Updates in Pulmonary Hypertension Pharmacotherapy. Ziad Sadik PharmD BCPS

Transcription

1 Updates in Pulmonary Hypertension Pharmacotherapy Ziad Sadik PharmD BCPS

2 Disclosure Information I have no financial relationship to disclose AND I will not discuss off label use and/or investigational use in my presentation

3 Learning Objectives 1. Describe appropriate recommendations for initial vs. sequential use of combination therapy in patients with pulmonary hypertension 2. Identify the newly approved oral pharmacotherapy and their place in therapy 3. Recognize the updates and challenges with new delivery methods of parenteral prostacyclins

4 Pulmonary Arterial Hypertension Progressive disease characterized by sustained elevations of pulmonary artery pressure (PAP) Increase in mean PAP 25 mmhg at rest (by right heart cath) Primary symptoms include dyspnea, angina and syncope Bad prognosis if left untreated (mean survival: 2.8 years) No curative treatment Treatment goals: reducing symptoms, improving QOL and survival ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. J. Am. Coll. Cardiol. 2009;53;

5 Pathways for PAH Pharmacotherapy Humbert et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation Dec 9;130(24)

6 Combination Therapy Rationale: Target multiple signaling pathways in parallel Supported by recent RCTs Using upfront combination (AMBITION) Adding another agent to stable patients (SERAPHIN, GRIPHON ) Ghofrani HA, Humbert M. The role of combination therapy in managing pulmonary arterial hypertension. Eur Respir Rev Dec;23(134):

7 Combination Therapy: Sequential vs. Upfront Traditional approach: Sequential combination therapy: Monotherapy if clinical deterioration double therapy if clinical deterioration triple therapy Even stable patients in RCTs had clinical worsening in > 40% in 3 years Growing trend/new standard: Initial combination therapy: 2 or more drugs in treatment-naïve patients Staggered initiation: short delay as to allow for adaptation of A/Es Cons: adverse effects AND cost of treatment Ghofrani HA, Humbert M. The role of combination therapy in managing pulmonary arterial hypertension. Eur Respir Rev Dec;23(134):

8 Pulmonary Hypertension Pharmacotherapy: UAE Monthly Cost Phosphodiesterase type 5 inhibitor Sildenafil (Revatio) 7,800 23,400 aed Tadalafil 1,800 aed Endothelin Receptor Antagonists Bosentan 16,700 aed Ambrisentan 15,300 aed Macitentan 14,400 aed Soluble Guanylate Cyclase Stimulator Riociguat 14,200 aed Prostacyclins / agonists Selexipag Oral 15,600 aed Iloprost INH 25,800 aed Treprostinil INJ 36,200 75,600 aed Ex of triple therapy: PDE5 inh + ERA + Treprostinil: Monthly cost per patient: 60, ,000 aed Yearly cost per patient: 700,000-1,400,000 aed UAE DOH price list. August 2018

9 Combination Therapy RCTs Sequential Combination Therapy STEP-1 Inhaled Iloprost + Bosentan 2006 PACES Epoprostenol + Sildenafil 2008 EARLY Background Therapy + Bosentan 2008 PHIRST Tadalafil + Bosentan 2009 TRIUMPH-1 Inhaled Treprostinil + Bosentan OR Sildenafil 2010 SERAPHIN Background Therapy + Macitentan 2013 PATIENT Background Therapy + Riociguat 2013 COMPASS-2 Sildenafil + Bosentan 2015 GRIPHON Background Therapy + Selexipag 2015 Initial Combination Therapy (patients naïve) BREATHE-2 Epoprostenol + Bosentan 2004 AMBITION Ambrisentan + Tadalafil 2015

10 Ambition Trial (2015): Tadalafil + Ambrisentan HR = 0.5. p<0.001 Galiè et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med Aug 27;373(9):834-44

11 Initial Double VS. Triple (recruiting) Macitentan + tadalafil +/- selexipag in treatment naïve newly diagnosed PH patients (expected Dec 2019)

12 2015 ESC/ERS Guideline: Risk Assessment Galiè et al ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. European Heart Journal (2016) 37,

13 2015 ESC/ERS Guideline and Future Directions: Choice of Initial Management x Galiè et al ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. European Heart Journal (2016) 37,

14 Recommendations for UPFRONT combination therapy Combination to avoid: synergistic hemodynamic effects Galiè et al ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. European Heart Journal (2016) 37,

15 Newly Approved Medication: Selexipag (FDA 2015; DOH 2017) Humbert et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation Dec 9;130(24)

16 Selexipag: GRIPHON Trial Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

17 GRIPHON - Methods Patients 1,156 PAH patients with NYHA FC I-IV symptoms 181 centers / 39 countries Selexipag (individualized dose: 200 mcg 1600 mcg BID) vs placebo Primary endpoint Composite of death from any cause or a complication related to pulmonary arterial hypertension up to the end of the treatment period Median follow up: 64 weeks Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

18 Methods And Population Titration schedule: 1/3 already on combination meds Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

19 GRIPHON Efficacy Endpoint HR= 0.6. P< Secondary Outcomes: Significant increase in the 6-MWD in patients on selexipag, P= Insignificant increase in WHO FC, P=0.28 Death or hospitalization due to PAH occurred in 23.5% in the placebo group and 17.8% in the selexipag group, P=0.003 Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

20 Adverse Effects: Similar to Parenteral Prostanoids Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

21 Effects Per Dose Achieved 23.1% 31.2% 42.8% Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med

22 Advances in Delivery Methods Of Prostacyclins -Implantable Pump -Disposable Pump

23 Dosing and Administration of Parenteral Prostacyclins 2 medications: Epoprostenol; Treprostinil Continuous infusion (lifelong) Dosing in ng/kg/min ; program pump in ml/hour SubQ (treprostinil ONLY) Intravenous (treprostinil and epoprostenol) Dilution Undiluted Dilute in ml CADD cassette Stability/ Refill needed 72 hours 48 h for treprostinil 24 h for epoprostenol (+/- ice packs) Pump to use CADD MS-3; I-Jet CADD Legacy pump Rounding Nearest ml/hour Nearest 0.1 ml/hour Main advantage(s) Less bulky Easier to prepare Required for advanced disease Clin Pharmacokinet Dec;55(12):

24 Adverse effects secondary to delivery system Pump malfunction. Acute interruption/dosage change decompensation IV route: catheter related infections/sepsis/thrombosis SubQ route: pain at injection site

25 Implantable Pump (IV access) Potential advantages: Decrease injection site pain/infections No programming errors from patient side Improve quality of life Pump refilled by physician (cath lab) Fix rate (adjust dose by adjusting concentration) New adjustable rate Average refills: every 3-4 weeks (or longer; based on type of pump) - Drug stability 112 days (16 weeks) Bourge et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016 Jul;150(1):27-34

26 Clinical Trials 1. DelIVery for PAH Trial (2016)- Syncrhomed II 10 US centers; 60 patients; up to 1 year follow up Needs to be stable on a dose for at least 4 weeks Catheter related complications: 0.27 vs 2.5/1000 patient-days(p<0.0001) No catheter-related bloodstream infections or occlusions occurred Plasma levels correlated with pre-implantation Decrease in device management time (0.6 vs 2.5 h/week; p<0.0001) Patient satisfaction 2. Similar results with another pump (LenusPro) patients followed for 19 [11 34] months Bourge et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016 Jul;150(1):27-34

27 Implantable Pump: New Challenges Risks with surgical placement Unable to titrate if needed except during refills Decrease in drug delivery accuracy with time Pump failure (10 % after four years of use) Bourge et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016 Jul;150(1):27-34

28 FDA Status Medtronic s SynchroMed II pump approved Dec 2017 Use of treprostinil in SynchroMED II pump approved July 31, 2018 Warning/precautions: Improper use of pumps may lead to fatal drug under/overdose Pump failure (10 % after four years of use) Patients who cannot tolerate a sudden cessation of Remodulin therapy may not be appropriate candidates Patients with hearing loss may not be able to hear pump error

29 Disposable Pump Combined With Treprostinil PF Under development PatchPump Small single-use pump (48h) Prefilled and preprogrammed Fully disposable Preservative free Potential for less injection site pain? FDA status: pending

30 References ACCF/AHA 2009 Expert Consensus Document on Pulmonary Hypertension. J. Am. Coll. Cardiol. 2009;53; Humbert et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation Dec 9;130(24) Ghofrani HA, Humbert M. The role of combination therapy in managing pulmonary arterial hypertension. Eur Respir Rev Dec;23(134): Galiè et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med Aug 27;373(9): Galiè et al ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension. European Heart Journal (2016) 37, Sitbon, et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med Kumar P et al. A Comprehensive Review of Treprostinil Pharmacokinetics via Four Routes of Administration. Clin Pharmacokinet Dec;55(12): Bourge et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016 Jul;150(1):27-34 Adams et al. The non-prostanoid IP receptor agonist, APD811 (ralinepag) has potent antiproliferative and vasorelaxant properties in human pulmonary artery. European Respiratory Journal : PA2378 Oudiz et al. Bardoxolone Methyl Evaluation in Patients with Pulmonary Arterial Hypertension (PAH) LARIAT study. Chest 2015; 184:639A