PIONEER-HCM Cohort B Results:

Transcription

1 PIONEER-HCM Cohort B Results: Reduction in left ventricular outflow tract gradient with mavacamten in symptomatic obstructive hypertrophic cardiomyopathy patients D Jacoby 1, S Lester 2, A Owens 3, A Wang 4, D Young 5, R Tripuraneni 5, M Semigran 5, SB Heitner 6 1 Yale School of Medicine, 2 Mayo Clinic Arizona, 3 University of Pennsylvania, 4 Duke University Medical Center, 5 MyoKardia, Inc., 6 Oregon Health & Science University Mavacamten is an investigational agent and is being developed in a collaboration between MyoKardia & Sanofi. NCT:

2 Hypertrophic Cardiomyopathy (HCM) and Mavacamten HCM is characterized by excessive myocardial contractility, left ventricular hypertrophy and reduced compliance Obstructive HCM (ohcm) occurs as a result of asymmetric LVH, abnormal MV and subvalvular apparatus, and resultant SAM-septal contact 1 Medical management is limited to drugs (e.g. β-blockers) or invasive procedures Mavacamten is an oral small molecule that modulates cardiac myosin ATPase In HCM mutant mice, mavacamten prevented hypertrophy and reduced myocyte disarray and interstitial fibrosis compared with placebo 2 1. Gersh et al. Circulation. 2011;124:e783-e Green et al. Science. 2016;351:617. 2

3 PIONEER-HCM: Study Design Starting dose No change or Dose Adjustment adjusted daily dose Washout Scr D1 W1 W2 W3 W4 W5 W6 W7 W8 W12 W16 Stress echo x x x x CPET x x Rest echo x x x x x x x x x x x x Starting Dose Dose Adjustment Algorithm Doses in Study Cohort A (n=11) 10 mg 60 kg 15 mg >60 kg Based on % decrease from baseline in LVEF 10 mg, 15 mg, 20 mg Cohort B (n=10) 2 mg Based on % decrease from baseline in resting LVOT peak gradient 2 mg, 5 mg D = day; Scr = screening; W = week. 3

4 4 PIONEER-HCM Trial Endpoints Primary Endpoint: Change in post-exercise peak LVOT gradient from baseline to Week 12 Key Secondary and Exploratory Endpoints: Proportion of patients achieving post-exercise peak gradient <30 mmhg at Week 12 Change from Week 12 to Week 16 in post-exercise peak LVOT gradient Change in LVEF from baseline to Week 12 Change in dyspnea symptom score from baseline to Week 12 Change in peak VO 2 and VE/VCO 2 from baseline to Week 12 Change in NYHA Class from baseline to Week 12 Change in N-terminal pro-b-type natriuretic peptide (NT-proBNP) from baseline to Week 12

5 Mean mmhg Mean mmhg Cohort A Results Support Adding Low-Dose Cohort B to PIONEER-HCM Key Results From Cohort A Post-Exercise LVOT Gradient Resting LVOT Gradient Cohort A (doses from mg) Mean ± SD p-value Post-exercise peak LVOT gradient, mmhg 112 ± Resting LVOT gradient, mmhg -55 ± Resting LVEF, % -16 ± Peak VO 2, ml/kg/min +3.5 ± Dyspnea numerical rating -3.1 ± NYHA Class -0.9 ± Majority of AEs were mild or moderate (98%); Most AEs (64%) were unrelated to mavacamten Heitner et al. HFSA 2017 oral presentation. *p=0.002 vs baseline. N<11 due to patient who terminated study early. Improved NYHA Class by at least 1 class in 7 of 10 patients. 5

6 Cohort A Results Support Adding Low-Dose Cohort B to PIONEER-HCM (cont) To refine the dose relationship seen in Cohort A, PIONEER-HCM was expanded via Cohort B to evaluate the effect of lower plasma concentrations Starting daily dose of 2 mg; can dose titrate to 5 mg daily Dose titration: based on percent decrease from baseline in resting LVOT peak gradient Allowed for background β-blocker therapy Heitner et al. HFSA 2017 oral presentation. *p=0.002 vs baseline. N<11 due to patient who terminated study early. Improved NYHA Class by at least 1 class in 7 of 10 patients. 6

7 Both Cohorts Enrolled Symptomatic ohcm Patients With Similar Baseline Clinical Parameters 7 Cohort A Cohort B n Age, mean (min-max), years 56 (22 70) 57 (22 71) Sex, % male NYHA Class 64% Class II; 36% Class III 50% Class II; 50% Class III Concomitant β-blockers, n (%) 0 (0) 9 (90) Parameter, mean ± SD Cohort A Cohort B Resting LVEF, % 70 ± 7 75 ± 5 Exercise LVEF, % 76 ± 8 76 ± 8 Resting LVOT gradient, mmhg 60 ± ± 63 Exercise LVOT gradient, mmhg 103 ± ± 43 Peak VO 2, ml/kg/min 20.7 ± ± 4.6

8 Post-Exercise Resting LVOT Gradient (mmhg) Mean Resting LVOT Gradient (mmhg) Cohort B Achieved Reduction in Post-Exercise Peak LVOT Gradient (1 Endpoint) and Reduced Resting LVOT Gradient W = week. N<10 for baseline. Washout Period 8

9 Resting LVEF (%) Change in Resting LVEF (Cohort B: Patient Level Data) W = week. N<10 (Weeks 1, 4, 5, 8, and 16). Mean Values Washout Period 9

10 Resting LVEF (%) Change in Resting LVEF (Cohort B: Mean Value) W = week. N<10 (Weeks 1, 4, 5, 8, and 16). Mean Values Washout Period 9

11 NYHA CLASS W = week. 11 Mavacamten Improves NYHA Functional Class (Cohort B) * (60%) 1 1 (10%) 2 5 (50%) 3 3 (30%) (70%) 3 5 (50%) 1 1 (10%) (20%) 4 Baseline W12 W16 Mean change -1.0 for W12 vs baseline; *p= subjects with 1 class improvement 1 subject with 2 class improvement 1 subject with no change Washout Period

12 Dyspnea NRS Improvement Rapid Improvement in Dyspnea Over Time (Cohort B) NRS = numeric rating scale; W = week. The length of the box represents the distance between the 25 th and 75 th percentiles The vertical lines extend to the group minimum and maximum values. 12

13 13 Improvement in Metabolic Exercise Parameters (Cohort B) Baseline Week 12 Change p-value Peak VO 2, ml/kg/min 19.4 ± ± ± VE/VCO ± ± ± Circulatory Power, mmhg ml O 2 /kg/min 2944 ± ± ± of 10 Cohort B patients had improvement in peak VO ml/kg/min 4 of these 5 were on β-blockers Similar to Cohort A, Cohort B was not powered for changes in peak VO 2

14 Cohort B Summary (2 mg, 5 mg daily doses) Enrolled 10 symptomatic ohcm patients in low-dose Cohort B 9 of the 10 patients were on background β-blocker medication Mean ± SD p-value Post-exercise peak LVOT gradient, mmhg 25.0 ± Resting LVOT gradient, mmhg ± Resting LVEF, % -5.5 ± Peak VO 2, ml/kg/min* ± Dyspnea numerical rating -3.0 ± NYHA class** -1.0 ± Patients who had background β-blocker medication had improvement in symptoms and LVOT gradient Based on 10 patients in Cohort B, the study was unable to distinguish a β-blocker effect (open-label, all patients on β-blockers were on low-dose mavacamten) Cohort B results suggest that function and symptom improvement may occur at more modest levels of peak VO 2 improvement (<3 ml/kg/min change from baseline to W12) Note: p-value reflects within-patient change from baseline and whether delta is significantly different from zero. *5 of 10 patients had 2.9 ml/kg/min improvement in pvo 2. **Improved NYHA class in 9 of 10 patients. 14

15 15 Safety Summary (Cohorts A and B) Most AEs were mild (80%) to moderate (19%) Most AEs were unrelated to mavacamten (79%) Atrial fibrillation # of Events Adverse Events ( 3 events) # Assessed related to study drug # of Patients One serious AE in Cohort A History of paroxysmal atrial fibrillation who had recurrent AF and cardioverted Patient elected to stop study drug at Week 4 Independent data monitoring committee found no safety concerns Fatigue Ventricular tachycardia Headache Dizziness URTI Ejection fraction decreased Nausea Heart rate irregular URTI = upper respiratory tract infection.

16 Provoked LVOT Gradient (mmhg) Cohorts A and B: Mavacamten Concentration vs Provoked LVOT Gradient Mavacamten Concentration (ng/ml) 16

17 PIONEER-HCM Study Summary Both Cohorts A and B in PIONEER-HCM achieved the primary endpoint of the study: a statistically significant reduction in post-exercise peak LVOT gradient Clinically meaningful reduction in provoked LVOT gradient can be achieved with doses of mavacamten, while maintaining an LVEF 50% Marked symptom improvements (NYHA functional class and dyspnea score) were observed in Cohort B (p=0.004 and p=0.008, respectively) Symptom improvement may occur at modest levels of peak VO 2 improvement (<3 ml/kg/min change from baseline to W12) Generally well-tolerated in Cohort A & B. One SAE (Cohort A) resulting in study withdrawal. Background rates of NSVT and atrial fibrillation were consistent with rates found in the literature for ohcm Patients symptoms, gradient, and LVEF tended to return to baseline values during washout period (W12-W16) Larger, longer term and placebo-controlled studies are planned to further assess efficacy and safety (EXPLORER-HCM) 17

18 18 Acknowledgments Thank you to all of the patients, caregivers, investigators & research teams Stephen B. Heitner, MD - Oregon Health and Science University Daniel Jacoby, MD - Yale School of Medicine Steven Lester, MD - Mayo Clinic Arizona Anjali Owens, MD - University of Pennsylvania Andrew Wang, MD - Duke University Medical Center Richard Bach, MD - Washington University Marty Maron, MD - Tufts Medical Center MyoKardia Team - Amy Sehnert and Brianne Leary