Latest Results from Clinical Trials (MAESTRO)

Transcription

1 EuroGUCH 2018 & 11 th Advanced Symposium on ACHD Munster April 2018 Latest Results from Clinical Trials (MAESTRO) Michael A Gatzoulis Adult Congenital Heart Centre & National Centre for Pulmonary Hypertension Royal Brompton Hospital/National Heart & Lung Institute, Imperial College, London, UK

2 Disclosures Professor Gatzoulis and the Royal Brompton Hospital Adult Congenital Heart Centre & National Centre for Pulmonary Arterial Hypertension have received unrestricted education grants from Actelion UK and Global, Pfizer UK and Bayer UK and have acted as consultants for Actelion UK and Global, Pfizer UK and Global, GSK UK and Bayer UK.

3 Adults with Eisenmenger Syndrome Survival Diller et al EHJ 2006 Standardised mortality ratio 3.8; 95% CI ; p<0.0001

4 Exercise capacity in adults with CHD MVO2 and underlying diagnosis Aortic coarction Tetralogy of fallout VSD Mustard-operation Valvular disease Ebsteins anomaly Pulmonary atresia Fontan-operation ASD (late closure) cctga Complex anatomy Eisenmenger ANOVA p< Mean ± SD 28.7 ± ± ± ± ± ± ± ± ± ± ± ± Diller et al Circulation 2005

5 Peak VO2 Predicts Combined End-Point of Hospitalization or Death in ACHD Diller et al, Circulation 2005

6 Eisenmenger syndrome Cyanosis = Multi-organ disease Heamatology (secondary erythrocytosis/thrombocytopenia) Haemoptysis/thrombosis Menorrhagia Renal dysfunction Increased uric acid (less commonly gout) Cholelithiasis Scoliosis Arthropathy (osteochondrosis) Acne Systemic infection Brain abscess (focal neurology not to be confused for hyperviscosity symptoms) Arrhythmias (atrial & ventricular) Syncope/Sudden cardiac death Right heart failure (late, often ominous sign)

7 3 Months of Iron Replacement Therapy (Oral) Tay et al. Int J Card July 2010

8 Endothelin Pathway BREATHE-5: Study design Screening Bosentan 62.5 mg bid 2:1 Randomization Placebo 62.5 mg bid Bosentan 125 mg bid Placebo 125 mg bid 2 weeks 4 weeks 12 weeks Baseline 16 Weeks Galie et al for Breathe-5, Circulation 2006

9 Bosentan reduces pulmonary vascular resistance indexed 300 PVRi (dyn sec cm -5 ) Change from baseline Placebo (n=17) Bosentan (n=36) T.E. = dyn.sec.cm -5 p=0.04 Galie et al for Breathe-5, Circulation 2006

10 Bosentan increases exercise capacity 60 6MWD (m) Change from baseline Placebo (n=17) Bosentan (n=37) T.E. = 53.1 m p= Galie et al for Breathe-5, Circulation 2006

11 Bosentan increased exercise capacity mean (± SEM) Change 6MWD (m) Ex-bosentan Ex-placebo m (23.9) m (8.0) Baseline BREATHE-5 Baseline BREATHE-5 OLE End BREATHE-5 OLE

12 WHO functional class Patients (%) Change in WHO functional class (all patients in WHO FC III at baseline of BREATHE-5) 18% 82% 64% 36% 35% 65% 65% 35% Class II Class III 0 To end To end To end To end BREATHE-5 BREATHE-5 OLE BREATHE-5 BREATHE-5 OLE Ex-placebo (n = 11) Ex-bosentan (n = 26) Gatzoulis et al for Breathe-5, Int J Card 2007

13 6MWT and O 2 Sats Predict Survival in Eisenmenger 210 Brompton pts: 29 died at FU 3.3 years Predicted 3-year survival Kempny et al, Int J Cardiol 2013

14 5 Year Mortality Prediction in Eisenmenger Syndrome (n=1,098) Kempny et al Circulation 2017

15 Eisenmenger Syndrome: Survival benefits with advanced therapy (n=229) No advanced therapies Advanced therapies 40 Cumulative mortality (%) Time (years) n n Cumulative mortality (%) p = Time (years) Dimopoulos et al Circulation 2010

16 German CHD Network: ES survival (n=153) Diller et al EHJ 2016

17 Contemporary survival in Eisenmenger syndrome: Relation to functional class (n=229) Cummulative mortality (%) All FC patients Time (years) Patients at risk n n FC III-IV FC I-II Time (years) Dimopoulos et al Circulation 2010

18 Pulido et al NEJM 2013

19 Pulido et al NEJM 2013

20 Pulido et al NEJM 2013

21 Evaluation of macitentan in patients with Eisenmenger syndrome: Results from the randomised controlled MAESTRO study Michael A. Gatzoulis, Michael Landzberg, Maurice Beghetti, Rolf M. Berger, Michela Efficace, Sophie Gesang, Jian guo He, Kelly Papadakis, Tomás Pulido, Nazzareno Galiè, on behalf of the MAESTRO study investigators MAG and ML equal contribution Circulation 2018 (under review)

22 Study design Multi-centre, double-blind, randomised, Phase III study Haemodynamic sub-study performed at selected centres *Only applicable for those not enrolled in the open-label extension; All patients who completed the study were eligible to enter the open-label extension (unless they discontinued treatment due to an AE related to study drug or liver enzyme elevations)

23 Patient population ES patients aged 12 years who fulfilled the following: ES established by echocardiography (large or non-restrictive open congenital heart defect and right-to-left or bidirectional shunt) Resting SpO 2 90% and >70% Mean PAP >25 mmhg, PAWP or LVEDP 15 mmhg and PVR 800 dyn sec cm -5 to IV 6MWD of 50 to 450 m The following were permitted: at a stable dose for at least 1 month prior to randomisation (not permitted in the sub-study) (not permitted in the sub-study)

24 Study endpoints Primary: 6MWD change from baseline to Week 16 Secondary: WHO FC, Borg Dyspnoea index and quality of life change from baseline to Week 16 Exploratory: NT-proBNP at end of treatment expressed as a percent of baseline SpO 2 from change baseline to Week 16 (at rest and 0 min after 6MWT) Haemodynamic sub-study: PVRi at Week 16 expressed as a percent of baseline Mean PAP, mean RAP, Qpi/Qsi, SVRi, PVRi/SVRi and 6MWD* change from baseline to Week 16 Safety: AEs, laboratory abnormalities and decreases from baseline in SpO 2 >10% at rest *Post hoc

25 Results: Patient characteristics 226 patients were enrolled (112 placebo, 114 macitentan) 3 patients in the macitentan group prematurely discontinued treatment (2 due to AEs, 1 other) and did not complete the study 2 patients in the placebo group prematurely discontinued treatment (due to AEs) all completed the study In the sub-study, 39 patients were enrolled (19 placebo, 20 macitentan) all completed the study

26 Baseline characteristics (1) *n = 109 for placebo and 112 for macitentan Galiè N et al. Poster presentation ESC 2017; P5462.

27 Baseline characteristics (2) **Isolated atrial septal defects, isolated ventricular septal defects, or both Mostly isolated ventricular septal defects (52.7% of total), followed by isolated patent ductus arteriosus (9.7%) n = 111 for placebo and 112 for macitentan

28 Primary endpoint: Change in 6MWD at Week 16 Difference between treatment groups consistent in pre-specified subgroups (location of cardiac defect, WHO FC, geographical region, PDE-5i at baseline and Down syndrome status) *Least-squares mean difference (macitentan minus placebo) from ANCOVA model (treatment, Down syndrome and baseline WHO FC and 6MWD as covariates)

29 PRESPECIFIED SUBGROUP ANALYSES FOR THE 6MWD (MAESTRO) Results consistent across the FC groups with respect to the overall group (interaction p value not significant)

30 Secondary and endpoints No significant changes in secondary endpoints or in SpO 2 Exploratory endpoint of NT-proBNP 125 Treatment effect (95% CL):* 0.80 (0.68, 0.94) % of baseline NT-pro-BNP (95% CL) at end of treatment Placebo n=104 Macitentan n= *Ratio of geometric means (macitentan: placebo) from ANCOVA model (including treatment, cardiac defect location, and baseline value as covariates); Unadjusted geometric means (95% CL)

31 Change in PVRi at Week 16 in the *Ratio of geometric means (macitentan: placebo) from ANCOVA model (including treatment, cardiac defect location and baseline value as covariates) Unadjusted geometric means (95% CL)

32 Change in 6MWD at Week 16 in the **Least-squares mean difference (macitentan minus placebo) from ANCOVA model (treatment and baseline value as covariates)

33 Adverse events* *Up to 30 days after study treatment discontinuation; **AEs occurring in more than 5% of patients in the macitentan group

34 Other adverse events and laboratory findings of interest* *Up to 30 days after study treatment discontinuation; ALT, alanine transaminase; AST, aspartate transaminase

35 Change in 6MWD in the double-blind and open-label study (observed data)*

36 Conclusions Macitentan did not show superiority over placebo on the primary endpoint of change from baseline to Week 16 in exercise capacity in ES patients Result influenced in part by the observed placebo effect and may be related to a number of factors, inherent in the MAESTRO trial design No safety concerns with use of macitentan in ES Novel elements of the study were inclusion of patients with Down syndrome, complex cardiac defects, WHO FC II (and III-IV) and PDE-5i background therapy

37 Bosentan to Macitentan Switch (Intention to treat) Dutch Study Rationale (for Macitentan) sonce a day dose sno need for monthly LFTs sbetter tissue penetration/profile than Bosentan in pre-clinical studies Patients/Methods s40/43 pts willing to switch from a PAH- CHD cohort of 2 Dutch Units son Bosentan for a median of 7.2 yrs sstable medication for 6 months prior to switching soutcome measures 6 months after switch compared to prior 6 months: shospitalization for Heart Failure ssyncope swho Class III/IV s6-mwd/o2 Sats/Ferritin/NT-proBNP stapse Blok, et al. Int J Cardiol 2017

38 Bosentan to Macitentan Switch (Intention to treat) Dutch Study Blok, et al. Int J Cardiol 2017

39 Bosentan to Macitentan Switch (Intention to treat) Dutch Study Switch from Bosentan to Macitentan was well tolerated Blok, et al. Int J Cardiol 2017

40 Macitentan in PAH-CHD population Royal Brompton (n=39; 24 new/15 switches, FU 6.1 months) Nashat, et al Unpublished 2018

41 Advanced PAH Therapy in Eisenmenger Syndrome: A goal-oriented, pro-active approach Better Prognosis Determinants of Prognosis Worse Prognosis Post-tricuspid shunt Level of shunt Pre-tricuspid shunt Simple defect (i.e. VSD, PDA) Mild Resting O 2 saturations 85-90% Complexity of CHD Cyanosis Complex defect (i.e. single ventricle) Moderate and severe Resting O 2 saturations <85% Transferrin saturation of >20% Iron deficiency anaemia Transferrin saturation of <20% I, II NYHA functional class II, IV Slow Rate of symptoms progression Rapid No Right ventricle failure: limited value for early prognostication Yes, guarded prognosis Longer (> 400 m) 6 minute walk distance Shorter (< 300 m) BNP plasma levels <13.9 pmol/l Normal CRP levels TAPSE 1.5 cm RA area < 25 cm 2 RA/LA < 1.5 No pericardial effusion Biomarkers (BNP, CRP) Echocardiographic markers BNP plasma levels > 30 pmol/l CRP levels >10 mg/l TAPSE < 1.5 cm RA area 25 cm 2 RA/LA 1.5 Pericardial effusion RAP < 8 mmhg and RAP > 15 mmhg and CI 2.5 L/min/m 2 Baseline haemodynamic CI 2.0 L/min/m 2 Decrease in PVRi 25% Acute vasoreactivity testing Decrease in PVRi 25% Brida et al Heart 2018 (in Press)

42 PAH and/or PVD in CHD Brida et al Heart 2018 (in Press)