SCIENTIFIC OVERVIEW
Addressing metabolic dysfunction from excess cortisol.
Excess cortisol impairs glucose control and drives treatment resistance in type 2 diabetes (T2D).
Cortisol is a natural glucocorticoid produced by the adrenal glands that plays a crucial role in regulating metabolism, the immune response, and the body's response to stress. At the normal level, cortisol contributes to glucose homeostasis in multiple ways.
However, when in excess, cortisol acts across different organ system pathways to decrease insulin production, increase insulin resistance, and increase gluconeogenesis (Figure 1).
This spectrum of dysfunction can cause or exacerbate type 2 diabetes and can render currently approved T2D therapies less effective.
Figure 1 - Pathways by which excess cortisol impairs glucose control and drives treatment resistance
Figure 2 – Intracellular regulation of cortisol by HSD-1 and HSD-2
A new understanding of cortisol regulation.
Cortisol’s effects are mediated exclusively by interaction with intracellular glucocorticoid, mineralocorticoid, and non-genomic receptors. Thus, only intracellular cortisol has biological effects.
Cortisol is synthesized de novo in the adrenal gland. When cortisol enters mineralocorticoid-sensitive tissues such as the kidney distal tubule, it is efficiently inactivated by the enzyme 11β-hydroxysteroid dehydrogenase type 2 (HSD-2) to the inert substance cortisone (Figure 2, A). Cortisone formed by HSD-2 enters circulation and then enters metabolically active tissues such as the liver, pancreas, muscle, and adipose. In those tissues, clofutriben’s target 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) reactivates cortisone to intracellular cortisol (Figure 2, B) in proximity to glucocorticoid receptors.
In this way, intracellular cortisol is regulated by the enzymes HSD-1 and HSD-2. HSD-1 converts inactive cortisone to active cortisol, while HSD-2 does the reverse.
How we’re modulating intracellular cortisol to improve glycemic control…
By utilizing a therapy that inhibits HSD-1, we can block the activation of cortisone to cortisol and thereby lower intracellular levels of cortisol in key metabolic tissues to reduce many of the adverse effects of cortisol excess. Our lead candidate, clofutriben, is a once-daily, oral HSD-1 inhibitor being developed for the millions of patients with type 2 diabetes with elevated cortisol. HSD-1 inhibition is a novel mechanism that complements existing antidiabetic agents by addressing a distinct source of metabolic dysfunction affecting multiple pathways to elevated glucose.
HSD-1 inhibition can reduce the ratio of active cortisol to inactive cortisone in the liver by 90%¹
… and address treatment resistance.
Many patients with type 2 diabetes remain unable to achieve adequate glycemic control even with the best therapies available today, including GLP-1 agonists and even injected insulin. Recent research points to elevated cortisol as a hidden driver of resistance for a large segment of these patients. By lowering intracellular cortisol, clofutriben targets biological processes that current agents don’t address, potentially helping patients regain control of their blood sugar when other options fall short.
Metabolic dysfunction from excess glucocorticoids like cortisol is pleotropic and can cause or exacerbate not only diabetes, but also hypertension, osteoporosis, hyperlipidemia, adiposity, and more.
Diabetes
Impaired Healing
Weight Gain
Depression
Heart Disease
Insomnia
Bone Fractures
Glaucoma
Muscle Weakness
Memory Loss
Exploiting the demonstrated potential of HSD-1 inhibition.
Several HSD-1 inhibitor candidates previously reached Phase 2 clinical trials with no significant class side effects observed. HSD-1 inhibitors were generally found to be safe and well-tolerated, as well as highly successful in engaging their targets and lowering intracellular cortisol levels.
However, the efficacy seen in conditions like type 2 diabetes was similar to available generic antidiabetic agents and therefore deemed not commercially attractive.
Sparrow is taking a different approach, with a better molecule.
Because HSD-1 inhibition would be expected to provide the greatest benefit to patients in whom excess cortisol exacerbates or causes their disease, clofutriben could be the ideal agent for patients with T2D and elevated cortisol.
With improved pharmacodynamic properties, clofutriben is poised to overcome drawbacks that hindered early HSD-1 inhibitors.
¹ Liu, Wei, et al. American College of Clinical Pharmacology, 2013. https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/cpdd.5.