The pharmacology data focus on the human body’s homeostatic response to potent HSD-1 inhibition by SPI-62.
Results highlight that urinary free cortisol is distinct from intracellular cortisol that causes symptoms in patients with Cushing’s syndrome or autonomous cortisol secretion.
Sparrow Pharmaceuticals, a clinical-stage biopharmaceutical company developing novel, targeted therapies to address unmet needs in both endocrinology and rheumatology, presented pharmacological data during an in-person poster session and a Rapid Fire e-Poster Presentation titled, “HPA Axis Modulation by a Potent Inhibitor Indicates 11β-Hydroxysteroid Dehydrogenase Type 1 (HSD-1) Is a Significant Contributor to Cortisol Levels” at the Endocrine Society 2022 Annual Meeting (ENDO 2022). Researchers examined glucocorticoid changes in healthy adults after administration of Sparrow’s lead therapeutic candidate, SPI-62, a HSD-1 inhibitor.
“For patients with Cushing’s syndrome, normalized urinary free cortisol, or UFC, is a standard therapeutic target, and yet it’s a biomarker that doesn’t measure the cortisol that can access intracellular receptors and cause symptoms,” says David A. Katz, Ph.D., CSO at Sparrow Pharmaceuticals. “In fact, studies have shown that UFC normalization doesn’t correlate with clinical endpoints in patients with Cushing’s syndrome. While many patients with autonomous cortisol secretion may have normal UFC, they suffer substantial cortisol morbidity affecting the liver, adipose, bone, and brain. As Sparrow conducts clinical trials for these patient populations, the goal is to find better ways to measure the cortisol that causes the fundamental problem.”
The study analyzed historical clinical trial data to better characterize how SPI-62 impacts cortisol levels and the body’s homeostatic response to those changes.
“For patients with Cushing’s syndrome, normalized urinary free cortisol, or UFC, is a standard therapeutic target, and yet it’s a biomarker that doesn’t measure the cortisol that can access intracellular receptors and cause symptoms.”
David A. Katz, PhD, CSO, Sparrow Pharmaceuticals
Conclusions of the study include:
- Half of hepatocellular cortisol with access to intracellular receptors is generated in healthy adults by HSD-1;
- ACTH increase compensates for the effect of HSD-1 inhibition on systemic cortisol levels;
- Secondary increases of androgen levels have not been associated to date with clinical consequences; and
- Large changes of the amount of cortisol that can bind intracellular receptors, and thus cause cortisol-related morbidity, can occur independently of urinary free cortisol levels.
HSD-1 converts cortisone to cortisol in tissues in which cortisol excess is associated with morbidity including liver, adipose, bone, and brain. SPI-62 is a potent HSD-1 inhibitor in clinical development for treatment of Cushing’s syndrome and autonomous cortisol secretion, and as adjunctive therapy to prednisolone in polymyalgia rheumatica. In prior clinical trials SPI-62 was generally well tolerated and associated with maximal liver and brain HSD-1 inhibition.
To view the abstracts, visit ENDO 2022’s website here.
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