A Study to Evaluate the Safety and PK of CRN04894 for the Treatment of Cushing's Syndrome

Study Overview
=================
Brief Summary
-----------------
A Phase 1b/2a, first-in-disease, open-label, multiple-ascending dose exploratory study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with CRN04894 (an adrenocorticotropic hormone [ACTH] receptor antagonist) in participants with ACTH-dependent Cushing's syndrome (Cushing's disease or Ectopic ACTH Syndrome [EAS])

Detailed Description
-----------------
This is a Phase 1b/2a, first-in-disease, open-label, multiple-ascending dose exploratory study to evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamic biomarker responses associated with CRN04894 (an adrenocorticotropic hormone [ACTH] receptor antagonist) over a 10-day treatment period in participants with ACTH-dependent Cushing's syndrome (Cushing's disease or Ectopic ACTH Syndrome [EAS]).Participants will receive oral CRN04894 once daily for 10 days, followed by monitoring during 4 'wash-out' days.

Official Title
-----------------
A Phase 1b/2a Open-label Multiple-ascending Dose Exploratory Study of CRN04894 in ACTH-dependent Cushing's Syndrome (Cushing's Disease or Ectopic ACTH Syndrome)

Conditions
-----------------
Cushing Syndrome, Cushing Disease, Ectopic ACTH Syndrome

Intervention / Treatment
-----------------
* Drug: CRN04894


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Male or female, aged 18-75 years Vaccination against COVID-19 according to current CDC recommendations Evidence of 'active' ACTH-dependent Cushing's syndrome within 14 days of Day 1 Participants with documented ACTH-dependent Cushing's syndrome taking short-acting steroidogenesis inhibitors (ketoconazole, levoketoconazole, osilodrostat, cabergoline or metyrapone) may participate after a 14-day washout period, if they meet other study inclusion criteria Exclusion Criteria: Women who are pregnant or lactating History of bilateral adrenalectomy Previous pituitary MRI findings of a lesion within 3 mm of the optic chiasm Presence of any known malignancy A UFC more than 5-fold ULN Use of mitotane Previous unsuccessful surgery for Cushing's syndrome within 6 weeks

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multiple Ascending Doses<br>Sequential, open-label, 10-day fixed-dose cohorts. | Drug: CRN04894<br>* CRN04894 is an orally active investigational agent which antagonizes the action of ACTH at its receptor administered as oral tablets.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of participants with treatment emergent adverse events (TEAEs) |  | Up to Day 15 | 
| Proportion of participants with adrenal insufficiency |  | Up to Day 15 | 
| Proportion of participants with safety findings determined by laboratory testing |  | Up to Day 15 | 
| Assessment of the maximum observed plasma concentration of CRN04894 |  | Up to Day 15 | 
| Assessment of the time to achieve maximum observed plasma concentration of CRN04894 |  | Up to Day 15 | 
| Assessment of the plasma area under the curve of CRN04894 |  | Up to Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from baseline in early morning serum cortisol |  | Day 11 |