Safety and Efficacy of BackBeat™ Cardiac Neuromodulation Therapy (CNT™) in Patients with Hypertension: Final Results of a Double-Blind Randomized Trial Karl-Heinz Kuck, MD On behalf of coauthors: Z. Kalarus, B. Merkely, P. Neuzil, M. Grabowski, G. Marinskis, A. Erglis, J. Kazmierczak, P. Mitkowski, T. Sturmberger, F. Malek, A. Kolodzinska, D. Burkhoff, A. Sokal, L. Geller and the Moderato 2 Study Investigators Study Sponsored By: BackBeat Medical, Inc. a subsidiary of Orchestra BioMed, Inc. 1
Disclosure Statement of Financial Interest I, (Karl-Heinz Kuck, MD) DO NOT have a financial interest/arrangement or affiliation with one or more organizations that could be perceived as a real or apparent conflict of interest in the context of the subject of this presentation. 2
BackBeat ™ Cardiac Neuromodulation Therapy (CNT ™ ) • Cardiac pacing to reduce blood pressure through two mechanisms: Reduction in LV Filling (preload) to provide an acute effect Neuromodulation to maintain effect chronically (afterload) • Delivered via implantable pulse generator (IPG) using standard lead positions IPG also provides standard pacemaker functionality 3
BackBeat CNT Initial Target Population • Hypertension patients indicated for pacemaker >1M pacemaker implants globally per year >70% of pacemaker patients have hypertension • ~ 60% uncontrolled despite treatment Older, co-morbid population at increased risk of major events High rate of Isolated Systolic Hypertension (ISH) 4
MODERATO I Study • Prospective, single-arm study of 27 patients with hypertension (office BP >150 mmHg) despite two or more anti-hypertensive medications and an indication for a pacemaker Effect of BackBeat CNT on OSBP Effect of BackBeat CNT on 24-hour ASBP +12M +18M +24M +1M +3M +6M Changes in ASBP from wk3 +1 Day +1M +3M Changes in OSBP from wk4 0 0 Pre-Activation (mmHg) Pre-Activation (mmHg) -2 -5 -4 -8.3 -11.1 -6 ±17.8 ±12.6 -10.1 -10 -13.1 -14.4 P=0.011 P=0.02 ±17.9 -11.6 -15.6 -8 ±13.0 -16.1 ±15.2 P=0.003 -16.8 ±14.3 ±10.1 ±15.1 P=0.007 P<0.001 ± 16.4 -10 P<0.001 -20 P<0.001 P<0.001 P=0.006 -12 -25 -14 -16 5 Petr Neuzil, et. al. Pacemaker-Mediated Programmable Hypertension Control Therapy. J Am Heart Assoc. 2017; Dec 23;6(12): e006974. DOI: 10.1161/JAHA.117.006974
MODERATO II Study • Prospective, multi-center, randomized, double-blind study of BackBeat CNT vs. Medical Therapy (Control) 9 sites in EU Pilot study to inform the design and power of the pivotal study • Objective : to assess the efficacy and safety of BackBeat CNT in reducing blood pressure in patients with hypertension despite medical therapy who are also indicated for a pacemaker 6
MODERATO II: Study Design 6 Month Follow-Up Post-Randomization (PR) 30-day Run-In (RI) Phase Standard Pacing only (No BackBeat CNT) Continue Med Therapy Day Time ASBP Moderato with Day Time ASBP ≥130 mmHg & BackBeat CNT ≥125 mmHg @ Randomization OSBP ≥ 140 Implant Week 3 mmHg BackBeat CNT + No Continue Med Therapy Withdraw 7 100% monitoring by external CRO. Independent Blinded Event Adjudication Committee (CEC) adjudicating all AE and SAEs. Blinded independent core labs for 24-Hours ASBP, OSBP, Echo and blood tests
MODERATO II: Main Patient Selection Criteria Inclusion Exclusion 1. ≥ 18 years of age 1. Permanent atrial fibrillation or significant paroxysmal atrial fibrillation 2. Requires the implant or replacement of a dual chamber pacemaker 2. LV ejection fraction <50% 3. Stable hypertension treatment with at least 1 anti 3. Symptoms of heart failure NYHA Class II or greater hypertensive drug for >1 month 4. Stroke or TIA within 12 months 4. Average day time ambulatory systolic blood pressure 5. Hypertrophic or restrictive cardiomyopathy or interventricular (ASBP) of ≥130 mmHg and office systolic blood septal thickness ≥15 mm pressure (OSBP) ≥140 mmHg 6. Estimated Glomerular Filtration Rate (GFR) <30 ml/min/1.73m 2 7. Prior neurological events (stroke or TIA) within the past year 8. Known carotid artery disease 9. Dialysis 10. Known secondary cause of HTN 11. Average ambulatory or office systolic BP >195 mmHg 12. Cannot or is unwilling to provide informed consent 8
MODERATO II: Study Flow Screened N=196 Screen Failure* N=128 Moderato Implant N=68 Excluded End Run-in Phase Day Time ASBP<125 mmHg N=21 Included Day Time ASBP≥125 mmHg N=47 Electronic Randomization blocked by site Control BackBeat CNT N=21 N=26 1 Patient Died +6 Months +6 Months N=20 N=26 9 *50 (39%) AMBP < 130 mmHg; 34 (27%) OBP < 140 mmHg; 15 (12%) withdrew consent; 5 (4%) EF < 50%, Other reasons (18%)
Patient Demographics: No Significant Differences Between Groups p-value Control BackBeat CNT (Control vs (n=21) (n=26) BackBeat CNT) Age 74.9 ± 8.5 73.2± 9.0 0.518 Gender 15 M / 6 F 15 M / 11F 0.375 Weight (kg) 88.5 ±16.0 86.1 ±17.5 0.63 LV EF (%) 58.4 ±4.9 59.8 ±6.3 0.414 Medical History Diabetes 9 (42.9%) 12 (46.2%) 0.999 Prior Atrial Fibrillation 6 (28.6%) 5 (19.2%) 0.505 Coronary Artery Disease 9 (42.9%) 10 (38.5%) 0.775 Stroke 0 ( 0%) 1 (3.8%) 0.999 Medications 3.3±1.4 3.3±1.6 0.886 10
Patient Demographics: Blood Pressure Prior to Randomization Comparable Between Groups p-value Control BackBeat CNT Control vs (n=21) (n=26) BackBeat CNT Isolated Systolic HTN 71.4% 88.5% 0.263 Screening 24-Hr Ambulatory SBP 142.8±11.8 139.3±10.3 0.287 24-Hr Ambulatory DBP 75.2± 9.8 73.8 ±5.0 0.533 AMB Heart Rate (24H) 64.7±12.5 64.1± 8.02 0.857 Screening Office BP Office SBP 165.2±15.4 161.4±14.1 0.381 Office DBP 82.4±13.0 82.6±8.49 0.955 Office Heart Rate 63.7±16.6 64.4± 8.3 0.860 Week 3 Run-In Phase 24-Hr Ambulatory SBP 136.3±12.5 136.3±9.2 0.995 AMB DBP (24H) 72.6±6.7 74.0±6.9 0.478 AMB Heart Rate (24H) 68.4 ± 8.5 69.6±9.5 0.670 Week 4 Run-In Phase Office SBP 154.4±15.5 153.1± 15.8 0.781 Office DBP 81.6 ±12.4 83.0 ± 10.8 0.693 Office Heart Rate 66.5±10.9 67.1±12.0 0.848 11
Primary Efficacy Endpoint (ITT) 24-Hour ASBP at 6 Months Post-Randomization vs. Week 3 Run-In Primary Efficacy Endpoint met: 8.1 +/-3.0, (p=0.01) Difference in BP Reduction at 6 Months -8.1±3.0 P=0.01 Changes in 24-Hour ASBP (mmHg) -3.1 24-Hour ASBP (mmHg) ± 9.5 6 months Post- P=0.17 Week 3 Run-In Randomization BackBeat CNT 136.3 125.2 N=19 Control 136.3 132.0 - 11.1 ± 10.5 Control P < 0.001 BackBeat CNT N=26 12
Primary Safety Endpoint (ITT) MACE through 6 Months Post-Randomization Primary Safety Endpoint Met: No Difference in MACE at 6 Months 6 Month MACE* BackBeat CNT Control 21 n 26 MACE 0 (0.0%) 2 (9.5%) Control MACE Patients • Pt 1: Death as a result of disseminated adenocarcinoma. Angina pectoris leading to right coronary angioplasty and stenting • Pt 2: Worsening atrial fibrillation requiring cardioversion MACE: major cardiac adverse events [including death, heart failure, clinically significant arrhythmias (i.e., persistent or increased atrial fibrillation, serious ventricular arrhythmias), myocardial infarction, stroke and renal failure] in treatment versus control groups calculated per patient 13 *All site reported adverse events and serious adverse events adjudicated by independent clinical events committee
Office Systolic Blood Pressure (OSBP) 6 Months Post-Randomization vs. Week 4 Run-In Significant Difference Between BackBeat CNT and Control in OSBP Reduction: -12.3 +/-5.4 (p=0.02) -12.3±5.4 P=0.02 0 OSBP (mmHg) -0.1 -2 ± 21.9 6 months Post- Changes in OSBP (mmHg) Week 4 Run-In P=0.94 -4 Randomization N=20 BackBeat CNT 153.1 140.8 -6 Control 154.4 154.0 -8 -12.4 -10 ±11.7 P < 0.001 Control -12 BackBeat CNT -14 N=26 -16 -18 14
24-Hour ASBP Post-Randomization vs. Week 3 Run-In ASBP Reduction Observed at Day 1 Post-Randomization and Maintained Through 6 Months +1Day +1 Month +6 Months -6.6 -8.1 -14.1 ±3.3 ±3.1 ±3.0 P<0.001 P=0.04 P=0.01 0 +1 Month -1.5 -3.1 ± 10.1 ± 9.5 Changes in 24-Hour ASBP (mmHg) P=0.5 -5.1 P=0.17 ± 12.4 P =0.08 N=20 -5 N=19 N=21 -11.1 -11.7 ± 10.5 -10 ± 9.3 P < 0.001 P < 0.001 -15.6 N=26 N=26 ± 10.7 -15 P < 0.001 Control N=25 BackBeat CNT -20 15
BackBeat CNT Responder Analysis 6 Months Post-Randomization vs. Week 3 Run-In High Overall Response Rate to BackBeat CNT with 54% Experiencing >10 mmHg Reduction in ASBP Despite Lower Starting ASBP and High % ISH BackBeat CNT Control (n=26) (n=19) % with Increase in ASBP 15% 47% % with Reduction in ASBP 85% 53% % with >5 mmHg Reduction in ASBP 65% 42% % with >10 mmHg Reduction in ASBP 54% 21% 16
Changes in Medications Throughout the Duration of the Study Improvement in ASBP in the BackBeat CNT Group Not Driven by Increase in Medications BackBeat CNT Control n=26 n=21 Number of pts w/ changes in 3 (11.5%) 7 (33.0%) prescribed medications Increase Decrease Increase Decrease 2 (7.7%) 1 (3.8%) 5 (23.8%) 1 (4.8%) Increase = increase in dose or additional drug(s) added Decrease = decrease in dose or drug(s) removed 17
Changes in Diastolic Blood Pressure, Heart Rate and Echo at 6 Months No significant differences in Diastolic Blood Pressure, Heart Rate or Echo Parameters (EF, EDV, ESV) between BackBeat CNT and control groups 18
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