HSD-1
The underappreciated source of intracellular steroids.
The traditional view of glucocorticoid (steroid) biology is incomplete.
Currently, when evaluating conditions of steroid excess, doctors focus on levels circulating in the bloodstream, whether secreted by the adrenal gland, or introduced exogenously as a medicine. But this is only a part of the reality.
What is more important is the amount of active steroids present at the intracellular level of key tissues, where the steroids are available to act on their receptors inside the cell to cause toxicity.
Understanding the roles of HSD-1 and HSD-2 as steroid regulators.
Intracellular steroids are regulated by the enzymes 11β-hydroxysteroid dehydrogenase type 1 (HSD-1) and 11β-hydroxysteroid dehydrogenase type 2 (HSD-2). HSD-1 converts inactive cortisone to active cortisol, while HSD-2 does the reverse. Together, they enable each cell to regulate the level of cortisol available to serve its beneficial functions without causing toxicities. When you think about it, this makes intuitive sense. For diverse organs and bodily functions, why would the intracellular level of the potent steroid cortisol be completely regulated by the distant, one-size-fits-all HPA-axis?
In reality, cortisol secreted by the adrenal gland is taken up by organs like the kidney where HSD-2 converts it to cortisone. Cortisol and cortisone both circulate in the bloodstream. However, due to differential protein binding properties, cortisone is ordinarily about five times more freely available to enter cells of key tissues. Once inside a cell, cortisone is activated by HSD-1 back to active cortisol. HSD-1 and HSD-2 act similarly on cortisol analogues such as prednisolone and its inactive form prednisone. In this way, HSD-1 is a major source of active intracellular steroids.
One important potential exception is the immune system, where HSD-1 appears to serve a less important role. This may allow for the separation of the desirable and undesirable effects of steroid medicines.
Both clinical and non-clinical evidence suggests that HSD-1 inhibition can reduce the toxicities of steroids, without substantially affecting the desired anti-inflammatory effects of steroid medicines.¹
In healthy adults, HSD-1 inhibition can reduce the ratio of active to inactive cortisol in the liver by 90%²
Exploiting the demonstrated potential of HSD-1 inhibition.
HSD-1 inhibition was a popular target in the pharmaceutical industry in the first decade of the 21st century. Several candidates 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 conditions previously pursued with HSD-1 inhibitors, such as type 2 diabetes, hypertension, and dementia, were not ideally suited for the mechanism. This is because while cortisol plays a role in each of these conditions, it is only one of many causes of these multi-factorial diseases. Therefore, though HSD-1 inhibition did demonstrate clinical efficacy in some cases, its level of efficacy in a general population was often not sufficient to warrant further development.
How we’re opening up new therapeutic avenues.
Building on the extensive prior experience with HSD-1 inhibition, Sparrow is exclusively developing our HSD-1 inhibitors for unmet needs in which excess steroids are the dominant causal factor.
¹ Othonos, Nantia, et al. TICSI, 2020. https://www.endocrine-abstracts.org/ea/0070/ea0070oc3.6
² Liu, Wei, et al. American College of Clinical Pharmacology, 2013. https://accp1.onlinelibrary.wiley.com/doi/pdf/10.1002/cpdd.5