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Emerging technologies

VBLOC Therapy - a new dawn?

Therapy designed as a less intrusive weight loss procedure
No therapy-related serious adverse events
Mean EWL for the study was 33% (p<0.001) at six months

In the next few years, much needed clinical data will be published on several new technologies that could play a significant role in future treatment strategies. One such treatment is VBLOC Therapy, a treatment that uses neuroblocking technology. The Maestro System, developed by EnteroMedics, delivers VBLOC Therapy and has been implanted in 400 plus patients over five years. According to the company, the device has an excellent safety profile and is a minimally invasive physiological surgical weight loss treatment that does not alter digestive system anatomy and supports positive lifestyle, and food choices.

The second generation Maestro System received CE Mark in March of 2011 and the Company recently announced that the first patients have been implanted in the ReCharge Study, a randomised, double-blind, parallel-group, multi-centre pivotal study testing the effectiveness and safety of VBLOC Therapy, delivered via EnteroMedics’ fully implantable rechargeable Maestro System. The trial is being conducted as part of the Food and Drug Administration (FDA) Premarket Approval (PMA) process. 


The study is expected to enroll approximately 234 patients at up to 12 sites in the US and Australia. All patients in the ReCharge Study will receive an implanted device and be randomised in a 2:1 allocation to treatment or control groups. The control group will receive a functional, but non-active device that will deliver no charge to the vagus nerve during the blinded study period. All patients are expected to participate in a weight management counselling programme. The company plans to complete enrolment by the end of 2011. 


“The Maestro System is the only surgical weight loss option to affect the physiology of hunger and fullness. With this device, the patient can achieve weight loss without imposing the compromises in safety, diet and lifestyle that are associated with existing surgical procedures for obesity,” said Dr Michael Sarr, Vice Chair of Research in the Department of Surgery at Mayo Clinic, and national principal investigator of the ReCharge trial. “The ReCharge study will be an important measure of the safety and efficacy of the Maestro System in a large study population, and builds off of clinically meaningful results seen in earlier feasibility studies.”


VBLOC Therapy 


Before the availability of proton pump inhibitors (drugs that reduce the amount of gastric acid released into the stomach for persons with ulcers), surgeons routinely cut the vagus nerve near the stomach to treat ulcers. This procedure is called a “vagotomy.” For a period of time following surgery, many of the people who underwent this procedure absorbed fewer calories from fat, lost weight and had decreased appetite. Since the nervous system is adept at accommodating for, or “working around”, a complete loss of the information provided by nerves, such as the vagus nerve, VBLOC Therapy has been designed to provide intermittent blocking. This intermittent blocking effect is intended to prevent accommodation. 


VBLOC vagal blocking therapy was designed to offer bariatric surgeons and their patients a less intrusive alternative to existing surgical weight loss procedures because the existing procedures may present significant risks and alter digestive system anatomy, lifestyle and food choices. VBLOC Therapy is delivered via the Maestro System through laparoscopically implanted leads to intermittently block the vagus nerve using high-frequency, low-energy electrical impulses. VBLOC Therapy is designed to treat obesity by targeting the multiple digestive and metabolic functions under control of the vagus nerve and to affect the perception of hunger and fullness. 


The vagus nerve begins in the brain and extends to multiple organs and regions of the digestive system. Each vagus nerve trunk provides direct two-way communication between the brain and the digestive system without the additional spinal cord processing of impulses that is typical for most other human nerves. 


The vagus nerve trunks are approximately 3-4mm in diameter and course along the anterior (front) and posterior (back) of the esophagus before they branch out from the esophagus to the stomach, pancreas, duodenum and gall bladder. The mechanisms responsible for obesity and the role played by the vagus nerve are not yet fully understood, however it is known that the vagus nerve appears to play a significant role in enabling multiple mechanisms including: 


  • Expansion of the stomach as food enters. 

  • Stomach contractions that break food into smaller particles. 

  • Release of gastric acid to continue food processing. 

  • Emptying of the stomach contents into the small intestine. 

  • Secretion of digestive pancreatic enzymes that enable absorption of calories. 

  • Sensations of hunger, satisfaction or fullness.


EMPOWER 


The company has previously announced the clinical results from the Australian patient cohort of its EMPOWER pivotal study delivered via EnteroMedics first generation externally charged Maestro System and from a caloric intake study of VBLOC vagal blocking therapy using the second generation Maestro System. The data were presented at the 23rd Scientific Meeting of the Obesity Surgery Society of Australia and New Zealand (OSSANZ), in November 2010.


EMPOWER is a multi-center, randomized, double-blind, prospective, placebo-controlled pivotal study in 294 subjects at 15 centres designed to evaluate the safety and efficacy of the company’s first-generation Maestro RF System in the treatment of obesity. With this system, patients receive therapy only when they wear the external charger. In October 2009, EnteroMedics announced that the EMPOWER study did meet its safety endpoint but did not meet its comparative primary and secondary efficacy endpoints due to an unanticipated therapeutic effect in the control group. In the Australian cohort, a total of 83 subjects were enrolled at two centers, with 61 subjects implanted. Main outcome measures were morbidity, mortality and excess weight loss (EWL) at 12 months. Results include:


  • Mean 12-month EWL was 25% for the treatment group and 17% for the control group; 

  • Weight loss was linearly related to hours of device use; subjects with greater than or equal to nine hours/day use achieved 37% and 21% mean EWL (treated versus control, p=0.02); 

  • No therapy-related serious adverse events or deaths were reported across the entire study population


“Our experience with VBLOC Therapy in Australia is highly encouraging in that we see significant weight loss without compromise in patient safety,” said Dr James Toouli, Professor of Surgery at Flinders University in Adelaide, Australia, and one of the study’s investigators. “VBLOC was found to be particularly effective when therapy was delivered over longer daily durations, with EWL reaching 37% at 12-months among treatment group subjects who used the device for greater than nine hours each day. These data, along with results from other on-going studies, suggest that VBLOC Therapy may represent a uniquely safe and effective surgical option for supporting weight loss in obese patients.” 


The overall EMPOWER study results showed that all patient, on average, had clinically meaningful weight-loss, that both the treatment and control arm subjects experienced comparable, significant, dose-dependent EWL at 12 months (n=253), and that there was an unanticipated therapeutic effect in the control group. The review further suggests that patients who used the device for the prescribed amount of time (greater than or equal to nine hours) the average EWL at 12 months was 23.1% EWL (n=79) (BMI) from implant for the treatment arm and 22.6% EWL (n=49) (BMI) from implant for the control arm. Subjects that received therapy for greater than or equal to 12 hours in the treated group had a EWL of 29.5% (n=16) (BMI) from implant. In June 2011, the company reported that 107 patients to reach 30 months have achieved a EWL of 19.8%. (Table 1)


Table 1: Updated 24 month data on EWL

Visit EWL N
6 Months -17.9% 271
12 Months -16.3% 265
18 Months -17.2% 188
24 Months -19.2% 164
30 Months -19.8% 107

Interim analysis: N at 18, 24 and 30 months are ptients who have reached those time pointsand were seen for a scheduled visit

VBLOC-DM2 ENABLE Trial 


The VBLOC- DM2 ENABLE trial is an open-label, prospective, multi-centre study of the second generation Maestro System, being conducted in Australia, Mexico, Switzerland and Norway and is designed to evaluate the efficacy of VBLOC therapy in obese subjects with type 2 diabetes mellitus. The study measures average percentage EWL, HbA1c (blood sugar), FPG (fasting plasma glucose), and blood pressure at one week, one month, three, six and 12 months and possibly longer in approximately 28 subjects. There were no deaths or medically serious device related adverse events reported during the VBLOC-DM2 ENABLE trial and the safety profile is similar to that seen in the other VBLOC trials. As of June 2011, the Company reported that the patients have an average EWL of 24.6% (Table 2), greater than a one percentage point reduction in HbA1c levels at 18 months (Table 3) and significant reductions in blood pressure (Tables 4 and 5). 


Table 2: %EWL (BMI mehtod from implant, company updated data)

Visit (post-device activation) % HbA1c change N P=
Week 1 (Baseline 7.8%) -0.3 28 0.002
Week 4 (Baseline 7.8%) -0.7 28 <0.001
3 Months (Baseline 7.7%) -0.9 26 <0.001
12 Months (Baseline 7.7%) -1.0 26 <0.001
18 Months (Baseline 8.1%) -1.2 13 <0.001

% EWL for all patients (N=24) is -22.6 at 18 Months. Two patients are not currently receiving therapy for unrelated medical reasons. Interim analysis. N is patients who have reached those time points and were seen for the scheduled visit. 

Table 3: HbA1c change in percentage points (company updated data):

Visit (post-device activation) EWL (> 12 hours therapy delivery per day) N
Week 1 -9.5 25
3 Months -20.8 26
6 Months -25.2 24
12 Months -27.2 24
18 Months -24.6 22 

Table 4: Change in mean arterial pressure (MAP) in hypertensive patients (baseline 99.5mmHg, company updated data): Table 3: HbA1c change in percentage points (company updated data): 

Visit (post-device activation) MAP change (mmHg) N P=
Week 1 -6.8 15 0.04
6 Months -12.5 13 <0.001
12 Months -7.8 14 0.03
18 Months -13.0 13 0.002

Table 5: Change in diastolic blood pressure (DBP) in hypertensive patients (baseline 87.2mmHg, company updated data): 

Visit (post-device activation) DBP change (mmHg) N P=
Week 1 -10.1 12 <0.001
6 Months -13.8 10 <0.001
12 Months -10.2 11 0.009
18 Months -15.9 10 <0.001

“The Maestro System continues to demonstrate clinically meaningful weight loss results, as well as a significant effect on hypertension and diabetes, two major co-morbidities of obesity,” said Dr Mark B. Knudson, EnteroMedics’ President and Chief Executive Officer. “As our ongoing studies mature past one or more years of follow up, the Maestro System clinical findings indicate that the weight loss results are durable. We continue our efforts to bring this safe and effective treatment option to major global markets where obesity has become an epidemic, while looking ahead to the ReCharge study as part of our US commercialisation strategy.” 


Caloric Intake Study 


As part of an early VBLOC trial, satiety and caloric intake were measured for 6 months in a cohort of ten patients. Follow-up included body weights; seven day diet records assessed by a nutritionist; calorie calculations; and visual analogue scale (VAS) questions to assess satiety by seven day or 24-hour recall at the following time periods: baseline, four and 12 weeks and six months post device initiation. A validated program, Food Works, was used to determine calorie and nutrition content. Results include: 


  • • Mean EWL for the study was 33% (p<0.001) at six months; 

  • • Calorie intake decreased by 45% (p<0.001), 48% (p<0.001) and 37% (p=0.02), at four and 12 weeks and six months, respectively, from a baseline of 2,062 kcal/day; and 

  • • VAS recall data, using a repeated measures analysis, documented fullness at the beginning of meals (p=0.006) and less food consumption (p=0.02) corroborating the reduction in caloric intake. 


“Data from the EMPOWER and caloric intake studies demonstrate a clear consistency of weight loss and safety among patients with obesity using VBLOC Therapy,” said President and Chief Executive Officer Dr Mark B Knudson. “The caloric intake study in particular provides insight into the direct effects of VBLOC Therapy on diet, satiety and corresponding weight loss over a six month period. We expect that the totality of our clinical experience and the ongoing support of the Australian bariatric surgical community will contribute to our objective of commercializing the Maestro System in this major international market.” 


Commercialisation 


The company has received CE Mark for the second generation Maestro System for the treatment of obesity using VBLOC vagal blocking therapy. The Company is currently seeking Australian Therapeutic Goods Administration approval for the Maestro System and is exploring select markets in Europe. The Maestro System is still limited to investigational use in the United States. 


EnteroMedics also announced that it has entered into an exclusive, multi-year distribution agreement with Device Technologies Australia Pty Limited, a major supplier of leading edge medical equipment and consumables to hospitals and healthcare professionals in Australia and New Zealand, to commercialise and distribute the Maestro System.

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