SPI-62 as a Treatment for Adrenocorticotropic Hormone-dependent Cushing's Syndrome

This is a multicenter, randomized, placebo-controlled, Phase 2 study to evaluate the pharmacologic effect, efficacy, and safety of SPI-62 in subjects with ACTH-dependent Cushing's syndrome. Each subject who provides consent and meets all inclusion and exclusion criteria will participate in a screening period (Days -35 to -8), a baseline period (Days -7 to -1), and a treatment period (Day 1 of Week 1 to Day 168 ± 3 days of Week 24) and, the option of long-term extension. Subjects have the option to continue with the study on active study drug and return to the site every 3 months for blood tests and study drug dispensing. The visits may be conducted remotely if testing can be arranged.

• SPI-62 (Drug): 11β hydroxysteroid dehydrogenase type 1 (HSD-1) inhibitor
• Placebo (Drug): Inactive tablets identical to SPI-62 tablets

Primary outcomes

• Change from baseline in urinary HSD-1 ratio [Baseline to 6 weeks]: The urinary HSD-1 ratio (tetrahydrocortisol + allotetrahydrocortisol ) / tetrahydrocortisone will be used as a biomarker of HSD-1 activity in liver. The primary analysis will include only subjects with Cushing's disease.

Secondary outcomes

• Treatment emergent adverse events [Baseline through 24 weeks of treatment]: Adverse events including clinically significant abnormal values on clinical laboratory evaluations, continuous glucose monitoring (CGM), 12-lead ECGs, vital signs measurements (including orthostatic vital sign measurements), physical examinations, and HPA and HPG axis biomarkers

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male or non-menstruating female
* 18 years or older
* Active and consistent cortisol excess
* Documented diagnosis of ACTH-dependent Cushing's syndrome including Cushing's disease, ectopic ACTH secretion, and ectopic CRH secretion.

Exclusion Criteria:

* Recent (within 6 weeks) surgery for Cushing's or surgery planned within 24 weeks of randomization.
* History of any fractionated radiation therapy for Cushing's within the past 2 years or conventional radiation therapy within 4 years.
* History of bilateral adrenalectomy or exogenous, pseudo, cyclic, or non-ACTH-dependent Cushing's syndrome (including certain inherited conditions).
* High risk of acute morbidity from corticotroph adenoma growth (similar to that which occurs with Nelson's syndrome) defined as current evidence of macroadenoma at risk of impingement of vital structures.
* Any current or prior medical condition, medical or surgical therapies, or clinical trial participation expected to interfere with the conduct of the study or the evaluation of its results, including but not limited to poor venous access or recent receipt or donation of blood products.
* Women who are currently pregnant, lactating or planning fertility and unwilling to adhere to approved contraceptives or abstinence.

• Frank Czerwiec, MD, Study director, Sparrow Pharmaceuticals (info@sparrowpharma.com)