Differentiated OADs for geriatric and post-menopausal population with impact on sarcopenia, visceral adiposity and other metabolic outcomes.
11HSDβ1 is a member of the short-chain dehydrogenase-reductase family and a key intracellular enzyme which catalyses the conversion of inactive cortisone to active cortisol. Tissue level 11HSDβ1 expression and activity is reported to be high in obese individuals with T2D. Reducing cortisol levels by inhibiting 11HSDβ1 activity in multiple metabolic tissues can provide an important therapeutic handle in these patient populations.
CNX-010-49 is the most advanced candidate from this program fulfilling the TPP of a next generation anti-diabetic, demonstrating significant impact on multiple metabolic parameters without causing HPA activation:
- Significant improvement in fasting and post-prandial hyperglycemia.
- Significant reduction of hyper-insulinemia.
- Significant decrease in serum TG.
- Improvement in insulin sensitivity.
- Sustained reduction in weight gain.
- Increased thermogenesis and improved adipocyte morphometry.
- Improvement in established serum markers of CVD.
Connexios’ leads have shown the selective inhibition across Muscle, Adipose and the liver that is critical for efficacy with this Mechanism of Action. Pre-clinical studies in different animal models have demonstrated the potential of these compounds to regulate core mechanisms specific sub-populations including the geriatric population and post-menopausal women who suffer from impaired growth hormone signalling and increased visceral obesity. The program also includes biomarkers that can link pathology in specific tissues to tissue-specific cortisol imbalance and can be used as companion diagnostics to assess the impact of therapeutic candidates during development
The program is currently in lead generation with multiple series of potent 11HSDβ1 Inhibitor generated.
Inhibition of 11HSDß1 by CNX-10-49 enhancing energy expenditure in the periphery by reducing adipose hypertrophy and improving brown adipose like character in treated DIO animals
Inhibition of 11HSDß1 by CNX-10-49 significantly reduces serum levels of multiple markers associated with CVD risk