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Gelesis hydrogel

Gelesis data shows hydrogel restores gut barrier function

Individuals with prediabetes and those with untreated type 2 diabetes had six times higher odds to achieve ≥10% weight loss compared to placebo
Treatment with Gelesis hydrogel prevented unwanted substances from entering the circulation in mice with severe gut wall injury, data suggest Gel-B (GS300) repairs the seal between intestinal epithelial cells

Gelesis has announced clinical data from its pivotal Gelesis Loss of Weight (GLOW) study suggesting that elevated fasting plasma glucose could be a useful and unique predictor to identify individuals who have higher adjusted odds to achieve significant weight loss with Gelesis100.

As observed in a previous pilot study, participants with prediabetes or untreated type 2 diabetes were particularly responsive to its lead product candidate for weight management, Gelesis100. In addition, participants with high insulin resistance improved their insulin sensitivity significantly on treatment, including the non-responders (defined as those achieving less than 5% total body weight loss). The data were presented in two posters at ENDO 2019, the Endocrine Society’s annual meeting.

“These findings provide compelling data that Gelesis100 may have particularly pronounced benefits for patients with elevated fasting blood glucose and diabetes. While additional studies with a longer time period need to be done, the metabolic and weight loss effects observed in the GLOW study support the concept that Gelesis100 could be an option for patients with high insulin resistance,” said Dr Harry L Leider, Chief Medical Officer of Gelesis. “We have already demonstrated that Gelesis100 is an effective tool for weight management. We now have data suggesting that the hydrogel may modulate the endocrine and metabolic systems to positive effect. We are eager to continue exploring the mechanisms behind these findings.”

Gelesis100

Gelesis100 is a non-systemic, superabsorbent hydrogel in development for the potential treatment of overweight or obesity. It is made by cross linking two naturally-derived building blocks, modified cellulose and citric acid, that create a three-dimensional matrix. Gelesis100 particles rapidly absorb water in the stomach and homogenously mix with ingested foods. Rather than forming one large mass, it creates thousands of small individual gel pieces with the elasticity (firmness) of solid plant-based foods (e.g., vegetables) without caloric value. The Gelesis100 hydrogel mass increases the volume and elasticity of the stomach and small intestine contents, promoting fullness and potentially increasing satiety to help patients lose weight. Once it arrives in the large intestine, the hydrogel is partially broken down by enzymes and loses its three-dimensional structure along with most of its absorption capacity. The released water is reabsorbed in the large intestine, and the remaining cellulosic material is expelled in the faeces.

Gelesis100 is considered a medical device because it achieves its primary intended purpose through a mechanical mode of action. This investigational product and its earlier prototypes have been studied in more than 450 patients (excluding patients treated by placebo) across five clinical studies throughout the United States, Canada, and Europe and in these demonstrating a strong efficacy, tolerability and safety profile. Other than an increase in overall gastrointestinal adverse events (AEs), most of which were assessed as mild, there was no difference in the incidence and severity of AEs between the Gelesis100 and placebo groups. In both treatment groups, most AEs were mild or moderate in intensity. No serious adverse events were observed in the Gelesis100 group.

The data come from subgroup analysis of the GLOW study, a pivotal multi-centre, double-blind, placebo-controlled study of Gelesis100. The overarching study showed statistically significant separation from placebo in the ITT population and found that nearly six in ten people treated with Gelesis100 were responders who lost, on average, 10% (about 22lbs) of their body weight over six months.

In this subgroup analysis, researchers found that 44% of patients with elevated fasting blood glucose or untreated type 2 diabetes were ‘super-responders’, meaning they lost at least 10% of their body weight (30lbs on average) when treated with Gelesis100 (p=0.007). Interestingly they had six times the odds of being super-responders, compared to placebo. Across the entire treatment group in the GLOW study, baseline fasting plasma glucose was correlated with greater weight loss (p=0.0144). The pronounced weight loss effect of Gelesis100 treatment in this population, which is at higher clinical risk, was also observed in the previous FLOW pilot study. The repeated findings suggest that Gelesis100 may be a new tool for aiding in weight management in patients at high risk of diabetes or diabetes-related complications.

“Participants with elevated fasting blood glucose and untreated type 2 diabetes had higher odds of achieving loss of at least 10% of their body weight. This was an important result as this population almost invariably has lesser weight loss in behavioral and medication trials,” said Dr Scott Kahan, director of the National Center for Weight and Wellness and a physician specializing in obesity.

A separate analysis found that patients with high insulin resistance – a significant driver of diabetes – had positive metabolic responses to treatment with Gelesis100. Insulin resistance was measured by homeostatic model assessment – insulin resistance (HOMA-IR). Patients with high IR at the start of the clinical trial (mean baseline HOMA= 5.0) had a statistically significant reduction in HOMA-IR over the six-month treatment period (-22.3 +/- 9.5%, p=0.021). Importantly this reduction was observed both in patients that were weight loss responders (with 5% or greater weight loss) and also in non-weight loss responders. The HOMA-IR decrease in the subgroup overall was driven by a significant reduction in fasting serum insulin.

The GLOW study was designed to assess change in body weight in adults with overweight or obesity after six months of treatment with Gelesis100. Topline results of the study were announced in September 2017. The study had two predefined co-primary endpoints: at least 35% of patients taking Gelesis100 achieving ≥ 5% weight loss (categorical endpoint) and placebo adjusted weight loss to be assessed in two ways (super-superiority margin of 3% and also simple superiority). The study met and exceeded the pre-defined categorical endpoint, with 59% of adults in the treatment group achieving weight loss of 5% or greater. As previously announced, the study did not meet the 3% super-superiority endpoint but demonstrated superiority of the Gelesis100 treatment over the placebo group (–6.4% vs. –4.4%, P=0.0007). Gelesis100-treated individuals had twice the odds of achieving at least 5% and at least 10% weight loss vs. placebo (adjusted odds ratio [OR]: 2.0, P=0.0008; adjusted OR: 2.1, P=0.0107, respectively).

The overall incidence of adverse events in the Gelesis100 treatment group was no different than placebo (71% in both groups). The most common AEs were gastrointestinal disorders (186 AEs in 96 [43%] subjects in the Gelesis100 arm, compared to 134 events in 72 [34%] subjects receiving placebo), infections and infestations (94 events in 74 [33%] subjects with Gelesis100 and 101 events in 70 [33%] subjects with placebo), and musculoskeletal and connective tissue disorders (38 events in 31 [14%] subjects with Gelesis100 and 45 in 34 [16%] subjects with placebo). There were no serious adverse events (SAE) in the Gelesis100 treatment group, whereas there was one (1) SAE in the placebo treatment group.

Gelesis100 has been extensively evaluated in clinical studies and has been submitted to the US FDA for review.

Restoring gut barrier function

Gelesis also announced preclinical data suggesting that the company’s proprietary hydrogel formulation, Gel-B (GS300), restored gut barrier function after damage. The gut barrier plays a key role in blocking intestinal toxins from entering the circulation and triggering disease. Building on previous preclinical work, Gel-B was engineered to elicit the mechanical and physical properties required to optimize intestinal tissue healing. The hydrogel, which represents a pioneering advance in the emerging field of mechanobiology, is being studied in diseases affected by gut barrier dysfunction, such as inflammatory bowel disease.

The study, also presented at ENDO 2019, assessed the effect of Gel-B on gut barrier function in mice following a severe insult to the gut wall by administering 3% dextran sodium sulfate for five days. Mice were randomly divided into four doses of Gel-B (0.5%- 4.0%), control or an active Anti-p40 mAb group. The mice treated with Gel-B had fewer epithelial barrier breaks in distal colon samples and lower infiltration of an ingested fluorescing agent into their circulation.

“These preclinical data support the ability of Gel-B to reverse increased intestinal permeability in a DSS mouse model,” said Dr Elaine Chiquette, Chief Scientific Officer of Gelesis. “We are continuing to advance our understanding of how our proprietary hydrogel platform technology can mechanically influence intestinal tissue repair.”

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