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A small molecule AMP activated protein kinase (AMPK) activator, denoted O304, as a novelinnovative drug for the treatment of type 2 diabetes

Periodic Reporting for period 1 - AMPK-DIAB (A small molecule AMP activated protein kinase (AMPK) activator, denoted O304, as a novelinnovative drug for the treatment of type 2 diabetes)

Reporting period: 2016-11-01 to 2017-08-31

This project aims to take the key step on the way towards establishing a small molecule AMP activated protein kinase (AMPK) activator, denoted O304, as a novel first-in-class innovative drug for the treatment of type 2 diabetes (T2D) and associated cardiovascular complications, including heart failure and peripheral arterial disease.
Today, diabetes is a constantly growing global epidemic that threatens the economies and health care systems of all nations, both Western economies and developing countries. Fuelled by rapid urbanization, changing lifestyles and the rise in obesity, T2D has become the major scientific interest of pharma companies that continuously pursue new business opportunities in early diagnosis and treatment of the disease.
Currently, the patients diagnosed with T2D are recommended a change in lifestyle and the drug Metformin is the first line of treatment for T2D. When Metformin treatment becomes insufficient, a number of add-on treatments are used, including insulin. None of the existing drugs, however, specifically increases glucose uptake and/or reduces insulin resistance in skeletal muscle a primary cause of obesity-induced T2D, and no current drug can reverse β-cell stress/dysfunction and induce β-cell rest, and typically about 40 % of the patients still do not reach the goal of reducing Hba1C to <7 %. In all, it is estimated that only approx. 10 % of T2 diabetics reach the goal of living a complication free life. Cardiovascular diseases (CVD), including heart failure remain the main cause of death among T2 diabetics.
Recognizing the unmet clinical need and a strong business opportunity, Betagenon has developed and pre-validated the first candidate AMPK activator drug in T2 diabetics. AMPK is a key regulator of energy balance, both on a single cell level and the whole organism level which is normally activated by physical activity and/or caloric restriction. On a cellular level, AMPK regulates both glucose and lipid metabolism. AMPK also governs whole body energy metabolism by the regulation of food intake in the hypothalamus and increases the delivery of nutrients and oxygen to tissues and organs by modulating cardiovascular function. The drug-mediated activation of AMPK may thus mimic physical activity and caloric restriction and be highly beneficial to T2 diabetics. Given the above, the interest in developing and commercializing AMPK activators as a treatment for T2D and CVD, including heart failure, and possibly obesity, is high among pharma companies internationally.
The current project is strategically focused on performing a Phase IIa proof-of-concept validation of O304 in type 2 diabetic patients stably on Metformin. This will enable Betagenon to commercialize the product through outlicensing to a Phase IIb and Phase III validation partner and ultimately bring it to the market. The commercial output will be new competitive advantages and accelerated growth for Betagenon.
The project progresses according to the clinical and commercial assumptions outlined in the proposal:
• As per September 2017, the Phase IIa clinical trial at the core of the project has been successfully completed. Currently, the team is performing the analysis of the results. The full and signed study report will be available in November, 2017.
• On the commercial side, the main assumption in the project was to deliver clinical data that generates interest from the potential big pharma license takers. The dissemination and communication activities performed by Betagenon have already attracted attention of such players. One potential license taker has already performed a complete extensive due diligence of Betagenon’s in vitro, cellular and animal disease model results, of chemistry and large scale production of O304, of patents-agreements and freedom to operate.

As such, the activities performed in the first reporting period show strong alignment with Betagenon’s market strategy by addressing the key areas required to successfully meet market demands: clinical acceptance and investor/partner acceptance:
• Clinical acceptance will be strengthened by the results generated through the Phase IIa validation. The clinical report will provide evidence that O304 is potentially a clinically viable and justifiable treatment option for T2 diabetics with potential for improved QoL and clinical outcomes.
• The investor/partner acceptance will be generated by the dedicated set of dissemination and exploitation activities included in the project. Betagenon actively promotes its research on the international level, targeting the clinical and pharma communities, and thus generating strong interest in licensing O304.
Currently, change of life style is the initial recommendation to T2 diabetics and Metformin is first-in-line treatment for T2D. The second-line therapy involves the use of other drugs in combination with Metformin. The established second-line therapy involves the use of sulfonylureas, a highly genericized class of drugs, in combination with metformin. The usage of this class of drug is likely to decline in future due to the recent approval of superior products and the anticipated approval of stronger products, such as GLP-1 agonists, DPP-4 inhibitors and SGLT-2 inhibitors. . None of the existing drugs, however, specifically increases glucose uptake and/or reduces insulin resistance in skeletal muscle a primary cause of obesity-induced T2D, and no current drug can reverse β-cell stress/dysfunction and induce β-cell rest, and typically about 40% of the patients still do not reach the goal of reducing Hba1c to <7%.

Physical activity and caloric restriction reduces energy levels both at the cellular and whole organism level, and are favourable in preventing/reducing obesity and associated metabolic and cardiovascular diseases. Reduced energy levels activate AMPK that blocks anabolic and stimulates catabolic pathways to restore energy charge. Thus, pharmacological activation of AMPK should in principle mimic physical activity and caloric restriction, hence the large interest in developing AMPK activators as a treatment for T2D and CVD, and possibly obesity.

As an AMPK activator, O304 appears to fulfil these hopes and expectations. O304 efficiently increases glucose uptake and reduces insulin resistance in skeletal muscle a primary cause of obesity-induced T2D. O304 also reverses β-cell stress/dysfunction and induce β-cell rest. O304 also increases energy expenditure and protects against diet induced obesity, fatty liver, hyperlipidemia and diabetes. CVD remains a major cause of death of T2 diabetics, and O304 increases peripheral blood flow and left ventricular function, and acts as an “Exercise mimetic”. Thus, as an AMPK activator O304 uniquely mitigates many of the metabolic and cardiovascular complications associated with the obesity epidemic. O304 has the unique potential to increase glucose uptake and reduce insulin resistance in newly diagnosed T2 diabetics and as such prevent the associated β-cell hyperactivity/failure and progression of the disease.
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