LuCI agent used for the treatment of obesity-associated metabolic disorders

Researchers led by Dr Ali Tavakkoli, Chief of the division of General and GI Surgery and co-director of the Center for Weight Management and Wellness at Brigham and Women's Hospital, have demonstrated that a LuCI (Luminal Coating of the Intestine), an orally administered intestine barrier coating, can ameliorate weight gain and improve insulin sensitivity in a long-term DIO rat model. The findings were presented in the paper, ‘‘Luminal Coating of Intestines: a potential novel anti-obesity therapy for obesity-associated type 2 diabetes,’ at the 25th World Congress of the International Federation Surgery of Obesity and Metabolic Disorders in Miami, FL.

Figure 1: Representative cartoon demonstrating the oral administration luminal coating of intestine as an alternative of highly invasive and irreversible bariatric surgeries. The coating is designed to form a transient physical barrier on mucosa against substances such as nutrients, acids, and enzymes, and a drug delivery platform that can deliver therapeutics (e.g. protein) protected from stomach acid and digestive enzymes.

Approximately 80% of patients who have gastric bypass surgery have significant weight loss and, importantly, early and weight-independent remission of T2D. While gastric bypass surgery is the most effective intervention for managing obesity and type-2 diabetes, it is an expensive intervention associated with some risks. As an orally administered agent, LuCI has demonstrated in preclinical testing to be a safe, non-invasive, and effective agent that replicates the effects of Roux-en-Y gastric bypass surgery. The coating is designed to form a transient physical barrier on intestinal mucosa leading to changes in nutrient absorption and hormonal secretions that replicates gastric bypass (Figure 1).

In the presentation, the researchers revealed the outcomes from an investigation into chronic LuCI administration on weight and glucose homeostasis in Sprague Dawley rats. The rats were administered a high fat diet received five weeks of daily LuCI or normal saline as control (n=8/group). Daily weights and glucose tolerance were monitored throughout the experiment. At five weeks, systemic blood was sampled through a surgically placed jugular vein catheter, before and during an intestinal glucose bolus, to investigate changes in key hormones involved in glucose metabolism. To elucidate the effects of LuCI on nutrient absorption, faecal output and food intake were measured simultaneously with the analysis of homogenized stool samples performed using bomb calorimetry.

At five weeks, LuCI animals weighted 8.3% less in total body weight and had lower fasting glucose levels than Controls (77.6±3.8 mg/dl vs. 99.1±2.7 mg/dl, p<0.001). LuCI-treated animals had lower baseline insulin and HOMA-IR, demonstrating significant improvement in insulin sensitivity. Post-prandially, LuCI group had increased GLP-1 and GIP secretion following a glucose challenge. Serum lipid analysis revealed lowered LDL levels suggesting the potential for reducing the cardiovascular risk (Figure 2).

Figure 2: Metabolic benefits of daily administration of LuCI in a rat model. (a) Weight over 35 days of LuCI and vehicle oral gavage. (b) Mean fasting glucose levels 5 weeks after beginning of treatment. (c) Systemic fasting insulin level 5 weeks after beginning of treatment. (d-e) Circulating plasma hormone levels measured 5 weeks using standard oral glucose tolerance test following daily gavage of LuCI or normal saline. (d) GLP-1 levels at time points indicated, (e) GIP levels at time points indicated. (f) Total cLDL particle counts after 5 weeks after beginning of treatment. The researchers then investigated whether LuCI’s effect on proximal bowel exclusion may play a role in energy consumption and the outcomes suggested that LuCI reduced calorie absorption in the gut with no difference in calorie consumption.

“Since LuCI’s effect is transient and without systemic absorption, LuCI has the potential to be beneficial for overweight or obese T2D patients,” they concluded. “Future studies should consider LuCI as a new potential therapeutic strategy to limit weight gain and prevent the development of T2D.”

Dr Tavakkoli added that his team would be looking to complete toxicology studies in the near future so they can carry out first-in-human studies, hopefully, in 2023.

AltrixBio, the company developing LuCI, was recently issued with US Patent 11,433,094, for its LuCI proprietary compound.

“This is a significant milestone with respect to our intellectual property portfolio, demonstrating our ongoing commitment to innovation and leadership in this field,” said Nancy Briefs, the CEO of AltrixBio. "The patent covers our breakthrough LuCI technology that has the potential to positively impact millions of patients, allowing them to avoid invasive bariatric surgery with a safe, effective, and affordable oral solution for treating type 2 diabetes and obesity."