AP 02-00 SERIES: ARTERIA FIRST IN CLASS THERAPEUTIC MOLECULE SERIES FOR THE TREATMENT OF CARDIOMETABOLIC DISEASE

Using cell based high through-put screening systems, Arteria has identified several molecules that effectively inhibit the capacity of CD36, a primary macrophage scavenger receptor, to capture oxidized lipoprotein. After hit selection, it was shown that a lead molecule of this new series, suppresses oxidized lipoprotein accumulation in macrophages and subsequent inflammatory response of lipid loaded cells while leaving unaffected the physiological function of the scavenger target. Several independent animal screening showed that single daily administration of pharmacological doses of the selected lead dramatically reduces the plasma level of triglyceride, and the concomitant appearance, onset and size of macroscopic and microscopic heart and aortic lesions in different rodent models with severe metabolic syndrome. In addition, this molecule can restore insulin sensitivity and left ventricular function.

These pharmacological data were also critically reviewed by both, clinical experts and pharmaceutical industry product development specialists. Their conclusion was that the novel lead and its potential back-up molecules are both pharmacologically potent and fulfil important currently unmet medical needs. Indeed, despite progresses in delaying atherosclerosis by controlling plasma cholesterol and hypertension, progressive heart insufficiency occurring as a result of obstructive coronary disease and lipotoxicity due to hypercholesterolemia, hypertriglyceridemia, type II diabetes, atherosclerosis and over eating leading to obesity remains a common and costly medical concern.

Arteria pre-clinical proof of concept data is highly significant. All animal experiments have been performed by independent and expert investigators that conducted their studies blindly and achieved essentially the same conclusions and interpretation of the data.

The beneficial effects on microscopic arterial lesion size and structure and on aortic lipid content are not only statistically significant but most impressive. Indeed, the observed selective and massive (greater than 50 % at 1 mg/kg) reduction of circulating triglycerides without any changes in food intake has never been achieved by any known dietary measure or pharmacological agents. Furthermore, several surrogate markers of inflammatory condition induced by the metabolic syndrome and atherosclerosis lesions are significantly improved by Arteria novel lead.

DIAP 2 : DIABETES TYPE 2

Diap-2 is a new patented molecule composed of metformin the reference drug for type 2 diabetes) and arginine, bridged by succinic acid. The choice of arginine relies on the fact that it is a natural compound, structurally relatively close to metformin and which is the natural precursor of nitric oxide (NO). Arginine per se has very little efficacy on glycemia but since both metformin and arginine use the same membrane transporters, synergy between both molecules can be expected. Succinic acid is a di-acid, entering the krebs cycle, and permits the chemical bridging between arginine and metformin. Due to an imide bound between succinic acid and arginine, the latter is expected to be liberated more progressively than metformin, which is simply bound as a salt. Arginine is prone to generate NO, the most important vasodilatator and which is also implicated in glucose transport when stimulated by insulin.

The experimental data appear to be highly significant. In a model of type 2 diabetes induced by low-dose streptozotocin, Diap-2 exhibits a glycemia-lowering efficacy which is twice that of metformin at equivalent oral dosage (Fig.4).

It should also be mentioned that in rats with severe, insulin- deficient diabetes, Diap-2 still shows remarkable efficacy, while metformin fails to reduce hyperglycemia. Should this preliminary observation be confirmed, it might open new applications for patients suffering insulin-requiring type 2 diabetes (about 6%) of the total type 2 diabetic population.

The combined utilization of arginine and metformin (both well-known molecules) in this arrangement raises hope for less clinical side-effects than classical new unknown molecules.

Finally, it is worth mentioning that Diap-2 does not increase insulin secretion and thus does not raise the risk of hypoglycaemia.