Our pipeline includes additional programs being evaluated for liver and chronic diseases with high unmet medical needs. These include:
MBX-2982: Targets G protein-coupled receptor 119 (GPR119), a receptor that interacts with bioactive lipids known to stimulate glucose-dependent insulin secretion. Preclinical data indicate that MBX-2982 is a potent selective orally-active GPR119 agonist that functions through a unique dual mechanism of action that acts directly on the beta cell to increase insulin secretion and stimulates release of the incretin GLP-1 from the gut. In recent preclinical studies (Nina Xiaoyan Li et al. Diabetes 2018;67:1401-1413), GPR119 agonists were shown to enhance glucagon secretion in response to low glucose levels and were able to prevent hypoglycemia in animal models.
Glucagon is a hormone secreted by the pancreas, that naturally reverses hypoglycemia by signaling the body to release stored glucose. This process is defective in individuals with insulin-dependent diabetes, such as Type 1 Diabetes (T1D). If left uncorrected, hypoglycemia can lead to unconsciousness or death. Preventing episodes of hypoglycemia in persons with diabetes is an unmet medical need. According to the 2016 global HAT study of 27,000 people, 4 out of 5 individuals with T1D reported hypoglycemia, with a rate of severe hypoglycemia (requiring assistance of another person) of approximately 5 events per patient-year.
We are providing MBX-2982 to the AdventHealth Translational Research Institute (TRI) in Orlando, FL to lead a Phase 2a proof-of-pharmacology study to determine whether MBX-2982 can enhance glucagon secretion during insulin-induced hypoglycemia in subjects with T1D (https://clinicaltrials.gov/ct2/show/NCT04432090). The study is funded by The Leona M. and Harry B. Helmsley Charitable Trust. The study will evaluate MBX-2982 for its ability to increase secretion of glucagon, a hormone that reverses low blood glucose levels (hypoglycemia) in individuals with T1D.
We have previously conducted clinical studies for MBX-2982 as a potential treatment for Type 2 Diabetes, demonstrating MBX-2982 was safe and well tolerated. CymaBay wholly owns and retains all rights to MBX-2982.
CB-0406: In 2020, we began to evaluate CB-0406, the active metabolite of the pro-drug arhalofenate that had previously been studied for chronic metabolic diseases. We initiated a single and multiple ascending dose study of CB-0406 in healthy subjects to establish its pharmacokinetics, safety and maximum tolerated dose. CB-0406 is a PPARγ non-agonist ligand that attenuates the expression of inflammatory genes. It has been shown to block innate immune responses to inflammatory triggers in macrophages, and to attenuate gouty inflammation when dosed as the pro-drug in mouse animal models and in a Phase 2 clinical study in gout patients. Based on pharmacokinetic studies in monkeys, we believe that CB-0406 may have greater exposure and potentially greater efficacy than does the pro-drug arhalofenate. Decisions on any future development are contingent on it achieving a favorable profile with respect to safety and exposure. The innate immune system plays a pivotal role in many diseases besides gout and thus we believe CB-0406 may have utility in various inflammatory diseases and are currently exploring potential opportunities to advance its development pending the results of the ongoing Phase 1 study.
CB-001: Targets G protein-coupled receptor 120 (GPR120), a receptor for Omega-3 fatty acids such as docosahexaenoic acid (DHA). Pharmacodynamic effects include insulin sensitization, stimulation of GLP-1 release, glucose sensitive insulin secretion (GSIS), improvement in hepatic steatosis and lipid profile, and anti-inflammatory activity. Preclinical target validation has been achieved.