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1 Emerging Pharmacological Treatment Approaches/Novel Pathways: Strengths, Gaps, Unmet Needs Robyn J Barst Columbia University College of Physicians & Surgeons New York, NY March 12, 211 Scientific Advisory Board Actelion, Bayer Healthcare, Eli Lilly, Gilead Sciences, GlaxoSmithKline, Ikaria, Lung Rx, Medtronics, Novartis, Pfizer, United Therapeutics Speakers Bureau/Honoraria Actelion, Gilead Stock Shareholder None Disclosure Information: Other Financial or Material Support None I Dana Point PH Classification PH encompasses multiple disease subtypes II III IV V Pulmonary arterial hypertension (PAH) Pulmonary hypertension owing to left heart disease (PH-LVD) Pulmonary hypertension owing to lung diseases and/or hypoxemia (PH-COPD or PH-ILD) Chronic thromboembolic pulmonary hypertension (CTEPH) Pulmonary hypertension with unclear multifactorial mechanisms Existing treatments are indicated only for PAH PH = pulmonary hypertension PAH = pulmonary arterial hypertension PH-COPD = pulmonary hypertension with chronic obstructive pulmonary disease PH-ILD = pulmonary hypertension with interstitial lung disease Objectives: Highlight efficacy/limitations of currently available PAH drugs Introduce most recent understanding of disease mechanisms Present new molecular targets for treatment of PAH (selection of molecules from new classes of drugs) Where have we been? German physician Ernst von Romberg (1891) first pathologic description (autopsy cases) sclerosis of pulmonary arteries without underlying cardiac or pulmonary disease Poor Prognosis: NIH PPH Registry Percent survival % 56% D Alonzo et al Ann Int Med 1991 Years 46% 38% Median survival: 2.8 yrs (n=194) Pediatric pts: 1 mos 1

2 Where are we now? PAH Specific FDA-Approved Therapies Oral Bosentan - ERA Ambrisentan - ERA Sildenafil - PDE 5 inhibitor Tadalafil - PDE 5 inhibitor Continuous parenteral infusion Epoprostenol - IV prostacyclin analog Epoprostenol Generic epoprostenol RTS epoprostenol Treprostinil - IV or SC prostacyclin analog Inhaled Iloprost prostacyclin analog Treprostinil prostacyclin analog Where are we now? German physician Ernst von Romberg (1891) first pathologic description (autopsy cases) sclerosis of pulmonary arteries without underlying cardiac or pulmonary disease Coumadin - improved survival PPH Single lung transplant PPH Responders to high-dose CCB improved survival PPH IV Epoprostenol approved 21 - Oral bosentan and SC treprostinil approved 24 - Inhaled iloprost and IV treprostinil approved 25 - Oral sildenafil approved 27 - Oral ambrisentan approved 29 - Present - Oral tadalafil, inhaled treprostinil, RTS epoprostenol, generic epoprostenol and IV sildenafil approved 211 PAH Evidence-based Treatment Algorithm Oral anticoagulants (E/B) IPAH/HPAH Supportive therapy and general measures Avoid excessive physical exertion (E/A) Diuretics (E/A) Birth control (E/A) Oxygen (E/A) Psychological and social support (E/C) Digoxin (E/C) Expert referral (E/A) Infection prevention (E/A) Supervised rehabilitation (E/B) Acute vasoreactivity test (A for IPAH) (E/C for APAH) ACUTE RESPONDER NON-RESPONDER WHO Class I-IV Strength of Amlodipine, Diltiazem, Recommendation WHO Class II WHO Class III WHO Class IV Nifedipine (B) Ambrisentan, Bosentan, Ambrisentan, Bosentan, Epoprostenol IV A Sildenafil Epoprostenol IV, Iloprost inh, Sildenafil B Sitaxsentan, Tadalafil Tadalafil, Treprostinil SC Iloprost inh Sustained response C Beraprost Treprostinil SC (WHO I-II) Iloprost IV, Treprostinil IV Iloprost IV, Treprostinil IV E/B Initial combination therapy (see below) Ambrisentan, Bosentan, E/C Sildenafil, Tadalafil YES NO Approved 29 Treprostinil inh Treprostinil inh INADEQUATE CLINICAL RESPONSE Amlodipine, Diltiazem, Nifedipine (B) Sequential combination therapy Prostanoids INADEQUATE CLINICAL RESPONSE + (B) + (B) Atrial septostomy (E/B) and/or PDE-5 I + (B) ERA lung transplant (E/A) >92% Adapted Barst et al JACC 29 A Meta-analysis of Randomized Controlled Trials in Pulmonary Arterial Hypertension Where are we now? Surgical Therapies Galie et a Eur Heart J 29 Atrial septostomy 1,2 Severe right heart failure refractory to medical therapy Option when costly medical therapy not available Risk of inadequate pulmonary flow and clinically significant hypoxemia Lung transplantation 3 1, 3, and 5 year survival rates: 77%, 63%, and 54%, respectively 1 Kurzyna et al Chest 27 2 Tapson Chest 27 3 Orens Int J Clin Pract 27 the authors review the published research to assess the strengths and weaknesses of the data that support the long-term clinical benefit of current PAH therapies. The authors conclude that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence, in the form of meta-analysis and registry data, suggest that patients are living longer compared with untreated patients; the reasons are likely multi factorial. Gomberg-Maitland et al JACC 211 2

3 Five-Year Survival from PAH Diagnosis Five-Year Survival from PAH Diagnosis PAH: the State of Limbo 6% ± 2% PAH remains an incurable disease Unacceptable 5 year survival rate Clinical disease progression continues 6% ± 2% Benza et al REVEAL Registry 21 ISHLT Benza et al REVEAL Registry 21 ISHLT Mantegna 156 Where are we going? Reverse Remodeling Self-Perpetuating Nature of PAH PVR Progression Threshold Normal Range Healthy Vessel Diseased Vessel Course of the Disease 3

4 Molecular Pathogenesis of PAH: Potential Targets for Treatment Where are we going? Tyrosine kinase inhibitors Soluble guanylate cyclase agonists Serotonin transport inhibitors Prostacyclin receptor agonist Rho-kinase inhibitors Vasoactive intestinal peptide Kv channel openers Rapamycin Endothelial progenitor cells Gene transfer therapy Inhaled nitric oxide Tyrosine-kinase inhibition: Rationale Animal data imatinib (PDGF antagonist) 1 : Reversal vascular remodeling Improved hemodynamics Reduced mortality Platlet-derived growth factor (PDGF) up-regulated in PAH patients vs normal controls 2 Newman et al Circ 26 1 Schermuly et al J Clin Invest 25 2 Perros et al Am J Respir Crit Care Med 28 Platelet-derived growth factor (PDGF) and PDGF receptor (PDGFR) expression in micro-dissected pulmonary arteries from patients with severe pulmonary arterial hypertension (PAH) and from control subjects 2 Tyrosine-kinase Inhibitors Imatinib in PAH with Inadequate Response to Established Therapy Changes in Efficacy Variables at 6 mos vs BL Imatinib in a patient listed for transplant Improvement in 6MWD, hemodynamics and FC over 6 mos from start of imatinib 2 mg qd 1 24-week, randomized, double-blind, PBO-controlled pilot IPAH, HPAH, APAH-CTD or APAH-repaired CHD Symptomatic on 1 PAH therapies 18 yrs FC II IV -1 Change in Change in CO Change in PVR Change in PAPm (mmhg) (L/min) (dynes.sec.cm -5 ) 6MWD (m) n=2 n=22 n=2 n=22 n=19 n=2 n=21 n=21 P=.2 P=.21,7 25,63 22,, , Screening N=61 Imatinib 2 mg n=28 Placebo Up-titration Imatinib 4 mg n=19 Down-titration 2 mg prn Placebo n= , -3,4,4,3,2,1, , 1 Ghofrani et al NEJM 25 Ghofrani et al AJRCCM 21 n=31 Baseline Week 2 Week 24-7 P=.3 Ghofrani et al AJRCCM P=.4-5 Imatinib Placebo 4

5 control Serum [1%] Time [d] [ 3 H]-thymidine incorporation (cpm/mg) Apoptotic Cells [% per field] Translational Research Approach: TKI Imatinib Cell Culture PH Model PDGF-R upregulation in PHT patients STI571 [µm] proliferation 1 treatment with STI control STI571 [µm] apoptosis RVSP [mmhg] J Clin Invest 25 J Clin Invest 25 NEJM 25 Phase II/III MCT s.c. + STI571 (2mg/d) PVR (dyn s cm ) PDGFRβ/GAPDH ratio From Bench to Bedside.2 Donor PAH I l o p r o s t / S i l d e n a f i l / B o s e n t a n Functional Class 6-min-walk PVR Time (months) 6-min-walk (m) FC Class Soluble Guanylate Cyclase Agonists as Target in PH BAY NO NO Synthase sgc Fe(II) heme GTP - vasodilatation - anti-aggregation - anti-remodeling - RV-hypertrophy L-arginine BAY BAY / HMR1766 sgc Fe(III) heme ox. Stress GMP PDE cgmp GTP Schermuly et al Circ 26 Anti-Remodeling: Riociguat in MCT PH Model Rats 2 7 µm percentage of total vessel count Vessel muscularization N P M N P M N P M N P M MCT Riociguat + MCT MCT 21 days 35 days p <.5 versus control animals without PH; p <.5 versus untreated animals with PH at day 35. N, non-muscularized; P, partially muscularized; M, fully muscularized BAY (Riociguat) Schermuly et al ERJ 28 Effects of Riociguat on 6MWD Effects of Riociguat: Pulmonary Arterial Pressure and Pulmonary Vascular Resistance Clinical Effects: Sustained Increase in 6MWD Increase in 6MWD (12 wk vs Baseline) 6MWD PAH + 73m 6MWD CTEPH : + 65m ( 6MWD add-on: + 67m) 6MWD ALL : + 68m p<.1 ) 6MWD All (at Baseline) 354 ± 111 m Change in 6MWD [m] 6MWD = six minute walking distance PAH = pulmonary arterial hypertension CTEPH = chronic thromboembolic pulmonary hypertension p<.1 majority on 2.5 mg tid BL Duration of treatment [weeks] Titration Phase All PAH CTEPH Grimminger et al ERJ 21 Mean decrease from baseline in pulmonary arterial pressure (mmhg) n = 2 n = 3 n = 5 n = 19 n = 29 n = 48 PAH CTEPH All p <.5; p <.1 Delta SBP -7 mmhg after 12 weeks Delta HR +3 BPM 12 week vs baseline Mean decrease from baseline in pulmonary vascular resistance (dyn.s/cm 5 ) PAH CTEPH All Ghofrani et al ERJ 21 Mean change (+/- SEM) in 6MWD from baseline (m) 12-week LTE study (patients on riociguat with data at month 15) LTE assessment time point (months) N = 31 (range: at different assessment time points) All patients (N = 31) CTEPH (n = 16) PAH (n = 15) Baseline 6MWD (m) Ghofrani et al ERJ 21 5

6 Clinical Effects: Improvements in FC Next Target: Multi-kinase Inhibitors? 12-week LTE study (patients on riociguat with data at month 15) Proportion of patients (%) WHO functional class I II III IV RV/LV+S ns TPVRi, mmhg x min x ml 1 x 1g BW Start of 12-week study (baseline) Start of LTE Month 15 of LTE Number of patients (n) Ghofrani et al ERJ 21 Grimminger et al Nature Reviews 21 p=.1, p=.5 vs placebo ns. p=.7 1 mg/kg vs placebo p=.2, p=.1, p=.4 vs placebo Dahal et al AJRCCM 21 Does Every Drug Work in MCT-PH? EGFRi attenuates MCT-PH No effects in Hypoxia-PH Serotonin Transport Inhibitors No expression changes in human PAH Tryptophan hydroxylase gene expression increased in pulmonary endothelial cells in IPAH Serotonin transporter expression increased in pulmonary vascular smooth muscle cells in PAH Fluoxetine protects against MCT-PH Dahal et al AJRCCM 21 MacLean Int J Clin Pract 27 6

7 Serotonin Receptor Antagonist: Terguride - Actions: - Serotonin 5-HT 2a and 2b antagonist - Partial dopamine D 2 antagonist - Adrenergic antagonist RV/LV+S MCT induced PHT anti-proliferative anti-thrombotic and anti-fibrotic relaxation of smooth muscle cells,8,6,4,2, MCT induced PHT Control MCT 14d MCT 28d TER.4 mg TER 1.2 mg Prostacyclin Receptor Agonist Selexipag: non-prostanoid, orally active, selective prostacyclin (IP) receptor agonist Phase 2 randomized 3:1, double-blind, placebocontrolled 4 month trial N=43 adult symptomatic PAH pts on ERA and/or PDE 5 Efficacyy endpoints include: PVR, 6MWD Effects of Selexipag on PVR Phase 2 Clinical Trial (in progress) Simonneau et al 21 Simonneau et al 21 P=.45 (95% CI:-45,-12) Effects of Selexipag on 6MWD Vasoactive Intestinal Peptide Reduced VIP Expression in PAH 28 amino-acid peptide Neurotransmitter Vasodilator Inhibits airway and arterial smooth muscle proliferation VPAC-1 and 2 VIP receptors activate camp and cgmp second messengers VPAC1 and VPAC 2 receptors are upregulated in bronchiolar smooth muscle in PAH VIP is one of the most abundant, biologically active peptides in human lung PAH patients have marked reductions of VIP in serum and lung VIP a potential therapy VIP serum conc. pg/ml n=45 n=12 Simonneau et al 21 Petkov et al J Clin Invest 23 Petkov et al JCI 23 Normal PAH 7

8 Change in 6MWD with inhaled VIP in PAH Rho-kinase Inhibitors Rho-Kinase Inhibition in MCT PH Model 6MWD (m) 5 µg 4 x/d N=8 Petkov et al JCI 23 Open label uncontrolled study Guilluy et al British Journal of Pharmacology (25) Laher and Zhang Journal of Cerebral Blood Flow & Metabolism (21) Dahal et al Eur Respir J 21 Rho-Kinase Inhibition in MCT PH Model Augmentation of Kv Channels Rapamycin Hypoxia inhibits voltage-gated potassium channels (Kv) in PASMCs Opens voltage-gated calcium channels, increasing cytosolic Ca 2+ and initiating constriction 1 Kv1.5 or Kv2.1 channels down-regulated in the PASMC in hypoxic-ph rat model and in IPAH Anorexigens and serotonin block Kv channels Dichloroacetate (DCA) increases expression/function of Kv2.1 channels and decreases remodeling and PVR in hypoxic- PH rat model Clinical applications: drug-eluting coronary stents, immuno-suppression in transplantation medicine, possible role in LAM Anti-proliferative and anti-remodeling properties Rapamycin in hypoxic-ph mouse model 1 Blocks cellular proliferative response to hypoxia Decreases RVH and cardio-myocyte diameter One-way ANOVA, Newman-Keuls Multiple Comparison Test Dahal et al Eur Respir J 21 1 Post et al Am J Physiol Paddenberg et al Respir Res 27 8

9 Inhaled Nitric Oxide Inhaled Nitric Oxide Inhaled Nitric Oxide Phase 2 study 211 Endothelial Progenitor Cells Myocardial Remodeling Conclusions Pro-angiogenic cells - repair and regenerate vasculature Pilot study (N=31) in China Randomized to conventional therapy or conventional therapy plus EPC infusion Baseline and 12 week assessment 6MWD improved 42 m in EPC group vs conventional therapy alone Non-significant improvement in hemodynamics No SAEs reported PDE5 inhibitor GSK3β PI3Kα/Akt RV Hypertrophy PDE5 p38 MAPK ERK1/2 Experimental: Mouse PA-banding cardiotrophin-1/mek1 Clinical: Pulm. hypertension ERK1/2 IGF-1 p38 MAP kinase inhibitors Reverse Remodeling Tyrosine kinase Inhibitors Goals: - prevent proliferation - increase contractility - improve exercise capacity - Improve survival PAH remains incurable Current treatment based on vasodilators Improvements in symptoms, exercise capacity, and prognosis Upfront combination treatments with may offer potential Importance to lower PVR as much as possible Wang et al JACC 27 Biochem Biophys Res Commun 23; Circ Res 23; Circ Res 25 NEJM 25; Genes Dev 25; Mol Cell Biol 25 9

10 Conclusions Future treatments address proliferative pseudomalignant nature of PAH TK represents promising target to reverse remodeling sgc stimulators potential for PAH - individual dose titration - combination with PDE5i to be studied Inhaled nitric oxide Agents from new drug classes emerging: - 5-HT antagonists - Prostacyclin receptor agonists - Rho-kinase inhibitors Further out on the Horizon. Therapies targeting the RV alone Cellular cardio myoplasty via cell transplant for cardiac repair Gene Therapy First human gene therapy trial underway endothelial progenitor cells over expressing NOS 1,2 Delivery of adenoviral vectors with BMPR2 gene to vascular endothelium in PH rat model reduced cell proliferation and hypoxic pulmonary hypertension 3 Direct gene transfer into skeletal muscle and liver of rat PH model (prostacyclin synthase) 4-6 modulates pulmonary vascular response 1 Zhao et al Am J Resp Cell Mol Biol Zhao et al Circ Res 25 3 Reynolds et al Am J Physiol Lung Cell Mol Physiol 27 4 Tahara et al Hum Gene Ther 24 5 Suhara et al J Thorac Cardiovasc Surg 22 6 Ono et al Eur J Cardiothorac Surg 24 Summary Complex molecular/genetic network involved in pathobiology of PAH Potential therapies under investigation at various stages of animal/human study Difficulty in defining each individual patient s disease makes it difficult to apply therapy uniformly Future: distribution of treatment effects Individualized therapy? 1