Kareus Therapeutics initiates Phase 1 trial in diabetes

KU-5039 said to be a potent and selective activator of AMP-kinase

Lloyd Dunlap
LA CHAUX-DE-FONDS, Switzerland—Kareus Therapeutics SA announced in a press release that the U.S. Food and Drug Administration (FDA) has approved its Investigational New Drug application for KU-5039, allowing the company to initiate a Phase 1 clinical trial. KU-5039 is being developed for the treatment of insulin resistance and diabetes.
 
KU-5039 is an orally active, new chemical entity discovered and developed by Kareus. It is reportedly a potent and selective activator of AMP-kinase (AMPK), a key regulator of cellular and whole-body energy homeostasis that coordinates metabolic pathways. Pharmacological activation of AMPK in animals promotes glucose uptake, fatty acid oxidation, mitochondrial biogenesis and insulin sensitivity.
 
In a poster session presented at the 73rd American Diabetes Association meeting last year, titled “Discovery of an Orally Efficacious, Novel AMPK Activator as Potent Insulin Sensitizer,” co-authors Sivaran Pillarisetti and Ish Khanna provided details on both the problem and how KU-5039 may effect a solution. Insulin resistance is the underlying defect in more than 90 percent of patients with type 2 diabetes mellitus and is the key pathologic mechanism for associated susceptibility to premature cardiovascular complications, the authors related. Currently there is no safe insulin sensitizer on the market that targets skeletal muscle insulin resistance. AMPK is an energy-sensing enzyme that is expressed in many insulin-responsive tissues, including liver and skeletal muscle. Activation of AMPK promotes glucose uptake in skeletal muscle and inhibits gluconeogenesis and lipogenesis in liver.
 
“We have developed a series of non-AMP mimetic, small-molecule activators of AMPK,” the Kareus team reported. “In cell-based assays, KU-5039 activated AMPK with sub-micromolar potency compared to AICAR at 500 µM. KU-5039 exhibited excellent oral availability including distribution and AMPK modulation across targeted tissues (liver and skeletal muscle).”
 
In a mouse model of diabetes and insulin resistance, KU-5039 stabilized plasma glucose to near-normal levels within seven days of treatment. The plasma insulin levels were undetectable and insulin resistance, as measured by homeostatic model assessment, was normalized by day seven.
 
“Unlike pioglitazone, whose insulin sensitization was associated with weight gain, KU-5039 treatment of dbdb mice resulted in no weight gain,” the team reported. “Similarly, KU-5039 showed markedly improved insulin sensitization with no effect on plasma lactic acid levels versus metformin. The lead KU-5039 represents a promising approach for the treatment of insulin resistance in type 2 diabetes without the side effects associated with marketed insulin sensitizers.”
 
KU-5039 will commence first-in-human trials to evaluate its safety, tolerability and pharmacokinetics profile in a randomized, double-blind, placebo-controlled study. The Phase 1 study will be conducted by Quintiles, a leading biopharmaceutical services provider, Kareus notes.
 
“This is a major milestone for Kareus, demonstrating the power of its innovation and ability to build a pipeline cost effectively,” commented Dr. Uday Saxena, co-founder and head of R&D strategy at Kareus.
 
Khanna, head of preclinical, said, “Our preclinical studies have established that KU-5039 is not only a potent insulin sensitizer in diabetic models, but has a superior side effects profile, including no weight gain, no lactic acidosis and no hypoglycemia in comparison to currently available anti-diabetic drugs. We believe KU-5039 represents an important step towards identification of more effective options to treat diabetes.”
 
Diabetes mellitus is a metabolic disorder affecting a large and growing population. The International Diabetes Federation estimates that about 400 million people worldwide have diabetes and approximately 4.6 million patients die from the disease annually. Insulin resistance, which is present in 90 percent of diabetic patients, is considered a major predictor for the onset of type 2 diabetes. In addition, multiple studies have documented an association between insulin resistance and accelerated cardiovascular disease in patients with type 2 diabetes, as well as in non-diabetic individuals.
 
Kareus Therapeutics SA is a biopharmaceutical company that discovers and develops novel molecules for treatment of unmet needs in age-related and chronic diseases. Founded by Dr. K. Anji Reddy, Kareus has a pipeline of clinical and preclinical assets with distinct product profiles. The company’s pipeline also includes a central nervous system candidate, KU-046, which is undergoing a Phase 1 trial, and a preclinical candidate to treat chronic pain.
 
Kareus’ business strategy is to form strategic alliances with leading pharmaceutical companies or partners with complementary skills to maximize the potential of its molecules. In 2011, Kareus entered into a strategic drug development alliance with Quintiles to progress Kareus’ preclinical programs (Alzheimer’s and type 2 diabetes) into early clinical development.

Lloyd Dunlap

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