Endoscopic application of pulsed electric fields by the Endogenex system® for duodenal Mucosal regeneration for elimination of INsulin in the treatmENT of type 2 diabetes: a first in human safety, feasibility and efficacy study

Metabolic syndrome is a cluster of conditions that are associated with insulin
resistance, hyperinsulinemia and type 2 diabetes (T2D). Pathophysiological
conditions characterized by insulin resistance and hyperinsulinemia can lead to
several, often overlapping, metabolic disease, including T2D, non-alcoholic
fatty liver disease (NAFLD), cardiovascular disease and polycystic ovarian
disease. (1, 2)

T2D is managed by lifestyle interventions and a variety of pharmacological
agents (3). Nevertheless, only 50% of T2D patients achieve their treatment
targets (4). For many patients, exogenous insulin administration remains the
final treatment option to manage their hyperglycemia. (5, 6) However this
approach does not treat the root phenomenon of the disease, i.e., insulin
resistance, and the resulting hyperinsulinemia contributes to weight gain and
further deterioration of the patients metabolic health. (5)

T2D can, however, be effectively treated by bariatric surgery. Patients
undergoing Roux-en-Y gastric bypass surgery demonstrate major improvements in
glycaemic control and metabolic and cardiovascular health, which occur
virtually immediately after surgery and well before any significant weight loss
is established.(7) Reintroduction of nutrients into the bypassed duodenal limb
quickly returns patients to their previous dysmetabolic state, highlighting the
importance of the duodenum in the insulin-sensitizing effect of bariatric
surgery and in the pathogenesis of the metabolic syndrome.

The important role of the duodenal mucosa is highlighted by specific endoscopic
procedures to treat T2D and concomitant metabolic diseases. In a recent
published European multicenter study that examined patients with sub-optimally
controlled T2D (using oral glucose-lowering medication), a single duodenal
mucosal resurfacing (DMR) procedure entailing hydrothermal ablation of the
duodenal mucosa, elicited a substantial improvement glycaemia, insulin
resistance, and liver transaminases at 12 and 24 months post-procedure.(8) A
subsequent one-armed pilot study found that 69% (11/16) of formerly
insulin-dependent T2D patients, had adequate glycemic control 6 months after
their insulin was replaced by a single DMR, GLP-1 RA and lifestyle counselling.
Moreover, the patients that were adequately controlled, experienced improved
glycemic and metabolic health, as reflected by significant decreases in HbA1c,
HOMA-IR and weight and liver fat %. (9) These studies strongly suggest that
regeneration of duodenal mucosa improves insulin sensitivity and glycaemic
regulation similar to bariatric surgery but trough a less invasive
procedure.(8, 10) However, the handling of the Revita system is very
challenging and the procedure is time consuming, which makes upscaling of this
procedure difficult. Moreover, the use of a balloon in the DMR technique causes
*patched* ablation areas, which possibly impedes the efficacy of DMR.
Overlapping ablations, or ablations of non-lifted duodenal mucosa, have shown
to be risk factors for a post-procedural duodenal stenosis.

Pulse Electric Field (PEF) duodenal mucosal regeneration (DMR) is a minimally
invasive endoscopic procedure that uses the Endogenex device (Endogenex Inc.,
Plymouth, MN, USA) to deliver PEF to the duodenum. The treatment is non-thermal
and does not require mucosal lifting for protecting submucosal tissue. This The
system uses a through-the-scope design that greatly improves technical
feasibility and will reduce procedure time. PEF induces mucosal renewal via
cell apoptosis and subsequent rapid regeneration. Data from animal and clinical
studies using thermally induced DMR suggest that this is followed by an
insulin-sensitizing effect that resembles the metabolic improvements after
bariatric surgery. PEF-induced DMR may allow for a more complete ablation with
regards to the mucosal area treated and a more controlled ablation with regards
to the depth of ablation minimizing the risk of damaging the deeper layers of
the duodenal wall (i.e. deep submucosa and muscularis propria).

In addition, PEF-DMR uses another type of energy, e.g. electroporation, that
might restore sympathovagal balance. Many studies have shown a functional
gut-brain axis in which gut-derived peptides, microbiota, metabolites, and
neuronal feedback inform the brain about energy status and then elicit an
appropriate feeding and metabolic response. (11)It is thought that the gut
brain-axis modulates central control of food intake and metabolism specifically
via the production of short-chain fatty acid butyrate. Oral butyrate
supplementation affected sympathestic tone and intestinal transit times as well
as physical activity and reduced liver fat in mice before. (11)Therefore,
PEF-DMR could result in even bigger changes in the neuronal feedback from the
gut to the brain that elicits improvement in metabolic health.

The objective of this first-in-human study is to evaluate the safety,
feasibility and efficacy of pulsed electric field (PEF) induced duodenal
mucosal regeneration (DMR) by the (Endogenex system) combined with (GLP-1
receptor agonist) in subjects with insulin-dependent type 2 diabetes mellitus
and an adequate beta cell reserve. The aimed effect is an adequate or improved
glucose regulation without the need for insulin therapy. Secondary effects
include improved cardiovascular, hepatological en metabolic parameters.

Single site, open label, un-controlled first-in-human study

A single PEF-DMR procedure, in combination with GLP-1RA to discontinue insulin
therapy.

To participate in this clinical study, subjects have to consent with 8 visits,
including blood samples drawn at every visit, physical examination (once during
screening and on indication during following visits) and potential burden
associated with undergoing MRI for liver fat fraction measurement (like
claustrophobia), contineous blood glucose monitoring and questionnaires.
Subjects also have to consent with undergoing 3 endoscopies (including 2
follow-up endoscopies) with duodenal mucosal biopsies. There are risks related
to any endoscopic procedure. Specific risks associated with this procedure
include: abdominal pain, bleeding, delayed gastric emptying, dental injury,
diarrhea, difficulty swallowing, fever, gastric dumping syndrome, headache,
hypoxia, infection, injury to esophagus, nausea, non-healing ulcer, nutritional
mal-absorption, pancreatitis, perforation, pneumoperitoneum, pulmonary
aspiration, sore throat, stomach or duodenal mucosa stricture and obstruction,
tightness and cramping and worsening diabetic symptoms including hypoglycemia.
Many of these risks and complications associated with the procedure are similar
to those associated with other commonly performed endoscopic procedures such as
duodenal biopsies and endoscopic mucosal resection.
In addition to the risks listed above, the Endogenex system has unique risks
associated with its catheters and control consoles used to complete the
procedure. This includes risks associated with the materials selected, its
design and construction. These risks include See section 4.4 for more
information.

The following steps have been taken to minimize risks associated with the
procedure (see section 4.4 in protocol)
The medical consequences and morbidity associated with T2D has been well
studied and documented and includes renal failure, blindness, peripheral
neuropathy, amputation, increased risk of myocardial infarctions, stroke and
peripheral vascular disease. In addition, treatment with insulin is associated
with weight gain and the risk of hypoglycemia. A successful intervention may
enable subjects to more effectively control their glycaemic levels or even
reduce or discontinue use of medications needed to treat their disease,
including insulin. This procedure potentially allows subjects to reduce
morbidity of the disease and through improved glycaemic and metabolic health.
As noted above, there are substantial potential benefits associated with the
procedure and the risk associated with the device and procedure have been
identified and minimized where possible. Thus, the balance of potential risks
and benefits associated with the Endogenex procedure warrants clinical research
and justifies its investigation.