Oral Administration of Gelesis100,A Novel Hydrogel, SignificantlyDecreases Body Weight inOverweight and Obese Subjects

INTRODUCTION

O verweight 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.

Overweight and obesity are responsible for in-creased morbidity and mortality (2). Weight loss of at least 5 to 10% appears to lower the risk of many of the comorbidities (3).

The therapeutic benefit of all currently avail-able anti-obesity tools is limited by their marginal efficacy and variable tolerability and safety profiles.

Gelesis100 is a novel, biocompatible hydrogel. 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 and elasticity of the stomach and small intestine contents, inducing satiety and reducing caloric intake. Gelesis100 is composed of two components which are used as food ingredients, but when cross-linked, form a unique structure that increases in volume

when hydrated. Gelesis100 does not create one big mass, rather thousands of small indi-vidual gel beads which have similar elasticity (rigidity) as ingested foods, but without any caloric value. Gelesis100 partially degrades in the large intestine and loses its three dimen-sional matrix structure and most of its absorp-tion capacity. The water is absorbed from the hydrogel back in the colon and Gelesis100 is expelled in the feces.

A previous study in humans has shown that single administration of 2 g of Gelesis100 sig-nificantly increases the post-meal feeling of satiety and decreases the feeling of hunger before the subsequent meal (4).

OBJECTIVESThe aims of this study were to assess the ef-ficacy, safety, and tolerability of chronic oral administration of Gelesis100 in non-diabetic overweight and obese subjects.

Body weight was the primary efficacy endpoint.

SUBJECTSOne hundred twenty-eight non-diabetic overweight and obese subjects were studied 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, PhD, 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, 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 = 43 and 3.75 g twice daily, n = 42) and a placebo/active com-parator arm (n = 43). Treatment was adminis-tered in capsules with 500 mL of water before lunch and dinner, in a double-blind, parallel- group fashion, over 12 weeks, in subjects on hypocaloric diet (-600 kcal/day). The placebo/active comparator capsule containedmicro-crystalline cellulose, a fiber which is used as a bulking agent.

For safety and tolerability, in addition to the standard adverse event (AE) reporting, gas-trointestinal symptoms that occurred during the study were recorded through a question-naire (solicited AEs).

Statistical analysis used analysis of covariance model with baseline weight, gender, and body mass index (BMI) as covariates, com-paring Gelesis100 arms to placebo/active comparator arm.

RESULTSOne hundred twenty-five subjects had at least one post-baseline body weight assessment (intention-to-treat “ITT” population) (Table 1).

One hundred ten subjects completed the treatment.

One hundred twenty-six subjects provided safety data (safety population).

In the ITT population, the mean (± SD) body weight percent changes from baseline to the end of treatment were -6.1 ± 5.1%, -4.5 ± 4.5%, and -4.1 ± 4.4%, with Gelesis100 2.25 g, Gelesis100 3.75 g, and placebo, respec-tively. Weight loss was statistically significant with Gelesis100 2.25 g (P = 0.026) (Figure 1). Lower tolerability leading to lower compliance may explain the observed efficacy result with Gelesis100 3.75 g.

Subjects on Gelesis100 2.25 g had higher rate of weight loss ≥ 10% and lower rate of weight gain (Table 2).

The extent of weight loss was more pro-nounced in subjects on Gelesis100 2.25 g with fasting glucose > median at baseline (-8.2 ±

5.3%; P = 0.006) (Figure 2), especially in those with impaired fasting glucose at baseline (-10.9 ± 4.3%; P = 0.019) (Figure 3).

There was a significant negative correlation between fasting glucose at baseline and change in body weight in Gelesis100 2.25 g arm (r = -0.50; P < 0.001) (Figure 4) contrasting with a lack of significant correlation in Gelesis100 3.75 g arm (r = -0.01; P = 0.968) and placebo arm (r = -0.06; P = 0.708) (Figure 5).

Treatment with Gelesis100 was safe and well tolerated. The most common AEs were of gas-trointestinal origin and included bloating, flat-ulence, abdominal pain, and diarrhea, with lower prevalence in Gelesis100 2.25 g arm compared to placebo and Gelesis100 3.75 g arms (Table 3). The most common non-gastro-intestinal AEs were common cold and headache. Serious AEs (SAEs) were observed in 3 subjects on placebo (gallstone and abdominal pain).

The AEs were usually of mild intensity, occurred at different times during the course of the study, and resolved within 1 week in most cases.

Dropout after randomization occurred in 2 sub-jects (5%) on Gelesis100 2.25 g, 10 subjects (24%) on Gelesis100 3.75 g, and 9 subjects (21%) on placebo. No AE was responsible for the dropout with Gelesis100 2.25 g.

CONCLUSIONChronic administration of Gelesis100 (2.25 g twice daily) to overweight and obese sub-jects significantly decreases the body weight. Weight loss is especially dramatic in subjects with impaired fasting glucose at baseline (pre-diabetic subjects). The treatment is safe and well tolerated.

Through its first-in-class, mechanical, and non-invasive approach, Gelesis100, as a med-ical device, is a product that is well-positioned to overcome the limitations of the current weight-loss tools and fulfill the overwhelming unmet medical need for a safe and effective weight-loss product in overweight and obese subjects, especially in those with prediabetes.

If confirmed in subsequent studies, Gelesis100 also has the potential to induce dramatic weight loss in overweight and obese subjects with type 2 diabetes.

TABLE 1. GENERAL CHARACTERISTICS OF THE ITT POPULATION AT BASELINE.

Parameter gelesis100 2.25 g

(n = 42)

gelesis100 3.75 g

(n = 41)

Placebo (n = 42)

Male (n) 13 (31%) 14 (34%) 13 (31%)

Female (n) 29 (69%) 27 (66%) 29 (69%)

age (years)* 42.4 ± 12.3 46.1 ± 11.2 44.0 ± 11.7

bMi* 31.2 ± 2.3 31.8 ± 2.5 32.0 ± 2.3

overweight (n) 14 (33%) 12 (29%) 12 (29%)

obese (n) 28 (67%) 29 (71%) 30 (71%)

glucose (mmol/L)*glucose (mg/dL)*

5.18 ± 0.5493 ± 10

5.20 ± 0.5094 ± 9

5.31 ± 0.5896 ± 10

*Mean ± SD.

TABLE 2. BODY WEIGHT RESPONSE IN THE ITT POPULATION.

Parameter gelesis100 2.25 g

(n = 42)

gelesis100 3.75 g

(n = 41)

Placebo (n = 42)

weight gain 3 (7%) 9 (22%) 7 (17%)

weight loss < 5% 21 (50%) 13 (32%) 18 (43%)

Weight loss ≥ 5% 18 (43%) 19 (46%) 17 (40%)

Weight loss ≥ 10% 11 (26%) 5 (12%) 5 (12%)

TABLE 3. GASTROINTESTINAL AEs* IN THE SAFETY POPULATION.

Parameter gelesis100 2.25 g

(n = 42)

gelesis100 3.75 g

(n = 41)

Placebo (n = 43)

any ae 31 (74%) 35 (85%) 36 (84%)

any gastrointestinal ae 25 (60%) 31 (76%) 32 (74%)

bloating 12 (29%) 15 (37%) 16 (37%)

Flatulence 11 (26%) 15 (37%) 13 (30%)

abdominal pain 9 (21%) 12 (29%) 15 (35%)

diarrhea 8 (19%) 10 (24%) 16 (37%)

*Gastrointestinal AEs were solicited and recorded through a questionnaire.

Figure 2. Body weight (% change from baseline, mean ± SEM) in ITT population with fasting glucose > median (5.15 mmol/L or 93 mg/dL) at baseline.

Figure 3. Body weight (% change from baseline, mean ± SEM) in ITT population with impaired fasting glucose (5.60 to < 7.00 mmol/L or 100 to < 126 mg/dL) at baseline.

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4. Heshmati HM, Tacchino R, Ron E, Sannino A, Zohar Y. Attiva, a novel superabsorbent biode-gradable hydrogel, increases the feeling of sati-ety in humans. In: Program of the 19th Annual Meeting and Clinical Congress of the American Association of Clinical Endocrinologists, April 21-25, 2010; Boston, MA, USA. Abstract #605.

Figure 4. Correlation between fasting glucose at baseline (mmol/L) and body weight change from baseline (%) in ITT population on Gelesis100 2.25 g.

Figure 5. Correlation between fasting glucose at baseline (mmol/L) and body weight change from baseline (%) in ITT population on placebo.

Figure 1. Body weight (% change from baseline, mean ± SEM) in ITT population.

The content of this document was presented in a Poster at the ICE/ENDO 2014 Meeting, Chicago, Illinois, June 21-24, 2014.