HMS5552, a novel Glucokinase activator for Type 2 Diabetes
Diabetes is a pandemic metabolic disorder which is growing at a rate of 10% y-o-y in China. China now houses a quarter of the world diabetes population with over 114M (11.6%) patients, while an additional 150M-400M are pre-diabetics. Hua's HMS5552 is an oral drug which increases the activity of the Glucokinase (GK) enzyme, a key regulator of glucose metabolism found in liver and pancreatic tissue, restoring the impaired GK activity affecting many of these diabetic patients. When activated, GK decreases liver glucose production and improves Glucose Stimulated Insulin Release (GSIR), which leads to whole body glucose homeostasis. Importantly, HMS5552 is a potent Glucokinase activator (GKA) engineered to activate the GK enzyme in a glucose-dependent manner, implying that it functions only when needed during periods of high blood glucose levels, reducing the risk of hypoglycemia.
Hua has in-licensed world-wide rights to the latest (4th generation) GKA compound from Roche which showed a superior pharmacology and efficacy profile, while being optimized with a novel chemical structure to decrease the metabolite-based side effects of previous generations. The most recent Phase Ic/IIa trial demonstrated an impressive 1% HbA1c average reduction in patients compared to their baseline blood levels after only 4 weeks of treatment. Typically, it takes more than 12 -16 weeks to see a noticeable effect from a new diabetes therapy, since this represents the average life span of the red blood cells that carry HbA1c. Discerning a greater than 1% reduction in HbA1c after only 4 weeks means HMS5552 is highly efficacious. In addition to the high efficacy, the month-long trial results showed an excellent tolerability and safety profile with low risk of hypoglycemia or other side effects (such as gastrointestinal discomfort) common in many other diabetes treatments.
HMS5552 has benefited from China CFDA's special "Green Channel" review status for innovative drugs, and is now starting Phase 2 clinical trials in China as well as Phase 1 GKA drug combination trials in the US. The company expects to have top-line results from these trials by YE2016.
mGluR5 NAM Program
CNS diseases are another area of research interest at our company. The metabotropic glutamate receptor subtype 5 (mGluR5) belongs to the family of Class C, G protein-coupled receptors (GPCR) which have historically been regarded as poorly druggable. mGluR5 is highly expressed in specific regions of the brain and has in recent years emerged as an exciting potential drug target for several CNS disorders including Parkinson's disease (PD) associated dyskinesia, depression, anxiety, fragile X syndrome (FXS), and drug abuse.
Classically, most marketed drugs are designed to directly bind at a specific protein’s active site, having to essentially compete against the endogenous ligand’s binding to show an effect. By contrast, drugs that are allosteric modulators are non-competitive because they bind proteins at a different area than the endogenous ligand’s binding site, yet are still able to affect its activity. Hence, allosteric modulators are not limited to simply turning the activity of a target protein “on” or “off” in a binary fashion. Instead, they can act more like dimmer switches, offering improved control over the intensity of activation or deactivation, while still allowing the body to retain control over initiating natural protein function. Finally, allosteric modulators are a class of orally-available, small molecule therapeutic agents that may offer a competitive advantage when targeting poorly druggable protein targets like mGluR5.
Our portfolio of novel mGluR5 allosteric modulators have demonstrated excellent potency, selectivity and preclinical efficacy profiles. They may offer a transformative new mechanism of action with the potential to become best-in-class drugs in a variety of CNS disorders in which mGluR5 dysfunction has been implicated in the pathogenesis.