RALEIGH, N.C.—This fall, Innovate Biopharmaceuticals Inc., a clinical-stage biotechnology company focused on developing novel therapeutics for autoimmune and inflammatory diseases, announced the possibility that its lead agent, larazotide acetate, may have the potential to be used in conjunction with other drugs to treat nonalcoholic steatohepatitis (NASH).
In a recent study, researchers assessed the effects of multiple doses of larazotide on various markers of NASH in a preclinical model called the DIAMOND mouse model. Researchers also kept an eye on the effects of larazotide on gut integrity, using a highly specific technique measuring epithelial barrier normalization and intestinal permeability. Agents that can prevent gut barrier permeability, or a “leaky” barrier, from worsening with the progression of NASH could pose a significant advantage in treating this disease. Preclinical data showed in high numbers that larazotide at the doses tested had a clear benefit in reducing this gut barrier permeability, a known pathological abnormality in chronic liver diseases, specifically NASH.
NASH is a severe disease of the liver caused by inflammation and a buildup of fat in the organ. In the United States, NASH affects an estimated 2 percent to 5 percent of the population. The underlying cause of NASH—which is a specific kind of non-alcoholic fatty liver disease (NAFLD)—is unclear aside from the fact that alcohol use is not the culprit, but it most often occurs in persons who are middle-aged and overweight or obese. It has been shown that chronic liver diseases, including NAFLD/NASH, may cause perturbations in the epithelial lining of the gut and disrupt barrier integrity, causing a normal intestine to become more permeable.
This “leaky gut” could cause passage of unwanted toxins and antigenic components to “cross-talk” to the liver via the blood circulation causing inflammation and damage to hepatocytes. This gut-liver axis is an emerging area of research in chronic liver diseases, such as NAFLD/NASH. There are currently no FDA approved treatments for NASH.
The DIAMOND (Diet Induced Animal Model Of Non-alcoholic fatty liver Disease) mice are a proprietary isogenic mouse strain licensed by Sanyal Biotechnology that develops NAFLD, NASH, fibrosis and hepatocellular carcinoma in response to a high fat high sugar Western Diet without poisons or other interventions. The mice become insulin-resistant, obese and dyslipidemic just like humans with metabolic syndrome, and disease progression parallels that of the human body right down to the histopathology.
Additionally, Innovate is looking for opportunities where larazotide may be used in conjunction with other drugs in late-stage clinical trials for NASH, which are already approved in other indications. Currently, Innovate is studying Novo Nordisk A/S’s Victoza (liraglutide) approved for type 2 diabetes and Intercept Pharmaceuticals Inc.’s Ocaliva (obeticholic acid) approved for primary biliary cholangitis in combination with larazotide in preclinical models with the goal of determining the optimal synergistic drug combination with different mechanisms of action.
“We are excited about looking at how larazotide could synergistically work with drugs in late-stage clinical trials for NASH, which are already approved in other indications. We believe that larazotide’s more upstream mechanism of blocking the inflammatory cascade without impacting the liver directly may support its potential therapeutic effect in NAFLD/NASH,” said Dr. Christopher Prior, CEO of Innovate Biopharmaceuticals.
Larazotide works to renormalize the dysfunctional intestinal barrier by decreasing intestinal permeability and reducing antigen trafficking, such as gliadin fragments in celiac disease, and bacterial toxins and immunogenic antigens in NASH. In several diseases—including celiac disease, NASH, Crohn’s disease, ulcerative colitis and irritable bowel syndrome—the intestinal barrier is dysfunctional with increased permeability.
In celiac disease specifically, larazotide is the only drug that has successfully met its primary endpoint with statistical significance in a Phase 2b efficacy clinical trial of 342 patients. Innovate completed the End of Phase 2 Meeting with the FDA in 2017 and is preparing to begin Phase 3 registration clinical trials for celiac disease, targeted to commence in the first half of 2019. Nearly 600 subjects have been exposed to larazotide in clinical trials, and a safety profile comparable to placebo has been demonstrated, earning the drug Fast Track designation from the FDA for celiac disease.
Added Dr. Arun Sanyal, professor and chair of the Division of Gastroenterology, Hepatology and Nutrition at the Virginia Commonwealth University (VCU) School of Medicine: “Increased intestinal permeability has been linked to many aspects of metabolic syndrome, including type 2 diabetes and nonalcoholic fatty liver disease. The demonstration of reduced gut permeability with larazotide in the setting of diet-induced obesity opens up the possibility of modulating the outcomes of metabolic syndrome, including NASH, via this mechanism and warrants further development for these indications.”
Moving forward, Innovate plans to submit the complete NASH preclinical results for publication at a major upcoming conference in 2019. The company also intends to launch a clinical program in NASH with a Phase 2 trial in 2019.