Successful completion of Phase I clinical trial of AMPK activator O304
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1 Successful completion of Phase I clinical trial of AMPK activator O304 O304 is safe and very well tolerated in young healthy subjects, in middle aged obese subjects, and in type 2 diabetics in combination with Metformin Significant Pharmacodynamic effects aimed for Type 2 diabetes and Cardiovascular Disease 1
2 AMP-activated protein kinase (AMPK) Master Regulator of Energy Balance Activated by energy shortage (reduced ATP) AMPK activation mimics caloric restriction and/or physical activity Increases glucose and lipid metabolism in multiple organs/tissues Improves cardiac function and peripheral blood flow to supply nutrients Pharmacological activation of AMPK a promising approach to prevent/cure T2D, obesity, fatty liver and CVD 2
3 AMPK activator O304 Mechanism of Action O304 suppresses the dephosphorylation of p-t172 AMPK without inhibiting PP2C A A Mimics ADP 3
4 O304 activates AMPK in the presence of excess ATP O304 and ADP acts in an addidative manner 4
5 O304 is a PAN AMPK activator * O304 suppresses the dephosphorylation by PP2C of human recombinant p-t172 AMPKα1,2 and β1,2 trimers 5
6 O304 activates AMPK and increases cellular ATP in non-transformed human cells 6
7 * O304 activates AMPK and suppresses lipid synthesis in human primary hepatocytes * O304 activates AMPK and increases glucose uptake in human primary skeletal myotubes 7
8 O304 is orally available O304 is orally available Long t1/2 8
9 In Type 2 Diabetics, O304 would initially be used in combination with Metformin Experimental setup: Mice fed high fat diet (HFD) gavaged with O304 +/- Metformin (100mg/kg/day each) 9
10 On-target O304+/-Metformin, not Metformin, significantly increases p-t172 AMPK in calf muscle 10
11 O304 +/- Metformin, not Metformin, potently protect against HFD-induced insulin resistance 6 weeks on HFD O304+Metformin most effective 11
12 O304 +/- Metformin, not Metformin, significantly protect against HFD-induced fatty liver O304+/-Metformin reduces expression of key lipogenic enzymes Pooled cdna 12
13 O304+Metformin protects against increase plasma total cholesterol O304+Metformin reduces liver and plasma PCSK9 13
14 O304+/-Metformin protects against obesity and increases energy expenditure 14
15 O304 +/- Metformin, not Metformin, protects against body weight and fat gain Metformin; 8% decrease in food intake O304+/-Metformin; No effect on food intake 15
16 O304+Metformin induces Browning of iwat and increases energy expenditure With no increase in core temperature 16
17 O304+Metformin normalizes established HFD-induced insulin resistance Mice on HFD for 7 weeks become obese, hyperglycemic, hyperinsulinemic Mice were fed HFD during the subsequent 4 week treatment No effect on food intake or body fat 17
18 (mmol/l) (ng/ml) High dose Metformin (250 mg/kg/day) Fasted (6h) Glucose ** ** 1 2,0 1,0 0,0 Fasted (6h) Insulin * * ** 1 20 HOMA-IR O304+Metformin most efficient * ** *** Vehicle Metformin 250 mg/kg O mg/kg O304 + Metformin 0 2 weeks on HFD 1 O304 (100 mg/kg/day) still more effective than high dose Metformin 18
19 High dose Metformin reduces food intake and increases blood lactate (adverse effects) O304 does not reduce food intake or increase blood lactate or amplify the effect of high dose Metformin
20 O304 1gr/kg/day for 7 days in rat does not increase blood lactate levels Cmax 800 u cmax 800 um 20
21 AMPK and cardiovascular function Loss of AMPK activity decreases cardiomyocyte contraction AMPK increases Ca2 + sensitivity of force development AMPK activation also enhances endothelial cell survival and vasodilation and reduces smooth muscle cell proliferation 21
22 O304+/-Metformin, but not Metformin, improve left ventricular stroke volume and contractibility in mice fed HFD 22
23 O304 increases peripheral blood perfusion in aged (14 mo) mice 23
24 Exercise in a pill O304 significantly improves endurance (running distance) of normal sedentary aged mice Distribution of mice exhibiting different running distance 24
25 Significantly lower plasma lactate levels at exhaustion in 14 month old mice treated with O304 25
26 Preclinical summary O304+/-Metformin Mitigates established Insulin resistance/diabetes Protects against Obesity, Fatty liver and Hyperlipidemia O304 improves Peripheral blood flow, Cardiac function and Endurance ( Exercise in a pill ) O304 acts by a different mechanism than Metformin O304 is both more efficient and safer than Metformin and have additional beneficial vascular effects, O304+Metformin most efficient 26
27 Phase I MAD4 study (17 days) O304 reduces significantly fasting plasma glucose in type 2 diabetics treated with Metformin 27
28 Phase I MAD5 study in middle aged obese subjects Setup for monitoring reactive hyperemia in calf muscle by MRI Relative T2* curves for the same patient at baseline (blue) and follow-up (orange) Gastronemicus
29 Linear fit (blue line) of the change in T2* during the hyperemic flow following release of the cuff Figure 3 shows the linear fit (blue line) of the change in T2* during the hyperemic flow following release of the cuff around the thigh.
30 Compared to baseline, O304 significantly increases the rate of hyperemic perfusion in gastronemicus Relevant for Peripheral arterial disease and diabetic vascular disease
31 Phase IIa study Proof-of-concept study of O304 in type 2 diabetics treated with Metformin and monitoring metabolic and cardiovascular effects Higher exposure (1,5-2x) and longer duration (28 days) than in the Phase I MAD4 (17 days) study in type 2 diabetics 31
32 Patent covering O304 granted in the US, EU, China and multiple smaller countries 32
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