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A little intestinal fortitude sees Fractyl on track to reverse the root causes of T2D

By David Godkin

Fractyl Health Inc. reported clinical updates on the Revita real world registry in Germany which has demonstrated clinical remission from type 2 diabetes (T2D) employing a device that resurfaces the duodenal mucosa, the innermost layer of the first portion of the small intestine, and a potential root cause of T2D. The idea behind Revita technology Fractyl CEO Harith Rajagopalan explained is to reverse changes to the structure and function of the duodenal mucosa that occur from a high-fat, high-sugar diet and that causes T2D.

“We proposed the idea of ablation because when you ablate an epithelial tissue under the skin or in the esophagus you trigger a regenerative healing response. We asked if ablating that duodenal mucosa can take you back to a healthier mucosa, post regeneration and renewal,” Rajagopalan said.

In addition, Fractyl announced a new telehealth program, Revita+, to combine behavioral recommendations for patients with advanced metabolic diseases, notably T2D. “We’re fortunate to work with Dr. Stephan Martin, Director of the West German Diabetes Center of Excellence, who has developed Revita+ for people with advanced T2D,” said Rajagopalan.

“If we ablate the dysfunction to regenerate the duodenal mucosa it stands to reason you want to offer patients an opportunity to really sustain those benefits by giving them the tools to change their diet to prevent that pathology recurring.”

The first of 15 patients enrolled in the registry recently saw HbA1c levels drop from a baseline of 7.6% to 5.3% (normal glucose range is regarded as 5.7% or less). More remarkably, perhaps, is that case study revealed discontinuation of all three glucose-lowering agents, metformin, DPP4 inhibitor and long-acting insulin for a loss of 20 pounds of excess weight.

Said Rajagopalan, “We are drawing attention to the fact that the physicians who cared for this patient found the results so notable they thought it worthy of a published, single case study.”

From bariatric to T2D

A cardiologist whose family has been touched by diabetes, in 2010 Rajagopalan saw many patients at Brigham Women’s Hospital with co-existing T2D and cardiovascular disease, both driven by underlying metabolic syndrome and dysfunction. “That made me realize we are busy addressing the downstream symptoms of this metabolic dysfunction, but really haven’t gotten a handle on the upstream root causes to change the trajectory of the disease.”

As Rajagopalan reviewed bariatric surgeries which help reduce food consumption and weight loss by removing a part of stomach, he had a revelation. Bariatric surgery could reverse obesity, T2D and cardiovascular risk “in almost an immediate way.” What was most appealing, he noted, was that this was a short-term intervention with long term benefit.

“And I compared that with drugs that had the opposite effect, i.e., long term interventions with short term benefit.” That led Rajagopalan to explore what it is about bariatric surgery that affects root cause disease “and how we might develop therapies to offer the same short-term intervention, long term benefit in a scalable manner.”

Helpful was an emerging scientific consensus that the gut is a root cause for diabetes and obesity, of which the duodenum played an important part, said Rajagopalan. “That was the jumping off point for starting the company, ” i.e., a venture backed company that rang up a $100 million series D Financing round in 2021 to expand clinical development programs in T2D.

Rajagopalan further explained the intestinal stem cells at the base of duodenal mucosa represent not just the first site for dysfunctional nutrient absorption from high fat/high sugar diets. It is also a key location for sensing and signaling mechanisms that tell the brain when you’re full and your doctor about your insulin sensitivity levels. These mechanisms can also become impaired.

The aim of the Revita procedure, said Rajagopalan, is to reverse metabolic dysfunction and persistent hunger by ablating the innermost layer of the duodenal mucosa. The roughly 45-minute endoscopic procedure is performed on an outpatient basis under anesthesia, at which point the patient is moved to a recovery room and released shortly after.

Encouraging signs

To date, more than three hundred subjects have participated in clinical trials testing the Revita technology’s effectiveness. One was a single arm, open label extension study “showing patients who undergo a single Revita procedure can achieve improvements in blood sugar control and prevention of weight gain for at least two years following the procedure,” said Rajagopalan.

Another clinical trial appears to support Fractyl’s contention that telehealth programs such as Revita+ provide effective behavioral recommendations for patients with advanced metabolic diseases such as T2D. Said the report, “At six months, 69% of patients were off insulin therapy with an HbA1c ≤7.5%.”

Concluded the study, a single duodenal mucosal resurfacing procedure and GLP-1RA “supported by lifestyle counseling, eliminated the need for insulin therapy in most patients with T2D through 18 months post procedure… while improving glucose regulation and metabolic health in all patients.” How sustainable might these results be?

Replied Rajagopalan, “what is encouraging is the idea that T2D could be made to regress and doesn’t have to be a chronically progressive condition that cannot be made to improve.” Revita offers the opportunity, he added, “to regress disease in a manner we believe qualifies as disease modification for the very first time.”