Project: M2001 as Prospective Drug for the Metabolic Syndrome

The Metabolic Syndrome comprises a cluster of diseases including visceral obesity, impaired glucose tolerance (IGT) leading to Diabetes type2 (NIDDM), combined dyslipidemia (increased plasma lipids with low HDL cholesterol), and essential hypertension. The Syndrome results in 3.5-fold increase in atherosclerotic cardiovascular disease (ASCVD), in higher risk of colon, prostate and breast cancer as well as in higher risk for some autoimmune diseases. The Syndrome and its individual diseases is genetically transmitted and driven by nutritional affluence. The Syndrome is epidemic in Western and Westernizing communities, with 50% prevalence in populations aged 50 and above, and overall prevalence of 25%. First line therapy for the Syndrome is life style change by dietary measures and physical exercise. However, the compliance to behavioral modification measures is poor. In light of its heavy health burden, treating the Syndrome is considered one of the most important challenges of medicine in affluent Western and Westernizing communities. _x000D_Grouping the apparently discrete diseases of the Syndrome into one disease entity implies common etiological targets and a comprehensive all-in-one treatment mode to be searched for. That in contrast to currently marketed as well as pipeline drugs that treat individual diseases of the Syndrome while falling short of offering a comprehensive treatment mode for the Syndrome entity. _x000D_SyndromeX MEDICA leads are highly stable, low-molecular-weight New Chemical Entities (NCEs) for oral use, designed to offer an all-in-one treatment mode for the Syndrome and its discrete diseases. Specifically, the MEDICA compounds consist of substituted long chain fatty acyl analogs that in contrast to natural fatty acids, are not beta-oxidized nor esterified into lipids, thus exploiting the “allosteric” activity of fatty acids in targeting unique transcription factors, kinases, transporters and channels involved in initiating and promoting the Syndrome, while avoiding the substrate role of natural fatty acids in generating fat and energy. The MEDICA prototype (MEDICA16) was the first to exploit the allosteric activities of natural long chain fatty acids (LCFA) in the Syndrome context. Medica16 has already offered a solid proof-of-concept for efficacy and safety in a series of obese, dyslipidemic, diabetic and atherosclerotic animal models for the Syndrome. Studies concerned with the MEDICA16 prototype have been reported in more than 40 publications in peer-reviewed prestigious journals (Annex A). MEDICA16 has paved the way for SyndromeX current lead, M2001, designed to be further developed as drug for the Syndrome and its discrete diseases._x000D_M2001 resulted from lead improvement of the MEDICA16 prototype in terms of respective efficacies, complemented by advanced insight of the transduction pathways to be targeted in order to cope with the complexity of the Syndrome entity. M2001 may offer an all-in-one treatment mode for combined dyslipidemia due to its statin-like efficacy in lowering plasma LDL-Cholesterol combined with robust decrease of plasma triglycerides in dyslipidemic animal models. Also, M2001 may offer first-line treatment mode for diabetes type 2 due its potent insulin-sensitizing capacity combined with normalizing hyperglycemia in animal models for diabetes type2. Furthermore, the anti-inflammatory anti-atherosclerotic activity of M2001 may offer a first-line treatment mode for the Syndrome-induced ASCVD. M2001 has accomplished all acute and subchronic toxicity studies required for IND submission for Phase I / IIa, including GMP synthesis in kg scale. M2001 is protected by composition of matter, use and method of treatment patents. _x000D_This proposal aims at accomplishing: _x000D_a. Phases I and limited IIa clinical studies for verifying the safety and efficacy of M2001 in humans. _x000D_b. In-deep analysis of the mode of action (MOA) of LCFA analogs as potential drugs for the Metabolic Syndrome and its associated disease components. _x000D_The proposed project is of crucial impact on health status of broad global and European populations at risk. M2001 may serve as benchmark for other LCFA analogs designed to mimic the allosteric efficacy of LCFA in treating human diseases. _x000D_The proposed consortium consists of: _x000D_a. SyndromeX Ltd. , an Israeli pharmaceutical SME that owns the MEDICA platform proprietary, including its M2001 lead. SyndromeX will coordinate the proposed project._x000D_b. Bridge BioResearch (BBR), a Danish SME that focuses on drugs for the Metabolic Syndrome, based on substituted LCFA (e.g., 2-hydroxy oleic acid (2-OHOA)). BBR will contribute expertise in dissecting the molecular MOA of substituted LCFA analogs. _x000D_c. BioLigands, a Danish SME that focuses on state-of-the-art global transcriptome profiling of drugs for the Metabolic Syndrome and its component diseases. BioLigands will contribute genomics, proteomics and bioinformatic aspects to the R&D of M2001 and 2-OHOA.

Acronym	MEDICA 2001 (Reference Number: 5138)
Duration	01/11/2010 - 31/10/2013
Project Topic	The Metabolic Syndrome comprises a cluster of diseases including visceral obesity, diabetes type2, dyslipidemia and essential hypertension, resulting in 3.5-fold increase in atherosclerotic cardiovascular disease. M2001 may offer an all-in-one treatment for the Syndrome and its discrete diseases.
Project Results (after finalisation)	The project confirmed the overall effect on energy expenditure and mechanism of action and helped to further elucidate these parameters in detail. More important an earlier seen effect on energy intake in rodents could not be replicated in a higher ranking species, dogs._x000D_
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
3	BBR Danmark ApS	Partner	Denmark
3	BioLigands Aps	Partner	Denmark
3	SyndromeX	Coordinator	Israel