Medication Management and New Therapies
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H. James Ford, MD University of North Carolina
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Medication Management and New Therapies
- 1. Medication Management and New Therapies Jimmy Ford, MD Professor of Medicine Director, Pulmonary Hypertension Program University of North Carolina at Chapel Hill
- 2. In the beginning….. • Blood thinners (warfarin) • Diuretics “water pills”—furosemide, torsemide, etc • Calcium channel blockers—diltiazem, etc (usually high dose) • Oxygen
- 3. •6 MW distance improved over 16 weeks •Hemodynamics improved •Epoprostenol dose average 9 ng/kg/min •Survival improved
- 4. Gaine et al. European Respiratory Review 2017 26: 170095
- 6. PAH specific FDA-approved Therapies (in U.S.) • 8 oral therapies • Bosentan—improvements in 6MW, time to clinical worsening, functional class, hemodynamics • Ambrisentan—improvements in 6MW, time to clinical worsening, functional class • Macitentan—improvement in morbidity and mortality • Sildenafil—improvements in 6MW, functional class, hemodynamics • Tadalafil—improvements in 6MW, functional class, time to clinical worsening • Riociguat—improvement in 6MW, functional class (PAH and CTEPH) • Oral treprostinil (Orenitram) • Selexipag--improvement in morbidity and mortality • 2 parenteral therapies • Epoprostenol—improvements in survival, 6MW, hemodynamics • Treprostinil (subcutaneous also)—improvement in 6MW, hemodynamics, functional class • 2 inhaled therapies • Iloprost—improvement in 6MW, hemodynamics • Treprostinil—improvement in 6 MW, hemodynamics
- 7. IV/SC Prostacyclins • Side effects: headache, jaw pain, flushing, diarrhea, nausea and vomiting, erythroderma, thrombocytopenia (low platelets) • Complex daily preparation • Individualized dosing • Catheter complications • Dislodgement/malfunction • Deterioration potential with cessation of therapy • Thrombus (clot) • Infection EPOPROSTENOL IV Half life 2-4 min Flolan = not room temp stable, ice packs required Veletri = room temp stable TREPROSTINIL IV or SC Half life 4 hours
- 8. Inhaled treprostinil (Tyvaso) [prostacyclin] Approved 2009 Inhalation [9 breaths four times daily, via TD- 100 system] Can titrate up to 21 breaths QID TRIUMPH-1 trial: 235 patients, functional class 2-3. Randomized, double- blind. Significant change in 6MWD at week 12 versus placebo. Cough, sore throat, Flushing, nausea, vomiting, diarrhea, headache, muscle cramps. Proprietary nebulizer system required. Treatment 4 times daily. Inhaled iloprost (Ventavis) [prostacyclin] Approved 2004 Inhalation [6-9 treatments daily, via I-neb device] AIR trial: 203 patients. Randomized, double- blind. Significant change in 6MWD at week 12 versus placebo. Flushing, cough, nausea, vomiting, diarrhea, headache, muscle cramps. Proprietary nebulizer system required. Treatment 6-9 times daily. Can be used for inpatients via conventional nebulizer set up.
- 9. Oral Treprostinil • Sustained release with plasma concentrations significant over 8-10 hours (10-12 hours with high fat/calorie meal) • Unlike other PAH oral therapies, oral treprostinil dose is titrated to effect • There is no maximum FDA approved dose • Tid dosing is generally more effective than bid • Should be given with high fat meal or snack for better absorption • Typical prostacyclin side effects, particularly GI side effects
- 10. Selexipag • FDA approved up to 1600 mcg bid • Dose is started at 200 mcg bid and titrated upward to goal, typically by 200 mcg intervals, every 1-2 weeks • Typical prostanoid side effects
- 11. PDE5 inhibitors • SILDENAFIL • FDA-approved at dose of 20 mg tid • Safety • Side effects: headaches, epistaxis, hypotension (transient), GERD, dyspepsia, diarrhea, myalgia. • Nonarteritic anterior ischemic optic neuropathy • Sudden hearing loss • Drug interaction with nitrates = systemic hypotension • FDA approved dose is 20 mg tid • Higher doses often used given hemodynamic findings (80 mg tid). • improvements in PVR, CI • TADALAFIL • FDA-approved at dose of 40 mg qd • recommended to start at 20 qd in renal and hepatic dysfunction • Safety • Side effects: headaches, epistaxis, hypotension (transient), GERD, dyspepsia, diarrhea, myalgia. • Nonarteritic anterior ischemic optic neuropathy • Sudden hearing loss • Drug interaction with nitrates = systemic hypotension • Advantage once daily dosing
- 12. Riociguat • FDA approved at 2.5 mg tid • PAH and CTEPH • Similar adverse effect profile as PDE-5 inhibitors • Start at 0.5-1.0 mg tid, uptitrate every 7-14 days to goal of 2.5 mg tid
- 13. Endothelin Receptor Antagonists Drug [Class] and Date of FDA Approval Route [dosing] Key Clinical Trial Data (Group 1 PAH patients) Pertinent Adverse Effects Special Considerations Bosentan (Tracleer) [ERA] Approved 2001 Oral [62.5 mg and 125 mg tabs, dosed twice daily; 62.5 mg bid for the 1st month] BREATHE-1 trial: 213 patients. Randomized, double-blind. Significant change in 6MWD at 16 weeks relative to placebo. TTCW, hemodynamics, functional class. Potential for hepatotoxicity Teratogenicity Flushing, headache, nasopharyngitis, peripheral edema. Monthly transaminase monitoring required and pregnancy testing for women of childbearing potential. Potential for drug interactions. Ambrisentan (Letairis) [ERA] Approved 2007 Oral [5 mg and 10 mg tabs, dosed once daily] ARIES 1 (202 patients) /ARIES 2 (192 patients): functional class 2-4 patients. Randomized, double-blind. Significant change in 6MWD compared to placebo at 12 weeks. TTCW, functional class. Teratogenecity Headache, nasal congestion, peripheral edema, sinusitis. Monthly pregnancy testing for women of childbearing potential. Minimal drug interactions. Macitentan (Opsumit) [ERA] Approved 2013 Oral [10 mg tabs, Dosed once daily] SERAPHIN trial: 742 patients, functional class 2-4. 45 percent reduction in morbidity and mortality composite endpoint in the 10 mg daily treatment group vs. placebo. Teratogenecity Nasopharyngitis, headache, anemia Monthly pregnancy testing for women of childbearing potential. Minimal drug interactions.
- 14. Sitbon et al. European Respiratory Journal 2018
- 15. High dose macitentan Unisus study Inhaled SGCs MK5475 INSIGNIA PAH study Ralinepag Once daily Possibly more potent Treprostinil palmitil inhaled— longer half life = less frequent dosing NEW APPROACHES TO KNOWN PATHWAYS
- 16. Sotatercept • New mechanism acting in the activin signaling/BMP2/TGF-beta pathway--> targeting dysregulated cell growth • PULSAR study (phase 2-lowered pulmonary vascular resistance) • STELLAR study (phase 3-increased 6MWD, multiple other endpoints improved) • Two trials ongoing: • HYPERION: newly diagnosed patients • ZENITH: high risk patients (FC III/IV or high risk scores) • Hopefully will come to market after FDA approval Q1/Q2 2024
- 17. Inhaled Seralutinib • Targets abnormal vessel growth, fibrosis and inflammation • One of a class of drugs known as Tyrosine kinase inhibitors TORREY: Completed phase 2 trial of inhaled seralutinib met endpoint of reducing pulmonary vascular resistance. Main side effect was cough. PROSERA: Soon to start Phase 3 study in Group 1 PAH.
- 18. ?
- 19. HOPE! • Thank you • Please hold questions for the expert panel at then end of the session
Editor's Notes
- Lets not forget the remarkable scientific progress that has been made in the last 3 decades. Multiple therapeutic options as you know have been brought forth and are now available to patients. Here is just a graphic snapshot of all the clinical trials that have been conducted and the resultant therapeutics that are now available to patients. This is no doubt an encouraging history for a disease which knew now specific therapies only 30 years ago.
- Here is a more practical look at the different therapies we have currently available. We have to now choose a PAH therapy. This is the current PAH therapy armamentarium. These are color coded based on class of drug: Green = ERA. PAH is a state of excess ET1 relative to normal controls. These block effects of circulation ET1 on endothelial and smooth muscle cells. Purple = PDE5i. PAH is a state of deficiency of NO. These drug block PDE5 which catalyzes degradation of cGMP and thus allows it to hang around longer and exert downstream effects of vasodilation and relaxation of smooth muscle, largely by modulating cellular calcium flux. Red—SGC stimulators. Same downstream effects as PDE5i Blue-prostacyclins of various forms –PAH is a prostaglandin deficient state, excess thromboxane Yellow—PG agonist, not and exact analogue per se. Listed next to these are the clinical trial endpoints that were positively effected in clinical trials upon which each drug’s approval is based. The details of each of these drug’s administration are outside the scope of this talk, but know that epo and trep are continuous IV or SC infusions. Epo is the only drug to show clear mortality benefit. The remainder are oral therapies, apart from inhaled treprostinil (only drug available in all forms) and iloprost. Side effect management and dosing and titration of all of these therapies can be quite complicated, yet another reason why therapy decisions are made based on good data and that they are prescribed at expert centers with experience and resources to deal with complex therapy issues, not the least of which is prior auth required for every single drug. In order to determine therapy, we must first perform some type of formal or informal risk assessement. Important to know what the key measures to follow are and what goals are. Will look at this in a minute.
- Not only have we developed new therapies, but we have adapted our approach to studying new drugs as needed to meet requirements to show efficacy in new ways and enroll a population of patients that is increasingly already on treatment when they are considered for trial enrollment. The length of studies has gone from very short to quite long, and to include larger numbers of patients. The pendulum has swung back in the other direction a bit now as we are studying new pathways of treatment.