Safety and Efficacy of BackBeat Cardiac Neuromodulation Therapy - - PowerPoint PPT Presentation

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Safety and Efficacy of BackBeat Cardiac Neuromodulation Therapy - - PowerPoint PPT Presentation

Jun 22, 2023 171 likes •394 views

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.

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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.

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SLIDE 2

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.

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SLIDE 3
  • 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

BackBeat™ Cardiac Neuromodulation Therapy (CNT™)

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SLIDE 4

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  • 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)

BackBeat CNT Initial Target Population

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SLIDE 5

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

+1 Day +1M +3M

  • 11.6

±10.1

P<0.001

  • 8.3

±12.6

P=0.02

  • 10.1

±13.0

P=0.007

Effect of BackBeat CNT on 24-hour ASBP

Changes in ASBP from wk3 Pre-Activation (mmHg)

  • 8
  • 6
  • 4
  • 2
  • 14
  • 12
  • 10
  • 16

Effect of BackBeat CNT on OSBP

+1M +3M +6M +12M +18M +24M

Changes in OSBP from wk4 Pre-Activation (mmHg)

  • 16.8

±16.4 P=0.006

  • 16.1

±15.1

P<0.001

  • 11.1

±17.8

P=0.011

  • 15.6

±14.3

P<0.001

  • 14.4

±15.2

P<0.001

  • 13.1

±17.9 P=0.003

  • 5
  • 10
  • 20
  • 25

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

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SLIDE 6

MODERATO II Study

  • Prospective, multi-center, randomized, double-blind study
  • f 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

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SLIDE 7

MODERATO II: Study Design

6 Month Follow-Up Post-Randomization (PR) Continue Med Therapy BackBeat CNT + Continue Med Therapy

Randomization Day Time ASBP ≥125 mmHg @ Week 3

Withdraw

No

30-day Run-In (RI) Phase

Standard Pacing only (No BackBeat CNT) Day Time ASBP ≥130 mmHg & OSBP ≥ 140 mmHg Moderato with BackBeat CNT Implant

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

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SLIDE 8

MODERATO II: Main Patient Selection Criteria

Inclusion Exclusion

1. ≥ 18 years of age 2. Requires the implant or replacement of a dual chamber pacemaker 3. Stable hypertension treatment with at least 1 anti hypertensive drug for >1 month 4. Average day time ambulatory systolic blood pressure (ASBP) of ≥130 mmHg and office systolic blood pressure (OSBP) ≥140 mmHg 1. Permanent atrial fibrillation or significant paroxysmal atrial fibrillation 2. LV ejection fraction <50% 3. Symptoms of heart failure NYHA Class II or greater 4. Stroke or TIA within 12 months 5. Hypertrophic or restrictive cardiomyopathy or interventricular septal thickness ≥15 mm 6. Estimated Glomerular Filtration Rate (GFR) <30 ml/min/1.73m2 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

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SLIDE 9

MODERATO II: Study Flow

Screened N=196 Moderato Implant N=68 Included Day Time ASBP≥125 mmHg N=47 BackBeat CNT N=26 +6 Months N=20 +6 Months N=26

1 Patient Died Excluded Day Time ASBP<125 mmHg N=21

Electronic Randomization blocked by site End Run-in Phase *50 (39%) AMBP < 130 mmHg; 34 (27%) OBP < 140 mmHg; 15 (12%) withdrew consent; 5 (4%) EF < 50%, Other reasons (18%)

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Screen Failure* N=128

Control N=21

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SLIDE 10

Patient Demographics:

No Significant Differences Between Groups

Control (n=21) BackBeat CNT (n=26) p-value (Control vs 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

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SLIDE 11

Patient Demographics:

Blood Pressure Prior to Randomization Comparable Between Groups

Control (n=21) BackBeat CNT (n=26) p-value Control vs 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

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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

  • 11.1

± 10.5

P < 0.001

  • 3.1

± 9.5

P=0.17

Changes in 24-Hour ASBP (mmHg)

N=19 N=26

  • 8.1±3.0

P=0.01

BackBeat CNT Control

24-Hour ASBP (mmHg)

Week 3 Run-In 6 months Post- Randomization BackBeat CNT 136.3 125.2 Control 136.3 132.0

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SLIDE 13

Primary Safety Endpoint (ITT)

MACE through 6 Months Post-Randomization

6 Month MACE* BackBeat CNT Control n 26 21 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

*All site reported adverse events and serious adverse events adjudicated by independent clinical events committee

Primary Safety Endpoint Met: No Difference in MACE at 6 Months

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

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SLIDE 14

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

  • 12.4

±11.7 P < 0.001

Changes in OSBP (mmHg)

  • 0.1

± 21.9 P=0.94

N=26 N=20

BackBeat CNT Control

  • 2
  • 4
  • 6
  • 8
  • 10
  • 12
  • 14
  • 16
  • 18

OSBP (mmHg)

Week 4 Run-In 6 months Post- Randomization BackBeat CNT 153.1 140.8 Control 154.4 154.0

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SLIDE 15

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

  • 8.1

±3.0 P=0.01

  • 15.6

± 10.7

P < 0.001

  • 11.7

± 9.3

P < 0.001

  • 11.1

± 10.5

P < 0.001

  • 1.5

± 10.1

P=0.5

  • 3.1

± 9.5

P=0.17

  • 14.1

±3.1 P<0.001

  • 6.6

±3.3 P=0.04

Changes in 24-Hour ASBP (mmHg)

N=25

N=20 N=19

N=26 N=26

N=21

+1 Month

  • 5.1

± 12.4

P =0.08

BackBeat CNT Control

  • 5
  • 10
  • 15
  • 20

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SLIDE 16

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

16 BackBeat CNT (n=26) Control (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%

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SLIDE 17

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 n=26 Control n=21

Number of pts w/ changes in prescribed medications 3 (11.5%) 7 (33.0%) 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

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SLIDE 18

Changes in Diastolic Blood Pressure, Heart Rate and Echo at 6 Months

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No significant differences in Diastolic Blood Pressure, Heart Rate or Echo Parameters (EF, EDV, ESV) between BackBeat CNT and control groups

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SLIDE 19

MODERATO II Conclusions

  • In patients with arterial hypertension and an indication for a

pacemaker, Backbeat CNT demonstrated:

 Significant reduction in mean ASBP and OSBP  No difference in MACE  No differences in diastolic blood pressure (DBP), heart rate (HR) or echo

parameters

 High responder rate in 88.5% patients with isolated systolic hypertension

(65% reduced > 5 mmHg; 54% reduced > 10 mmHg)

  • Next steps: pivotal, double-blind study to test safety and efficacy

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SLIDE 20

THANK YOU!

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SLIDE 21

Pressure overshoot indicating increased SVR Short AV pacing

180 160 140 120 100 A

Systolic BP (mmHg)

BackBeat CNT Mechanism of Action

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Utilizing Programmed Variable Pressure Patterns, BackBeat CNT Modulates ANS Response Bioelectronic Control of Ventricular Filling Immediately Reduces Blood Pressure (BP)

BackBeat CNT Activation

BP reduction activates sympathetic ANS response via natural pressure sensors (baroreceptors), driving physiologic changes that push BP back to original levels BackBeat CNT- induced neuromodulation enables immediate & sustained reduction in BP BackBeat CNT No overshoot indicating modulated ANS

180 160 140 120 100 E

Systolic BP (mmHg)