • Japan (N=46): Rx naive ▫ Cath improved (PVR 12%, p<0.05) ▫ 6MWD improved 33m (p<0.05) • US and Europe (N=36): ERA / PDE5 OK ▫ Max and fixed dosing groups ▫ Endpoints: walk, FC, cath Kuneida T. Effects of long-acting beraprost sodium in Japanese patients with PAH. Int Heart J. 2009;50:513-529 FREEDOM STUDIES: 12 to 16 Week RCT: FREEDOM M • PEAK: 6MWD 23 m p<0.05 • TROUGH: 6MWD 13 m p<0.05 • No change: FC, TTCW FREEDOM C FREEDOM C (Figure) • 6MWD 11 m, p=0.07 • No change: FC, TTCW • DFI improved Walk Distance FREEDOM C2 • 6MWD 10 m, p=0.09 • No change: FC, TTCW, QOL, NTBNP Jing ZC et al. [FREEDOM M]. Circulation 2013;127:624. Tapson VF et al. [FREEDOM-C]. Chest 2012; 142:1383. Tapson VF et al. [FREEDOM-C2]. Chest 2013;144:952. Results = primary endpoint 2 = hemodynamic improvement in phase 2 study Results – Background Rx Trials and po PGI2 Trials = primary endpoint 2 = hemodynamic improvement in phase 2 study Dosing and tolerability • FREEDOM RCT ▫ M: 3.6 2.2 mg bid ▫ C: 3 mg bid (median) ▫ C2: 3.1 1.9 mg bid UT Southwestern: Dosing (7.2 mg/24 hr) (6 mg / 24 hr) (6.2 mg / 24 hr) • FREEDOM Extension • 12 months: 8.4 mg / 24 hr • UT Southwestern: 8.6 mg / 24 hr • Side effects • Nausea • Headache • Diarrhea White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481 Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. Baseline Demographics Characteristic Age in Years: mean (range) Gender: male : female PAH Etiology: n (%) Idiopathic/heritable/appetite suppressant/stimulant use Collagen vascular disease Other (porto-pulm, HIV) Congenital systemic-to-pulmonary shunt Baseline 6MWD (meters): median (range) Baseline Remodulin Dose (ng/kg/min): median (range) Remodulin Route of Administration: (SC:IV) Time on Remodulin (years): median (range) PAH Background Therapy: n (%) ERA + PDE-5 I PDE-5 I only ERA only n = 33 50 (18 - 80) 8 : 25 23 (70) 7 (21) 2 (6) 1 (3) 446.5 (279-705) 57 (25 - 111) 28 : 5 3.5 (0.6-9.3) 9 (27) 21 (64) 3 (9) Oral Tre Dosing Mean ± SD Median (range) Baseline Remodulin Dose (ng/kg/min) Total Daily Dose of Oral Treprostinil (mg) At Transition* Week 24 Total Daily Oral Treprostinil Dose (mg)*** TID (n=23) 63 ± 21 60 (27-111) 34 ± 12 33 (11-60) 40 ± 14 39 (17-82) Pharmacokinetic Parameters Median Six Minute Walk Distance 447 • Median change in 6MWD from Baseline to Week 24 was +16.7 meters 463 Hemodynamics and Echocardiography Mean Change from Baseline Baseline Week 24 mean ± SD (range) mean ± SD (range) PAPm (mmHg) 38 ± 13 (12 – 69) 40 ± 16 (13 – 73) +2.2 + 8.6 (-12 –26) CO†* (L/min) 5.6 ± 1.5 (3 – 10) 5.3 ± 1.2 (3 - 8) -0.3 + 1.3 (-3 – 2) CI†* (L/min/m2) 3.0 ± 0.5 (2 – 4) 2.8 ± 0.6 (2 – 4) -0.1 + 0.7 (-1 – 1) PCWP (mmHg) 10 ± 2 (5 – 14) 11 ± 4 (4 – 17) +0.6 ± 4.6 (-8 - 11) PVR† (mmHg*min/L) 5.2 ± 2.4 (1 - 9) 5.8 ± 3.5 (1 – 14) +0.8 + 2.4 (-3 - 8) RAPm (mmHg) 6±2 (2 – 8) 6±3 (1 – 12) +0.5 + 3.7 (-7 – 8) TAPSE‡ (cm) 2.0 ± 0.4 (1.1 – 3.0) 2.0 ± 0.4 (1.1 – 3.0) +0.3 + 0.3 (-0.6 – 0.6) Assessment N = 30 except where †N = 29 and ‡n=33 Only the Fick method was used for CO and in the CI calculation above for the purposes of this analysis Late failures were not a surprise… Transition study: optimal parenteral patients may succeed with oral • Careful patient selection: impressive clinical response to parenteral drug with good hemodynamics and RV function • Meticulous followup to guard against late deterioration Treprostinil: utility in iv / sc to po transitions • Declines any dose (2) • Unable to uptitrate at >12 mos (6) • Other (3) • Start IV Rx (17) • Death (3) Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. Hemodynamics: UTSW cohort (N=34) *Follow-up catheterization at 117 months of therapy Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. Transition to IV therapy: N=13 Dosing and tolerability • FREEDOM RCT ▫ M: 3.6 2.2 mg bid ▫ C: 3 mg bid (median) ▫ C2: 3.1 1.9 mg bid UT Southwestern: Dosing (7.2 mg/24 hr) (6 mg / 24 hr) (6.2 mg / 24 hr) • FREEDOM Extension • 12 months: 8.4 mg / 24 hr • UT Southwestern: 8.6 mg / 24 hr • Side effects • Nausea • Headache • Diarrhea White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481 Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. Typical dosing: intravenous prostacyclins vs po tre • PK Study ▫ 12 mg / 24 hr 20 ng/kg/min iv UTSW Dosing: Rationale • Clinical experience • SC treprostinil mortality data: ▫ 10 ng/kg/min increase in dose ▫ Dose >40 ng/kg/min • Other centers (survey, below) White RJ et al. Pharmacokinetics… J Cardiovasc Pharmacol. 2013;61:474-481 Oudiz RJ. Dosing considerations… Am Heart J 2009;157:625-35 Benza RL et al. Prognostic factors associated with increased survival…sc treprostinil. J Heart Lung Transplant. 2011;30:982. Jim White, MD 45 Treprostinil: Add on therapy • Declines any dose (2) • Unable to uptitrate at >12 mos (6) • Other (3) • Start IV Rx (17) • Death (3) Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. Hemodynamics: UTSW cohort (N=34) *Follow-up catheterization at 117 months of therapy Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, publication pending. Avail at http://www.jstor.org/stable/10.1086/682224. UTSW Cohort: Walk and Hemodynamics Chin KM et al. Longterm therapy with oral treprostinil … Pulmonary Circulation, epub ahead of print. Avail at http://www.jstor.org/stable/10.1086/682224. Oral Therapy: Change in PVR vs. Dose Oral Treprostinil – tid dosing option In God We Trust, All Others Bring Data - W. Edwards Deming Jones A et al. Pharmacokinetics of 3 times a day dosing… J Cardiovasc Pharmacol. 2014;63:227-232. Conclusions • Oral treprostinil, the only currently approved oral prostacyclin, should not be utilized as add-on therapy in PAH patients who are ▫ Responding adequately to therapy ▫ Not responding adequately to therapy ▫ Currently doing well on iv/sc therapy • IV/SC and inhaled therapy remain better proven therapies • Increased dosing frequency is an interesting idea ▫ Further study is needed 53 CASE STUDY History • 50-year-old female admitted with complaints of chest pain and shortness of breath. She states for the last 3 months, has been having progressively worsening shortness of breath, chest heaviness off and on with and without activity, and overall joint pain. Has no swelling in the ankles, orthopnea. No palpitations, syncope or near syncope Past Medical History • SLE follows with rheumatology • No history of MI or CAD. • stress test in 2009, negative for ischemia • echo in 2009 which showed EF 60%, no pulmonary hypertension. • Childhood asthma • Scleroderma ER admission • • • • On arrival to the emergency room, her BNP was found to be 800. D-dimer was elevated 2.21 CTA chest showed the following: • No evidence of pulmonary embolism • Cardiomegaly with congestive heart failure signs • Prominent pulmonary arteries • Probable pulmonary artery hypertension. She was admitted for evaluation. She was given 1 dose of IV Lasix Pertinent History • PAST SURGICAL HISTORY: C-section x 2 • ALLERGIES: NONE • SOCIAL HISTORY: The patient denies any tobacco or alcohol use. No caffeine use, is a homemaker, is divorced. • HOME MEDICATIONS: Gabapentin 100 mg TID Echo Conclusion 1. Dilated right ventricle, which appears thickened, also somewhat hypokinetic with evidence of paroxysmal motion of the interventricular septum secondary to pressure overload, associated with a dilated right atrium and severe pulmonary hypertension with pulmonary artery systolic pressure estimated at 97 mmHg. 2. Normal left ventricular cavity size, thickness and contractility with an ejection fraction in the 60% range. 3. Normal valvular structures. 4. No obvious masses, thrombus, vegetations or pericardial effusion. 5. Trace mitral insufficiency, mild to severe tricuspid insufficiency. 6. Trace small pericardial effusion. 7. Grade 1 diastolic impairment. The Plan • Treated with Diuretics and Steroids with some improvement in symptoms. • Transferred to the PH center for further evaluation. The real story • She presented with progressive dyspnea and near syncopal symptoms. She has a diagnosis of SLE and Scleroderma made about 5 years ago. That time she had DOE which was moderate. She has had slowly progressive dyspnea and exercise intolerance until the last 3 months, when she became unable to walk up a flight of stairs without having to stop 3 times. Prior to that time she was able to climb a flight of stairs without stopping, but had to stop and rest at the top. She also had dizziness and near syncopal episodes when bending over. She has lost 3 jobs because of her limitations, and has not been able to follow up regularly with any physicians because of loss of her insurance. She recently established with a free clinic and is able to see a Rheumatologist there. Physical Exam Findings General Appearance: Awake; alert and oriented X 3; no acute distress. Neck: supple; no JVD; no carotid bruit; JVP normal. Cardiovascular: Regular rate and rhythm, pulses normal; no rubs 1/6 HSM; normal PMI, no RV heave. Pulmonary: Decreased BS bases, good air movement, no wheezes, no rales, no rhonchi. Extremities: No edema, cyanosis, clubbing; pedal pulses and DP intact. Neurological: alert, no motor deficits and memory normal. Cath Data Clinical Testing Condition Baseline 1 50 mcg/kg/min 100 mcg/kg/min 150 mcg/kg/min SBP mmHg DBP mmHg MAP mmHg Pulse 134 93 103 73 165 87 113 88 156 78 102 103 157 70 96 103 FA O2 Sat PA O2 Sat 96 75 97 74 97 78 97 83 RA mean mmHg PCWP mean mmHg 2 3 7 7 6 3 7 2 PAS mmHg PAD mmHg PAM mmHg 93 32 55 96 33 56 101 34 60 106 35 62 CO (Fick) l/min CI (Fick) l/min/m2 3.58 2.1 3.34 2 4.06 2.4 5.74 3.4 PVR (dynes) SVR (dynes) 1162 2257 1174 2539 1123 1892 836 1240 WHATCHAWANNA DO? Which of the current therapies available today would you select for this patient? A. B. C. D. Hi ho! Hi ho! IV is the way to go. Down with Hickmans, I love subQ. Orentiram would be divine but not with wine. A little bit of this a little of that. I am a oral combination brat. E. It is the i.n.h.a.l.e. Inhaled the drug is the one for me. Social Situation • Patient has 2 daughters • One teenager • One in early 20’s – has her own apartment • Patient had mental status changes • Work up negative for any acute process • Psych evaluation- suspect Bipolar disorder, but family says this behavior is new. • Possible related to medications • Patient now states she no longer wishes to be on parenteral therapy • What prostacyclin would you now choose for the patient and why? 66 QUESTIONS & ANSWERS Thank you 67 Winner of the debate A. Kelly Chin, MD B. Jim White, MD C. It is a tie! Obtaining CME/CE credit If you would like to receive continuing education credit for this activity, please visit: http://pha.cds.pesgce.com