Role of Combination PAH Therapies

Transcription

1 Role of Combination PAH Therapies Ronald J. Oudiz, MD, FACP, FACC Associate Professor of Medicine, David Geffen School of Medicine at UCLA Director, Liu Center for Pulmonary Hypertension Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center at Harbor-UCLA

2 PAH Treatment History Dresdale describes PPH s - Controversy over embolic vs thrombotic - NIH registry shows natural hx. of PPH: poor outcome with conventional treatment 1980 s - Burroughs-Wellcome (Glaxo) develops synthetic PGI 2, clinical trials begin s - IV epoprostenol approved for PPH - Concerns over risk/benefit ratio arise Late 1990 s - United Therapeutics licenses vasodilator UT-15, clinical trials begin. - Pulmonary vascular disease is better-defined. - Wave of new drug trials for PH epoprostenol approved for 2 o PH (APAH) - SQ treprostinil and oral bosentan approved for IPAH and APAH IV treprostinil & inhaled iloprost approval oral sildenafil approval oral ambrisentan approval

3 PAH Drugs (FDA-approved) What can we expect from these therapies? epoprostenol treprostinil iloprost bosentan ambrisentan } prostanoids endothelin antagonists sildenafil PDE-5 5 Inhibitor

4 Median Change from Baseline in 6-Minute Walk Exercise Test at Week 12 Median Change (meters) Six Minute Walk *P< Six Minute Walk 62 Treatment: Barst RJ et al. NEJM 334: , Epoprostenol Baseline = 315 m Conventional Baseline = 270 m S.T.E.P.. Trial: Iloprost vs. Placebo FDA-Approved Walk Distance (meters) Bosentan: 6-min Walk Test (ITT) Change From Baseline to Week Placebo (n = 69) Bosentan 125 or 250 mg BID 60 (n = 144) -40 Baseline Week 4 Week 8 Week 16 Six Minute Walk mg/bid 125 or 250 mg/bid p = Mean ± SEM Six Minute Walk placebo-adjusted 50 ARIES 1: Primary Endpoint Change in 6MWD at Week mg = 51.4 m (p = ) 5 mg = 30.6 m (p = ) Change in Six-Minute Walk Distance (m) 75 Six Minute Walk STRIDE-2: Change in Six Minute Walk Distance from Baseline to Week Sitaxsentan* 100 mg Bosentan Sitaxsentan 50 mg Placebo Weeks m m m -6.5 m * p=0.03 sitaxsentan 100 mg vs. placebo; p=0.05 bosentan vs. placebo RJ Barst et al. (May, 2005). The STRIDE-2 Trial: Does Selectivity Matter in Endothelin Antagonism for PAH? Paper presented at the American Thoracic Society international conference, San Diego, CA. In Press: RJ Barst et al. JACC m Change in 6MWD (m) Six Minute Walk m -7.8 m Week 0 Week 4 Week 8 Week 12 Wilcoxon rank-sum test compared to placebo Error bars = standard error of the mean Placebo 5 mg 10 mg Oudiz RJ. Chest. 2006;130 (Suppl 1):121S.

5 SUMMARY of PAH THERAPIES FDA-approved Hemodynamic changes Six-minute walk Route RAP PAP CI PVR (mmhg / %) (mmhg / %) (L. m -1. m -1 / %) (dynes / %) Base (m) mean pl corr %chg Epoprostenol IV -2.2/-17-5/-8 0.3/15-320/ NYHA III-IV IV Treprostinil SQ -0.5/-5-2.3/ /5-3.5/ (med) 16 NYHA II-IV IV Iloprost (+bos) INH NA -6/ /13-164/ NYHA II-IV IV Bosentan PO -1.3/ /-3 0.5/21-223/ NYHA III-IV IV Sildenafil (20 mg) PO NYHA II-IV IV

6 alpha normal range 6MW 300 amb 1 amb 1 bera bos epo ilo AIR ilo STEP sild (20 mg) sitax I sitax II trep by baseline epo amb 1 amb 1 ilo AIR trep bos ilo STEP bera sild (20 mg) sitax II sitax I by magnitude trep ilo STEP sitax II bera sitax I ilo AIR bos sild (20 mg) amb 1 amb 1 epo

7 Predictors of Mortality in PH: baseline 6-minute Walk Miyamoto, et al.. AM J RESPIR CRIT CARE MED161: , 492, 2000.

8 Follow-up * 6-minute Walk - monotherapy may not be enough * after 3 months of epo Sitbon O, et al. J Am Coll Cardiol 2002;40:780-8.

9 Predictors of Mortality in PH: baseline NYHA Functional Class Sitbon O, et al. J Am Coll Cardiol 2002;40:780-8.

10 Follow-up * NYHA Functional Class - monotherapy may not be enough * after 3 months of epo Sitbon O, et al. J Am Coll Cardiol 2002;40:780-8.

11 monotherapy may not be enough Plasma BNP as a Prognostic Indicator of Mortality in Patients With PPH Baseline BNP Follow-up BNP Survival rate (%) BNP < 150 pg/ml BNP 150 pg/ml p=< Survival rate (%) BNP < 180 pg/ml p=< BNP 180 pg/ml p=< Time (months) Time (months) By multivariate analysis, higher BNP at baseline (RR = , p=0.0348) and at follow-up (RR = , p=0.0243) were independent predictors of mortality Nagaya N, et al. Circulation. 2000;102:

12 ACCP Consensus PAH Treatment Guidelines Alternative Strategy:

13 Alternative Strategy: Hit early (NYHA I,II) and Hit hard (IV prostanoids, use 2 or 3 PAH drugs) re-evaluate when stabilized

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15 Possible mechanisms operating at the cellular level to influence pathophysiology of pulmonary hypertension. Note cell surface receptors, triggers, and related factors that may be involved. (Courtesy of John H. Newman, MD)

16 Combination Therapy in PAH Theoretic benefits: Multiple pathophysiologic processes are counteracted Short-term efficacy improved Long-term survival/more reversal of disease Synergistic effects?

17 Combination Therapy in PAH Actuality: Data is limited Mostly case reports/small studies/anecdotal reports some RCTs provide basis; others may not safety and cost remain concerns (but some payors are paying already) New trials are being planned/underway

18 Evidence for combination PAH therapy

19 Bosentan added to epoprostenol

20 n = 33

21 Inhaled iloprost added to bosentan

22 STEP Trial: Iloprost added to bosentan Post-inhalation change in 6-MWD (Week 12) n = 67 Iloprost Placebo Meters Change Meters Change Walked from Baseline Walked from Baseline Baseline (m) Mean Week 12 (m) Mean m m p-value (vs. baseline) Placebo-adjusted Difference: +26 m p = McLaughlin, et al. AJRCCM 2006

23 STEP Trial: Change in NYHA Class (Week 12) Iloprost Placebo (n=32) (n=33) Change at Week 12 p-value From Baseline Improved by 1 class 11 (34%) 2 (6%) No change in class 20 (63%) 31 (91%) Worsened by 1 class 0 1 (3%) Missing 1 (3%) 0 McLaughlin, et al. AJRCCM 2006

24 STEP Trial: Time to Clinical Worsening Number with clinical worsening at 12 weeks: Iloprost: 0 (0%) Placebo: 5 (15%) p = 0.02 (Log-rank test) McLaughlin, et al. AJRCCM 2006

25 Hemodynamics at Week 12 (post-inhalation) Iloprost Placebo Percent Percent Baseline Change Change Baseline Change Change p-value +SD mpap % % <.0001 PVR % % <.0001 msap % % 0.61 HR % % 0.54 CO % % 0.82 MVO % % McLaughlin, et al. AJRCCM 2006

26 COMBI Trial: Inhaled iloprost added to bosentan (Europe, open- label, IPAH only) Trial stopped early (no apparent benefit) Hoeper et al. Eur Resp J 2006

27 Sildenafil added to IV iloprost

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29 Ghofrani, et al. Circ 2003 iloprost + sildenafil

30 Ghofrani, et al. Circ 2003 iloprost + sildenafil

31 Sildenafil added to bosentan

32 open label study; no control group n = 58 patients receiving bosentan at Hannover Medical School also receiving a prostanoid (inhaled, p.o., IV) sildenafil added in 9 pts because 6MWD < 380 and peak VO 2 < 10.4 ml min min -1 / kg mg sildenafil p.o. TID for 2 weeks 50 mg sildenafil p.o. TID as needed (see above) NYHA: III= 7, IV=2 up to 12 month assessment after sildenafil Hoeper, et al. ERJ 2004

33 Hoeper, et al. ERJ 2004

34 NYHA: III= 7, IV=2 NYHA: III=4, II=5 after months peak VO 2 increased from Hoeper, et al. ERJ ± 2.3 to 13.8 ± 1.5 ml min min -1?kg -1 6 of 9 patients achieved 6MWD > 380 and peak VO 2 > 10.4 ml min min -1?kg -1 All patients reported minor headache and flushing when sildenafil was added to bosentan; heartburn reported by one patient (resolved within a few days without dose adjustments) no hypotension, no syncope

35 Sildenafil added to treprostinil

36 656 ± 205 sec* 465 ± 167 sec *P = baseline 12 weeks Gomberg-Maitland M, et al. AJC 2005

37 Subjects were excluded if they had life expectancies of <6 months or clinically relevant concurrent medical conditions that may have interfered with the evaluation of the efficacy and safety of the medication or if they had received other investigational drugs 30 days previously Gomberg-Maitland M, et al. AJC 2005

38 Summary: Combination Therapy for PAH sildenafil bosentan epoprostenol, treprostinil, iloprost It s All Mickey Mouse or is it?

39 123 patients treated with goal-directed, combination therapy

40 Goal-directed therapy Eur Resp J. 2005

41 Goal-directed PAH therapy Eur Resp J. 2005

42 Sildenafil Add-on to Stable Epoprostenol Therapy (PACES study) 16-week study N=267, patients stable 3 months on epoprostenol At 16 weeks 7 deaths in placebo group; 0 in sildenafil group 20% 18% 16% 14% 12% 10% 8% 6% 4% 2% 0% Clinical Worsening Event at 16 Weeks Placebo Sildenafil Simonneau G. Am J Respir Med. 2007;175:A300.

43 Sildenafil Added to Epoprostenol 6MWD Change from Baseline (PACES study) Mean change from baseline (m) Sildenafil Placebo * N=267 Weeks *P< vs placebo. ITT population. Simonneau G. Am J Respir Med. 2007;175:A300.

44 Sildenafil Added to Epoprostenol Time to Clinical Worsening (PACES study) Percentage without clinical worsening event Sildenafil 40 Placebo Days from Randomization N=267 P= (stratified log rank test), ITT population. Simonneau G. Am J Respir Med. 2007;175:A300.

45 PAH Drugs in Combination n Ghofrani, et al. Circ PDE-5 + PGI Humbert, et al. (BREATHE) ERJ ERA + PGI Hoeper, et al. ERJ ERA PDE-5 PGI McLaughlin, et al (STEP) AJRCCM PGI 2 + ERA Oudiz, et al EJHF PDE-5 + ERA or Prostacyclin 14 In press - Simmonneau, et al. (PACES) PDE5 + PGI Under study - COMPASS ERA + PDE5 (phase III) - Pfizer 1243 PDE5 + ERA -TRIUMPH PGI 2 + PDE5 or ERA -AMB323 ERA + (PGI 2 and/or PDE5) -Oral Remod PGI 2 + (ERA and/or PDE5)

46 Combination Therapy: Considerations Example combo results 6-min walk distance How do you measure efficacy? Which is it? Before 3 mos Rx 1 1 year later 3 mos Rx mos Rx 2 only

47 Cardiopulmonary Exercise Testing in PAH Basis: PVR RV failure Exercise Cardiac Output V/Q mismatch CPET measures: VE/VCO 2 VO 2 VCO 2 AT Symptoms of DOE & fatigue O 2 delivery to tissues ATP regeneration lactate & CO 2 production

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49 Cardiopulmonary Exercise Testing in PAH Basis: PVR RV failure Exercise Cardiac Output V/Q mismatch CPET measures: VE/VCO 2 VO 2 VCO 2 AT Symptoms of DOE & fatigue O 2 delivery to tissues ATP regeneration lactate & CO 2 production

50 Change in Peak VO SILDENAFIL Peak VO 2 L/min P = Patients Controls months before sildenafil Change in VE/VCO 2 60 VE/VCO 2 at AT better P = Controls Patients 35 SILDENAFIL -14 months before sildenafil

51 Combination Therapy: Considerations Drug interactions: sildenafil and bosentan sildenafil increases bosentan levels bosentan decreases sildenafil levels sitaxsentan and warfarin sitaxsentan increases warfarin effect (CYP 2C9) ALL: overvasodilation

52 Combination Therapy: Considerations Costs

53 Combination Therapy: Considerations

54 Summary: Role of Combination PAH Therapies Certain combinations are at least additive, and probably safe No published guidelines exist for combining therapies Endpoints for determining response to combination Rx are unclear Goal-oriented therapy (benchmark 6MW or BNP, for ex) is coming, and will require >1 PAH Rx in at least 50% of patients Formal trials are underway which may change FDA labeling Cost and safety issues need to be worked out