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Vagal Blocking Treatment of Obesity & Obesity-Related Co-morbidities

Vagal Blocking Treatment of Obesity & Obesity-Related Co-morbidities. Disclosure. These clinical trials were completely funded by EnteroMedics Inc., St. Paul, MN, USA. Vagus Nerve: The Connection Between Gut and Brain. “If the gut is a ‘puppet on a string’

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Vagal Blocking Treatment of Obesity & Obesity-Related Co-morbidities

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  1. Vagal BlockingTreatment of Obesity & Obesity-Related Co-morbidities

  2. Disclosure These clinical trials were completely funded by EnteroMedics Inc., St. Paul, MN, USA

  3. Vagus Nerve: The Connection Between Gut and Brain “If the gut is a ‘puppet on a string’ controlled by the brain centers, the vagus may legitimately lay claim to being the string!” M.Camilleri, Neurogastroenterol Motil 2007; 19:333.

  4. Science Underlying Vagal Blocking • 20% of vagus nerve fibers send instructions from the brain to the gut • MOTOR • Gastric acid secretion • Digestive enzyme secretion • Gastric capacity/motility • Glucose regulation • SENSORY • Satiety (Hunger) • Satiation (Fullness) • Energy metabolism • Blood pressure regulation • 80% of vagus nerve fibers send instructions from the gut to the brain 4

  5. Neuromodulation Spectrum NeuroStimulation • Low frequency • Increasesneurophysiologic activity • NeuroBlocking • High frequency • Interrupts neurophysiologic activity • Examples: • Obesity • Obesity related Co-morbidities • Pain management Examples: • Parkinson’s Disease • Pain management • Depression • Epilepsy • Obesity

  6. Block and Recovery of Vagus NerveRodent Model Results in Controllable and Reversible Block Relative Amplitude CAP Block 1 min 3 min 4 min 5 min 2 min Baseline 10 min 15 min

  7. Block and Recovery of Pancreas: Porcine PES Model Stimulating results in 55 ml/hr1000x difference! Blocking results in 0.05 ml/hr Pancreatic Exocrine Secretion (PES)

  8. Vbloc® therapy: Targeting the Causes of Over-Eating • Hunger and Satisfaction • Suppresses appetite • Addresses mind-body link • Fullness and Decreased Food Intake • Limits gastric expansion thus reducing meal size • Delays gastric emptying for longer fullness • Energy Metabolism • Inhibits enzymes to reduce digestive efficiency • Helps normalize natural glucose production, controlling diabetes

  9. Maestro®ReChargeable System Neuroregulator • Delivers intermittent 5000 Hz pulses • Laparoscopic vagal lead placement • Subcutaneous rechargeable neuroregulator Leads Lead head

  10. Vbloc for Obesity Rationale Supported in Human Trial Significant impact on hunger and fullness drives successful weight loss Earlier Fullness and Less Hunger Reduced Portion Size Reduced Calories % EWL from Implant Earlier fullness Change from Baseline (%) Calories (kcal %) Reduced hunger Pre-implant 4 weeks 12 weeks 6 months Therapy Initiation 4 weeks 12 weeks 6 months

  11. Vbloc therapy: Ongoing RCT Studies • ReCharge (2011-2016) • Prospective, double blind, placebo controlled, randomized trial in 233 Subjects • BMI range 35 to 39.9 with co-morbidity; 40 to 45 with or without • Enrolled, completed in 2011 • Builds on previous trial learning • Uses 2ndgeneration device with internal power source, 12+ hrs therapy delivery • No charge will be delivered to vagus nerve • Efficacy endpoint greater EWL in treated vs. control (10%) and responder analysis in treated arm EMPOWER (2008-2013) • Prospective, double blind, placebo controlled randomized trial in 294 Subjects • BMI range 35 to 39.9 with co-morbidity; 40 to 45 with or without • Used 1st generation device with external power source • 3 % device or implant SAE rate, no therapy SAEs • Clinically significant weight loss was observed in patients who used the device ≥ 9 hours per day in both arms • An unanticipated therapeutic effect appeared to have been delivered to subjects in the control arm

  12. EMPOWER Trial: % EWL by Hours of Use in Treatment Group < 6hr (n = 25) 6 - 9hr (n = 61) 9 - 12hr (n = 63) >12hr (n = 16)

  13. VBLOC-DM2 Feasibility Study To evaluate effects of vagal block over 30 months on weight loss, glycemic control and blood pressure in obese subjects with type 2 Diabetes (DM2).

  14. Patients & Methods • Design: • Prospective, open-label, multi-center, 30 month trial • Cohort • 28 patients with obesity and DM - 2, 15 with hypertension • Inclusion criteria: • BMI 30 to 40 • NIDDM, <12 yrs duration • HbA1c levels 7% to 10%, inclusive • Absence of significant diabetic complications • Data collection: • EWL • Glycemic (FPG, HbA1c) • Blood pressure control

  15. Treatment Protocol • Age : 51±2 yrs , BMI: 37±1 kg/m2, 61% female • Biphasic pulses at a frequency of 5000 Hz applied to block vagal neural impulses: 5 min on / 5 min off • All patients received standard weight management counseling sessions

  16. Effect on % EWL p < 0.0001 EWL from Implant (%) 4 Wk Implant 1 Wk 6 Mo 12 Wk

  17. in HbA1c & Fasting Plasma Glucose 30 Mo Change in HbA1c (percentage points) 7.1 6.8 * 6.8 * 6.7 6.8 6.8 * * * * * * * p=.0.01 HbA1c Baseline = 7.8± 0.2% n=28 * p=.0.01 FPG Baseline = 151 ± 7 mg/dl n=28 * * * *

  18. Reductions in Elevated DBP and SBP Change in DBP and SBP (mmHg) 79 130 77 77 77 128 126 127 * 73 72 * * 123 * 72 123 * * * 118 * * * p= 0.009 Baseline = 88±2mmHg n=12 * p= 0.03 Baseline = 140±4mmHg n=8 * No change in normotensive subjects

  19. Reductions in Mean Arterial Pressure MAP (mm Hg) 93 91 91 92 88 * * 86 * 87 * * * * p= 0.04 Baseline = 100±2mmHg n=15 *

  20. Conclusions In obese subjects VBLOC Therapy was associated with: • Low SAE rate (excellent safety) • Clinically significant weight loss • Control of hunger and appetite • Reduction in calorie intake • Improvements in glycemic control in type 2 diabetics • Reductions in BP in hypertensive patients

  21. Adelaide Bariatric Centre Adelaide, SA, Australia James Toouli, MD, PhD Lilian Kow, MD, PhD Acknowledgements Mayo Clinic Rochester, Minnesota James Swain, MD Michael Sarr, MD Tufts Medical Center Boston, Massachusetts Sajani Shah, MD Scott Shikora, MD Cleveland Clinic Foundation, FL Weston, Florida Raul Rosenthal, MD Oregon Health & Science Univ. Portland, Oregon Bruce Wolfe, MD University Hospital Basel, Switzerland Henryk Zulewski, MD Daniel Frey, MD St. Olavs Hospital Trondheim, Norway Baard Kulseng, MD, PhD Gjermund Johnsen, MD, PhD Cleveland Clinic Foundation, OH Cleveland, Ohio Bipan Chand, MD University of California, Irvine Irvine, California Ninh Nguyen, MD Institute of Weight Control Sydney, Australia Roy Brancatisano, MD Anthony Brancatisano, MD, PhD University of Minnesota Minneapolis, Minnesota Sayeed Ikramuddin, MD Charles Billington, MD Scottsdale Bariatric Center Scottsdale, Arizona Robin Blackstone, MD Instituto Nacional de la Nutrición Mexico City, Mexico Miguel Herrera, MD, PhD Juan-Pablo Pantoja, MD Scripps Clinic Del Mar, California Ken Fujioka, MD Mark Takata, MD Virginia Commonwealth University Richmond, Virginia James Maher, MD Washington University School of Med St. Louis, Missouri Dominic Reeds, MD J. Christopher Eagon, MD Johns Hopkins University Baltimore, Maryland Michael Schweitzer, MD Stanford University School of Med Stanford, California John Morton, MD

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