Progress in PAH. Gerald Simonneau

Transcription

1 Progress in PAH Gerald Simonneau National Reference center for Pulmonary Hypertension Bicetre University Hospital, INSERM U 999 Paris-Sud University Le Kremlin Bicêtre France

2 Clinical Classification of Pulmonary Hypertension Simonneau G, et al. J Am Coll Cardiol 2009 & 2014

3 * IV Treprosinil as 2 nd line Tx when SC not tolerated. Oral Selexipag not yet approved Drugs approved for PAH in Europe ERA dual (ET A &ET B ) ERA selective(et A ) Bosentan Ambrisentan Endothelin pathway Prostacyclin pathway Prostanoids IP receptors agonists Epoprostenol IV Epo thermostable IV Iloprost inhaled PDE-5 inhibitor sgc stimulators Sildenafil Tadalafil NO / cgmp pathway Macitentan Treprostinil SC (IV*) Riociguat Oral Selexipag

4 Progress in PAH Evolving Paradigm in the evaluation of novel therapies in PAH New approach for the use of combination therapy Development of oral drugs targeting the Prostacyclin pathway

5 1.Barst R, N Engl J Med 1996, 2.Rubin L, N Engl J Med 2002, 3. Simonneau G, Am J Crit Care Med Olchewski O N Engl J Med 2002,, 5. Galiè N, N Engl J Med 2005, 6. Galiè N, Circulation Galiè N, Circulation 2009, 8. Ghofrani H, N Engl J Med 2014 Until recently, most of RCTs have used 6 WD as the Primary E-P Primary End-point Duration Sample Size Epoprostenol (1) 6-MWD 12 Wks 81 Bosentan (2) 6-MWD 16 Wks 213 Treprostinil s.c. (3) 6-MWD 12 Wks 470 Iloprost (4) Combined E-P (6-MWD & FC) 16Wks 203 Sildenafil (5) 6-MWD 12 Wks 277 Ambrisentan (6 ) 6-MWD 12 Wks 202 & 192 Tadalafil (7) 6-MWD 16 Wks 405 Riociguat (8) 6-MWD 17 Wks 445

6 Evolving primary endpoints in PAH Trials 6-MWD 6-MWD A A simple,reproducible simple,reproducible and and valid valid tool tool to to assess assess excercise excercise capacity capacity Initially Initially thought thought 6-MWD 6-MWD was was a a reliable reliable surrogate surrogate of of outcome outcome Accepted Accepted by by regulatory regulatory authorities authorities for for registration registration of of PAH PAH drugs drugs 6-MWD -Today, there is growing evidence that 6-WD is not a reliable surrogate of outcome In addition, short-term trials are not appropriate for evaluating new drugs in a chronic and severe disease Expanding knowledge in PAH sugest to move from 6 MWD to more clinically relevant primary endpoints like morbidity and mortality in Phase III RCTs McLaughlin VV, et al. J Am Coll Cardiol 2009

7 Relationship between 6MWD and long-term outcome Evidence from the SERAPHIN trial* The relationship between 6WMD,and long-term outcome was investigated in 595 patients with available data included in the Seraphin trial* Hazard ratios were calculated to determine the association between PAH-related Death or Hospitalisation at the EOT and between all cause death up to EOS with -Baseline 6MWD -Absolute 6MWD reached at month 6 -Change in 6MWD from baseline to month 6 *Effect of Macitentan on Morbidity and Mortality in PAH Pulido T et al. New Engl J Med.2013.

8 Association between baseline 6MWD and long-term outcome R Souza et al (submitted) PAH related death or hospitalization at EOT All cause death up to EOS

9 Association between absolute 6MWD at Month 6 and long-term outcomes PAH related death or hospitalization at EOT All cause death up to EOS R Souza et al (submitted)

10 Association between change in 6MWD from baseline to Month 6 and long-term outcome R Souza et al (submitted) PAH related death or hospitalization at EOT All cause death up to EOS

11 Recent morbidity-mortality trials in PAH TRIAL Inclusion Period Maximum Follow-up Seraphin (n=742) : Primary end-point met Macitentan vs placebo 64% pre- treated with PDE5-inh or Prostanoids Griphon (n=1156) : Primary end-point met 1.5 year 3 years 3.5 years 3 years Selexipag vs placebo 80% treated with PDE5-in and or ERA Ambition (n=605) : Primary end-point met 3.8 years 3 years Ambrisentan+Tadalafil vs monotherapy 11

12 Seraphin: Study design Multicentre, double-blind, randomised, placebocontrolled event-driven, phase III clinical trial Macitentan 10 mg Screening 28 days Randomisation May Dec 2009 Macitentan 3 mg Placebo Variable double-blind treatment duration (event-driven) End of study (EOS; 285 events) March 2012 investigating long-term benefits of macitentan in PAH patients with a novel and robust endpoint, measuring time to the first morbidity or mortality Pulido T, et al. N Engl J Med 2013; 369:

13 Seraphin : Morbidity and mortality primary endpoint worsening of PAH or Decrease in 6MWD o f at least 15%, confirmed by a 2nd test on a different day Time to first morbidity or mortality event Initiation of i.v. or s.c. prostanoids. or Atrial septostomy or AND Worsening of PAH symptoms AND Need for new PAH treatment All events adjudicated by a blinded independent committee Lung transplantation or All-cause death Pulido T, et al. N Engl J Med

14 Primary endpoint: Time to the first morbidity and mortality event Patients without the event (%) Risk reduction of primary endpoint event vs placebo Macitentan 10 mg: 45% Placebo Treatment difference Patients at risk Time from treatment start (months) Macitentan 10 mg Placebo 10 mg Hazard ratio (HR) 0.55 Log-rank p-value < Pulido T, et al. N Engl J Med 2013.

15 SERAPHIN :Different components of the morbiditymortality 1st end-point Placebo n = 250 Macitentan 10 mg n = 242 Patients with an event n (%) 116 (46.4) 76 (31.4) Type of the 1st event, n (%) PAH worsening 93 (37.2) 59 (24.4) Initiation of Prostanoids 6 (2.4) 1 (0.4) Deaths All causes 17 (6.8) 16 (6.6) Pulido T, et al. N Engl J Med 2013

16 Death as first event in morbidity-mortality trials -PAH is a progressive disease and death is generally preceded by a clinical deterioration - Sudden death is rare especially in Functional Class II or III patients - Sudden death is relatively more frequent in class IV unstable patients, but this population is excluded from current RCTs

17 Seraphin : All causes of deaths at the EOT Patients with an event (%) All causes of deaths: 36% Risk Reduction (p = 0,20) Placebo Macitentan 10 mg Patients with an event (%) Deaths due to PAH 56% Risk Reduction (p = 0,07) 6 Placebo Macitentan 10 mg (months) (months) Pulido T, et al. N Engl J Med 2013; Suppl.

18 Summary (1) Until now, changes in 6MWD have served as primary E-P in pivotal RCTs of PAH Today, >10 drugs are currently approved in PAH. So, the level of requirement for the approval of new drugs need to be markedly increased PAH is a chronic life-threatening disease and recent proceedings and guidelines support the use of long-term outcome studies to assess the effects of novel therapies on disease progression

19 Summary (2) Since PAH is a progressive disease, death is rarely the first recorded event and generally preceded by a clinical deteriorarion In morbidity- mortality trials the treatment effect for the primary end-point is mainly driven by the rates of worsening events In Seraphin, when death is analyzed at the EOT or EOS there were trends toward risk reduction of deaths with macitentan 10 mg With Seraphin,Griphon and Ambition trials, we are entering a new era for drug evaluation in PAH

20 Progress in PAH Evolving Paradigm in the evaluation of novel therapies in PAH New approach for the use of combination therapy Development of oral drugs targeting the Prostacyclin pathway

21 Rationale for combination therapy Malignant nature of PAH requires more aggressive approach Successfully used in chronic heart failure, HIV, cancer Combination therapy PAH pathogenesis: several pathways are involved Potential for synergistic effects Sequential or up-front?

22 Sequential combination therapy in PAH Background therapy Added therapy Patients (n) Study duration Primary endpoint Primary EP met STEP 1 Bosentan Iloprost weeks 6MWD No PACES 2 Epoprostenol Sildenafil weeks 6MWD Yes PHIRST 3 Naïve or bosentan Tadalafil 405 (206) 16 weeks 6MWD Yes NO TRIUMPH-1 4 Bosentan or sildenafil Treprostinil (inhaled) weeks 6MWD Yes FREEDOM-C 5 Bosentan and/or sildenafil Treprostinil (oral) weeks 6MWD No FREEDOM- C2 6 Bosentan and/or sildenafil Treprostinil (oral) weeks 6MWD No IMPRES 9 2 drugs Imatinib weeks 6MWD Yes SERAPHIN 7 Naïve or sildenafil Macitentan weeks Morbimortality Yes (10 mg) PATENT 8 Naïve or ERA Riociguat weeks 6MWD Yes

23 Patent Study:Patients characteristics A Ghofrani et al New Engl J Med 2013

24 Patent Study:Primary endpoint (6MWD) A Ghofrani et al New Engl J Med 2013

25 Seraphin Syudy:Demographics and baseline characteristics All patients n=742 Placebo n=250 Macitentan 3 mg n=250 Macitentan 10 mg n=242 Female sex, % Age, years, mean ± SD 45.6 ± ± ± ± 15.0 Time from diagnosis, years, mean ± SD 2.7 ± ± ± ± 3.6 6MWD, m, mean ± SD 360 ± ± ± ± 93 WHO FC, % I/II III/IV Background PAH therapy, % PDE-5 inhibitors Oral/inhaled prostanoids

26 Morbidity and mortality in patients not on background PAH therapy 100 Patients without the event (%) Macitentan 10 mg (n=88) Risk reduction of primary endpoint event vs placebo Macitentan 10 mg: 55% 0 0 Placebo (n=96) Time from treatment start (months) Macitentan 10 mg: Hazard ratio = 0.45; log-rank p =

27 Morbidity and mortality in patients on background PAH therapy 100 Patients without the event (%) Macitentan 10 mg (n=154) Risk reduction of primary endpoint event vs placebo Macitentan 10 mg: 38% 0 0 Placebo (n=154) Time from treatment start (months) Macitentan 10 mg: Hazard ratio=0.62; log-rank p=0.0094

28 PAH paradigm the next regimen? Current Dogma 2 drugs regimen Sequential approach Alternative Approach Upfront combination combining 2 or 3 Drugs

29 Placebo + Epoprostenol (n=10) 0 Bosentan +Epoprostenol (n=19) 0 % change in PVR Baseline Week 16 Baseline Week 16

30 Effect of up-front combination therapy : bosentan & epoprostenol Epoprostenol + bosentan (n = 23) p = Epoprostenol monotherapy (n = 46) -48 ± 17% -29 ± 17% Baseline 4 months Baseline4 months Cumulative survival (%) Epoprostenol + bosentan (n = 23) p = 0.07 Epoprostenol (n = 46) Time (months) Kemp K, et al. J Heart Lung Transpl 2012

31 Upfront triple combination therapy: Effect on haemodynamics Upfront triple combo therapy: i.v. epoprostenol + bosentan + sildenafil 19 incident (i.e. newly diagnosed) patients with Idiopathic (n=9) or Heritable (n=10) PAH Mean age 39 ± 14 years (18 63) NYHA FC III (n=8) or IV (n=11) Severe haemodynamics: CI < 2.0 L/min/m 2 or PVR > 1000 d.s.cm -5 Sitbon O, et al. Eur Respir J. 2014;43:

32 Upfront triple combination therapy: Effect on FC and 6MWD Prospective, observational analysis of idiopathic or heritable PAH patients (n = 19) treated with upfront combination therapy (epoprostenol, bosentan and sildenafil) * * ** # # # 32 ± 19 months *p < 0.01 versus baseline; ** p < 0.01 versus 4 months Sitbon O, et al. Eur Respir J. 2014;43:

33 Upfront triple combination therapy: Effect on haemodynamics mpap (mmhg) Baseline Month 4 Final follow-up # RAP (mmhg) 11.9 ± ± 4.9* 5.2 ± 3.5* mpap (mmhg) 65.8 ± ± 14.0* 44.4 ± 13.4* CI (l/min/m 2 ) 1.66 ± ± 0.69* 3.64 ± 0.65* PVR (d.s.cm -5 ) 1718 ± ± 260* 492 ± 209* # 32 ± 19 months *p < 0.01 versus baseline Sitbon O, et al. Eur Respir J. 2014;43:

34 Upfront triple combination therapy: Long-term outcome / survival Long-term follow-up (n=18) Median follow-up: 39.2 months (range: months) All patients well and alive in NYHA FC I-II 6 patients with mpap < 30 mmhg (incl. one < 20 mmhg) Survival (n=19) 1-year 2-year 3-year Actual 100% 100% 100% Transplant-free 94% 94% 94% Expected* [95% CI] 75% [68%-82%] 60% [50%-70%] * according to the French equation (Humbert M, et al. Eur Respir J 2010) 49% [38%-60%] Sitbon O, et al. Eur Respir J. 2014;43:

35 Upfront triple combination therapy Epoprostenol monotherapy (n=46) Epoprostenol + bosentan combination therapy (n=23) Epo + bosentan + sildenafil combination therapy (n=18) PVR (d.s.cm -5 ) PVR (d.s.cm -5 ) diapo trithérapie à compléter Baseline 4-mo. 0 Baseline 4-mo. Baseline 4-mo. -29 ± 17% -48 ± 17% - 69 ± 8% Kemp K, et al. J Heart Lung Transplant 2012;31: Sitbon O, et al. Eur Respir J. 2014;43:

36 Initial dual oral combination therapy in PAH Experience from the French Reference Center 52 incident (i.e. newly diagnosed) patients with PAH Mean age 54 ± 18 years, F : M 37 : 15 Initial dual combination therapy with ERA (bosentan or ambrisentan) and PDE5 inhibitors (sildenafil or tadalafil) 80% receiving the up-front treatment with bosentan and PDE5 inhibitors

37 Initial dual oral combination therapy in PAH Baseline First reassessment* RAP (mmhg) 9.6 ± ± 4.9 mpap (mmhg) 55.0 ± ± 12.1 PAWP (mmhg) 8.7 ± ± 4.3 CO (L/min) 3.96 ± ± 1.76 CI (L/min/m 2 ) 2.20 ± ± 0.76 PVR (dyn.s.cm -5 ) 1076 ± ± 292 Mean blood pressure (mmhg) 98.8 ± ± 13.4 Heart rate (bpm) 91 ± ± 11 SvO 2, % 58.6 ± ± 8.2 *median 4.1 months [IQR: ]

38 Initial dual oral combination therapy in PAH Baseline First reassessment* NYHA FC (UNK : I-II : III : IV), n Clinical signs of RHF, n 1 : 5 : 38 : 8 2 : 29 : 19 : 2 29 (56%) 14 (27%) 6MWD, m 312 ± ± 111 Borg Dyspna Index 4.1 ± ± 1.7 *median 4.1 months [IQR: ]

39 1. Humbert M, et al. Eur Respir J Initial dual oral combination therapy in PAH Actual survival compared to expected survival according to the French equation 1 Patients, at risk (n)

40 The AMBITION trial A randomised, multicenter study of first-line AMBrIsentan and Tadalafil combination therapy in subjects with pulmonary arterial hypertension To compare 2 treatment strategies in treatment-naïve patients: Upfront combination therapy (ambrisentan AND tadalafil) vs Monotherapy (ambrisentan OR tadalafil) Event-driven trial Primary objective : time to clinical failure Secondary objectives: change from baseline to week 24 in NT-pro-BNP; Percentage of subjects with satisfactory clinical response; 6MWD; FC; Borg score; safety and tolerability GSK Press Release 8 September 2014

41 Ambition Sudy : Drugs titration 41

42 AMBITION:Results First-line treatment of PAH with the combination of ambrisentan 10 mg and tadalafil 40 mg reduced the risk of clinical failure by 50% compared to pooled ambrisentan and tadalafil monotherapy arm (hazard ratio = 0.502; p=0.0002). Consistent efficacy findings across key subgroups (NYHA FC II and III) Hospitalisation for worsening of PAH was the main component of the primary endpoint The combination was also statistically significant vs the individual ambrisentan and tadalafil monotherapy groups for the primary endpoint. GSK Press Release 8 September 2014

43 Combination Therapy: Summary There is growing evidence that combination of drugs targeting different pathophysiologic pathways is effective and safe in PAH either as sequential or up-front Up-front combination therapy appears to be superior to initial treatment with monotherapy The superiority of up-front combination therapy versus optimized sequential combination therapy remains to be demonstrated

44 Progress in PAH Evolving Paradigm in the evaluation of novel therapies in PAH New approach for the use of combination therapy Development of oral drugs targeting the Prostacyclin pathway

45 Dugs approved for PAH in Europe Prostacyclin pathway Epoprostenol IV Epo thermostable IV Iloprost inhaled Treprostinil SC (IV*) Oral Selexipag

46 Oral Treprostinil Phase III Studies Treprostinil is a stable prostacyclin analogue available for continuous SC or IV administration (only if too many side effects with SC form), and for inhalation (only in the US). Oral form of treprostinil has been developed Phase 3 studies with oral treprostinil FREEDOM-M FREEDOM-C FREEDOM-C2

47 FREEDOM-C1 and C2: Negative results FREEDOM-C1 FREEDOM-C2 Tapson et al. Chest. 2012;142: Tapson et al. Chest. 2013;144:952-8.

48 FREEDOM-M: 6MWD Median treatment effect on 6MWD (m) Hodges-Lehmann estimate of treatment effect by visit n=228* P= P= P=0.013 P=0.065 Mean dose, mg BID 2.3 ± ± 1.9 * all the secodary end-points are negative Jing et al. Circulation. 2013;127:

49 Selexipag: First in class oral non-prostanoid IP receptor agonist ACT987 (drug) MRE-269 (major metabolite) N O O O O S N N N H Hydrolysis N N N O O OH ACT987 Orally available diphenylpyrazine derivative MRE-269 Potent and highly selective prostacyclin receptor agonist Kuwano K, et al. J Pharmacol Exp Ther 2007; 326:

50 Selexipag phase II trial Objective of phase II proof-of-concept study: To assess the efficacy, safety and tolerability of selexipag in PAH patients Maximum allowed doe of 800 µg bid

51 Selexipag phase II: Significant reduction in PVR Per protocol analysis ITT analysis % of baseline PVR at Week 17 [95% CL] (geometric means) Placebo n = 6 Treatment effect: 30.3% (95% CL: 44.7, 12.2; p = ) Selexipag n = 29 % of baseline PVR at Week 17 [95% CL] (geometric means) Placebo n = 10 Treatment effect: 33.0% (95% CL: 47.0, 15.2; p = ) Selexipag n = 32 Simonneau G, et al. Eur Respir J 2012; 40:

52 Selexipag (ACT ) in Pulmonary Arterial Hypertension GRIPHON trial GRIPHON: ProstaGlandin I 2 Receptor agonist In Pulmonary arterial HypertensiON Large, international, multicenter, long-term phase 3 study Double-blind, placebo-controlled study assessing the safety and efficacy of selexipag on morbidity and mortality in patients with PAH Event-driven study Primary outcome measure: Time to first adjudicated morbidity or mortality event (up to 7 days after last studydrug intake) NCT :

53 GRIPHON trial results 1156 PAH adult patients included and treated for up to 4.3 years. 80% on background treatment with ERA and/or PDE-5i Uptitration of selexipag allows each patient's maintenance dose to be individualized based on tolerability (to a maximum of 1600 mcg bid)

54 GRIPHON trial Main results Main result: selexipag reduced the risk of a morbidity or mortality event vs placebo by 39% (p<0.0001) Consistent efficacy findings across subgroups (different doses / etiologies / treatment naïve or on background therapy ) The most common AEs that occurred with higher frequency on selexipag than placebo were in-line with those known in PGI 2 therapies: Actelion press release, 16 June 2014.

55 Lessons from oral prostanoids Targeting prostacyclin signalling pathway is of major importance in PAH. While prostacyclin analogues have good efficacy in PAH, their delivery systems have many limitations. First experiences with oral prostacyclin analogue (beraprost, treprostinil) are quite desapointing due to minor efficacy and importance of adverse effects. The first in class oral non-prostanoid IP receptor agonist selexipag has been shown to reduce morbidity and mortality events in an event-driven long-term study.