Gelesis100 Significantly Decreases Carbohydrate

Intake In Overweight And Obese Subjects With High

Fasting Glucose

INTRODUCTION

Overweight and obesity are becoming major health problems worldwide (1). The World

Health Organization estimated that the worldwide prevalence of obesity has nearly doubled between 1980 and 2008. In 2008, approximately 500 million adults around the globe were obese and it is projected that by 2015, this number will reach 700 million.

Increased energy intake and especially increased carbohydrate component of food (e.g., added sugars) are major drivers of overweight and obesity epidemics (2).

Gelesis100 is a novel, biocompatible hydrogel engineered to rapidly absorb and release water at specific locations in the gastrointestinal tract. Gelesis100 is administered in capsules, each containing thousands of tiny hydrogel particles that, when hydrated, expand in the stomach and mix with ingested foods. Gelesis100 increases the volume, elasticity, and viscosity of the stomach and small intestine contents, inducing satiety and reducing food intake. The hydrogel particles are synthesized through a multi-step, proprietary process using a specific form of modified cellulose and citric acid, both of which are considered GRAS (Generally Recognized As Safe) by the Food and Drug Administration and commonly used in the food industry. In this process, the modified cellulose is cross-linked with citric acid to form a three dimensional matrix, resulting in the desired properties of Gelesis100. Gelesis100 is designed to act through a physical mode of action, exclusively in the gastrointestinal tract. The Gelesis100 particles do not cluster or stick together, but rather, remain as small individual gel beads that have similar elastic response (rigidity) as ingested foods but with no caloric value. Gelesis100 partially degrades in the large intestine and loses

its three dimensional matrix structure along with most of its absorption capacity. The released water is absorbed back in the large intestine and Gelesis100 is eliminated in the same manner as food.

The weight-loss results from the First Loss Of Weight (FLOW) study with Gelesis100 have been presented at a recent medical meeting (3). The data showed that administration of Gelesis100 (2.25 g twice daily) over 12 weeks to overweight and obese subjects results in a significant decrease in body weight. Weight loss was dramatic in subjects with impaired fasting glucose at baseline (prediabetic subjects, fasting glucose from 5.60 to < 7.00 mmol/L or 100 mg/dL to < 126 mg/dL). The treatment was safe and well tolerated.

OBJECTIVESThe aim of this presentation is to report the effect of chronic oral administration of Gelesis100 on macronutrients intakes (percent energy from carbohydrate, fat, and protein) in non-diabetic overweight and obese adult subjects based on fasting plasma glucose at baseline (> or ≤ median of all study subjects). These parameters were the exploratory endpoints of the FLOW study.

SUBJECTSOne hundred fourteen non-diabetic overweight and obese adult subjects (38 males, 76 females) with a mean body mass index (BMI) ± standard deviation (SD) of 31.7 ± 2.4 and a mean age ± SD of 43.8 ± 12.0 years who completed the study were assessed at five sites, in three European countries (Denmark, Italy, and Czech Republic).

Arne Astrup1, MD; Mette Kristensen1, PhD; Lucio Gnessi2, MD, PhD; Mikiko Watanabe2, MD; Stepan Svacina3, MD;Martin Matoulek3, MD, PhD; Pavol Hlubik4, MD; Hana Stritecka5, PhD; Franco Contaldo6, MD, PhD;

Fabrizio Pasanisi6, MD, PhD; Hassan M Heshmati7, MD; Yishai Zohar7; Eyal S Ron7, PhD; Lorien E Urban7, PhD;Alessandro Sannino8, PhD; Christian Demitri8, PhD; Cosimo Saponaro8.

1University of Copenhagen, Frederiksberg C, Denmark; 2Policlinico Umberto I, Rome, Italy; 3General Hospital in Prague, Prague, Czech Republic; 4Nutrition Disorder Center, Hradec Kralove, Czech Republic; 5Faculty of Military Health Sciences, Hradec Kralove, Czech Republic;

6Federico II University Hospital, Naples, Italy; 7Gelesis, Boston, MA, USA, 8Gelesis, Lecce, Italy.

METHODSSubjects were randomized to two Gelesis100 arms (2.25 g twice daily, n = 41 and 3.75 g twice daily, n = 34) and a placebo arm (n = 39). Treatment was administered orally in capsules with 500 mL of water before lunch and dinner, in a double-blind, parallel-group fashion, over 12 weeks, together with an energy-restricted diet (600 kcal below the daily energy requirement of each subject as calculated by the Harris-Benedict equation). The placebo capsule contained microcrystalline cellulose, a fiber with potential weight-loss properties.

Subjects received instructions at baseline, without enforcement thereafter, to optimize energy intake from macronutrients (carbohydrate 45-50%, fat 30%, protein 20-25%). Total energy and macronutrients intakes were assessed by 24-h dietary recall at baseline and after 12 weeks of treatment. The dietary recall included all the meals consumed during 24 h prior to the visits and assessed total energy intake, carbohydrate intake, fat intake, and protein intake.

Blood samples for the measurement of plasma glucose were collected by venipuncture on fasting subjects (10 to 12-h fast).

Statistical analysis compared Gelesis100 arms to placebo arm in each subgroup of subjects (fasting plasma glucose at baseline > or ≤ median of all study subjects). Comparisons used analysis of covariance adjusting for relevant baseline parameters (gender, age, body weight, BMI, total energy intake, % energy from carbohydrate, fat, and protein intakes).

RESULTSBased on the median of all study subjects at baseline, 56 completer subjects had high (> 5.15 mmol/L or > 93 mg/dL) and 58 had low (≤ 5.15 mmol/L or ≤ 93 mg/dL) fasting plasma glucose (Tables 1 and 2).

Changes in total energy and percent energy from macronutrients intakes are reported in Tables 3 and 4 and Figures 1, 2, 3, and 4.

Unlike subjects with low fasting glucose, subjects with high fasting glucose on Gelesis100 2.25 g and Gelesis100 3.75 g had a significant decrease in percent energy from carbohydrate intake and a significant increase in percent energy from protein intake from baseline to the end of treatment compared to those on placebo. Changes in percent energy from carbohydrate intake (mean ± SD) were –4.6 ± 9.1 (P = 0.003), -2.9 ± 11.6 (P = 0.043), and 4.7 ± 11.1, with Gelesis100 2.25 g, Gelesis100 3.75 g, and placebo, respectively. Changes in percent energy from protein intake (mean ± SD) were 5.0 ± 7.6 (P = 0.012), 5.6 ± 6.9 (P = 0.045), and 2.5 ± 7.3, with Gelesis100 2.25 g, Gelesis100 3.75 g, and placebo, respectively.

DISCUSSIONThe significant decrease in percent energy from carbohydrate intake following chronic administration of Gelesis100 in subjects with fasting plasma glucose > 5.15 mmol/L (> 93 mg/dL) at baseline may support the glucostatic theory of appetite control (4).

According to this theory, an increase in blood glucose concentrations results in increased feelings of satiety whereas a drop in blood glucose concentrations has the opposite effect. Factors favoring a trend toward hypoglycemia and/or glucose instability might induce an excess energy intake and particularly a high percent energy from carbohydrate intake (5, 6) causing subsequent weight gain.

Glycemic instability is suspected to be more pronounced in subjects with initial high fasting glucose. Gelesis100 by creating a more robust glycemic control (7) may induce more decrease in percent energy from carbohydrate intake and more weight loss, especially in subjects with prediabetes (3). The shift to a higher percent energy from protein intake following the decrease in percent energy from carbohydrate intake can also contribute to a higher weight loss since protein dose-dependently increases satiety through postprandial increases in circulating satiety hormones such as GLP-1 and PYY (8), and also has a higher thermic effect of feeding (9).

CONCLUSIONChronic oral administration of Gelesis100 to overweight and obese subjects induces a significant decrease in percent energy from carbohydrate intake and a significant increase in percent energy from protein intake in subjects with fasting plasma glucose > 5.15 mmol/L (> 93 mg/dL) at baseline.

The findings of this study may support the glucostatic theory of appetite control as an explanation for the dramatic weight loss results observed in prediabetic subjects in the FLOW study.

TABLE 2 . GENERAL CHARACTERISTICS IN SUBJECTS WITH LOW FASTING GLUCOSE(≤ 5 .15 MMOL/L OR ≤ 93 MG/DL) AT BASELINE .

ParameterGelesis100 2.25 g

(n = 20)Gelesis100 3.75 g

(n = 20)Placebo (n = 18)

Male (n) 4 (20%) 4 (20%) 6 (33%)

Female (n) 16 (80%) 16 (80%) 12 (67%)

Age (years)* 38.3 ± 12.4 45.3 ± 11.6 38.1 ± 8.3

BMI* 30.7 ± 2.4 31.6 ± 2.7 31.5 ± 2.8

Glucose (mmol/L)* 4.76 ± 0.26 4.85 ± 0.27 4.85 ± 0.21

Glucose (mg/dL)* 86 ± 5 87 ± 5 87 ± 4

*Mean ± SD.

TABLE 3 . CHANGE FROM BASELINE (MEAN ± SD) IN SUBJECTS WITH HIGH FASTING GLUCOSE (> 5 .15 MMOL/L OR > 93 MG/DL) AT BASELINE .

ParameterGelesis100 2.25 g

(n = 21)Gelesis100 3.75 g

(n = 14)Placebo(n = 21)

Total energy (%) -28.4 ± 23.4 -14.0 ± 30.4 -4.5 ± 31.6

Carbohydrate (%) -4.6 ± 9.1* -2.9 ± 11.6** 4.7 ± 11.1

Fat (%) -0.7 ± 6.9 -4.6 ± 12.4 -7.7 ± 9.4

Protein (%) 5.0 ± 7.6*** 5.6 ± 6.9**** 2.5 ± 7.3

*P = 0.003 vs placebo. **P = 0.043 vs placebo. ***P = 0.012 vs placebo. ****P = 0.045 vs placebo.

TABLE 4 . CHANGE FROM BASELINE (MEAN ± SD) IN SUBJECTS WITH LOW FASTING GLUCOSE (≤ 5 .15 MMOL/L OR ≤ 93 MG/DL) AT BASELINE .

ParameterGelesis100 2.25 g

(n = 20)Gelesis100 3.75 g

(n = 20)Placebo(n = 18)

Total energy (%) -16.9 ± 26.5 -23.4 ± 29.9 -11.5 ± 37.6

Carbohydrate (%) 0.1 ± 9.5 6.4 ± 13.8 -3.8 ± 9.0

Fat (%) -2.0 ± 8.6 -9.3 ± 15.3 1.4 ± 8.5

Protein (%) 2.8 ± 5.2 3.5 ± 7.9 1.4 ± 4.2

TABLE 1 . GENERAL CHARACTERISTICS IN SUBJECTS WITH HIGH FASTING GLUCOSE (> 5 .15 MMOL/L OR > 93 MG/DL) AT BASELINE .

ParameterGelesis100 2.25 g

(n = 21)Gelesis100 3.75 g

(n = 14)Placebo (n = 21)

Male (n) 9 (43%) 8 (57%) 7 (33%)

Female (n) 12 (57%) 6 (43%) 14 (67%)

Age (years)* 46.2 ± 11.4 45.8 ± 11.9 49.0 ± 12.8

BMI* 31.7 ± 2.1 32.4 ± 2.4 32.3 ± 2.0

Glucose (mmol/L)* 5.63 ± 0.35 5.65 ± 0.36 5.75 ± 0.45

Glucose (mg/dL)* 101 ± 6 102 ± 6 104 ± 8

*Mean ± SD.

Placebo (n = 18), Gelesis100 2.25 g (n = 20), Gelesis100 3.75 g (n = 20)

Figure 4. Percent energy from macronutrients (change frombaseline, %, mean ± SEM) in subjects with low fasting glucose

(≤ 5.15 mmol/L or ≤ 93 mg/dL) at baseline.

Placebo (n = 21), Gelesis100 2.25 g (n = 21), Gelesis100 3.75 g (n = 14)

Figure 3. Percent energy from macronutrients (change frombaseline, %, mean ± SEM) in subjects with high fasting glucose

(> 5.15 mmol/L or > 93 mg/dL) at baseline.

The content of this document was presented in a Poster at the 22nd European Congress on Obesity, Prague,Czech Republic, May 6-9, 2015.

Placebo (n = 21), Gelesis100 2.25 g (n = 21), Gelesis100 3.75 g (n = 14)

Figure 1. Total energy intake (change from baseline, %, mean ± SEM) in subjects with high fasting glucose (> 5.15 mmol/L or > 93

mg/dL) at baseline.

Placebo (n = 18), Gelesis100 2.25 g (n = 20), Gelesis100 3.75 g (n = 20)

Figure 2. Total energy intake (change from baseline, %, mean ± SEM) in subjects with low fasting glucose (≤ 5.15 mmol/L or ≤ 93

mg/dL) at baseline.

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