A Ph2b to Evaluate Tildacerfont in the Reduction of Glucocorticoid Steroid Doses in Adult CAH

A Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of SPR001 (Tildacerfont) in Reducing Supraphysiologic Glucocorticoid Use in Adult Subjects With Classic Congenital Adrenal Hyperplasia

An investigation of the ability of Tildacerfont to reduce supraphysiologic glucocorticoid dosing in classic Congenital adrenal hyperplasia (CAH) subjects up to 76 weeks of treatment. Optional open label extension up to 240 weeks.

This is a study that evaluated the ability of tildacerfont to reduce the glucocorticoid steroid dose used by adult subjects with CAH. The first 24-weeks were a double-blind, placebo controlled, comparison of tildacerfont vs placebo. The following 52-weeks allowed all subjects to move to open label tildacerfont to continue to reduce steroid dose where appropriate, and observe long term safety. Subjects were offered a long term open label extension up to 240 weeks.

Inclusion Criteria:

1. Male and female subjects ≥18 years old at screening
2. Has a known childhood diagnosis of classic CAH due to 21-hydroxylase deficiency based on genetic mutation in CYP21A2 and/or documented (at any time) elevated 17-hydroxyprogesterone (17-OHP) and currently treated with hydrocortisone (HC), HC acetate, prednisone, prednisolone, methylprednisolone, dexamethasone (or a combination of the aforementioned glucocorticoid [GCs])
3. Has lower limit of detection ≤ androstenedione (A4) ≤ 2.5x upper limit of normal (ULN) at screening measured before a morning GC dose
4. Has been on a stable, supraphysiologic dose of GC replacement (defined as ≥30 mg/day and ≤60 mg/day in HCe) for ≥1 month before screening
5. For subjects with the salt-wasting form of CAH, subject has been on a stable dose of mineralocorticoid replacement for ≥1 month before screening
6. Agrees to follow contraception guidelines. Male subjects must also agree to refrain from donating sperm throughout the Treatment Period and for 90 days after the last dose of study drug
7. Is able to understand all study procedures and risks involved and provides written informed consent indicating willingness to comply with all aspects of the protocol

Exclusion Criteria:

1. Has a known or suspected diagnosis of any other known form of classic CAH (not due to 21-hydroxylase deficiency)

2. Has a history that includes bilateral adrenalectomy or hypopituitarism

3. Has a history of allergy or hypersensitivity to tildacerfont, any of its excipients, or any other CRF1 receptor antagonist

4. Shows clinical signs or symptoms of adrenal insufficiency

5. Has had a clinically significant unstable medical condition, medically significant illness, or chronic disease occurring within 30 days of screening, including but not limited to:

   1. An ongoing malignancy or <3 years of remission history from any malignancy, other than successfully treated localized skin cancer
   2. eGFR of <45 mL/min/1.73 m2
   3. Current or history of liver disease (with the exception of Gilbert's syndrome)
   4. History of alcohol or substance abuse within the last year, or any significant history of alcohol or substance abuse that would likely prevent the subject from reliably participating in the study, based on the opinion of the Investigator
   5. Active hepatitis B, hepatitis C, or HIV at screening
   6. Subjects who plan to undergo bariatric surgery during the study are excluded
   7. Any other condition that would impact subject safety or confound interpretation of study results

6. Psychiatric conditions, including but not limited to bipolar disorder, schizophrenia, or schizoaffective disorders that are not effectively controlled on medication and may have an adverse impact on study compliance. Symptoms including hallucinations, delusions, and psychosis are exclusionary. Additionally:

   Increased risk of suicide based on the Investigator's judgment or the results of the C-SSRS conducted at screening and baseline (eg, C-SSRS Type 3, 4, or 5 ideation within the past 6 months or any suicidal behavior within the past 12 months) b. Hospital Anxiety and Depression Scale (HADS) score >12 for either depression or anxiety at screening or baseline

7. Has clinically significant abnormal ECG or clinical laboratory results. Abnormal results that must be reviewed and discussed with the Medical Monitor to determine eligibility for this study include but are not limited to:

   1. Any clinically meaningful abnormal ECG results, including QTcF >450 ms for male participants or >470 ms for female participants
   2. ALT >2x ULN
   3. Total bilirubin >1.5x ULN
   4. Total bile acids >5x ULN

8. Routinely works overnight shifts

9. Subjects with travel plans/work schedules that result in significant and frequent changes in time zones (>2 hours) will require Medical Monitor approval for enrollment

10. Females who are pregnant or nursing

11. Use of any other investigational drug from 30 days or 5 half-lives (whichever is longer) before screening to the end of the study

12. Use of the following drugs from 30 days or 5 half-lives (whichever is longer) before the start of the Treatment Period to the end of the study:

    1. Rosiglitazone, aromatase inhibitors, testosterone, growth hormones, or any other medication or supplement that could impact subject safety or confound interpretation of study results
    2. The drugs which are:

    i. Moderate to strong inhibitors and/or inducers of CYP3A4 ii. Sensitive substrates or narrow-therapeutic-range substrates of CYP3A4 (except hormonal contraception containing ≤35 μg ethinyl estradiol) iii. Sensitive substrates or narrow-therapeutic-range substrates of BCRP (except those that can be administered QD in the morning, separated by approximately 10 hours from evening administration of study drug)

13. Donation or receipt of blood from 90 days before Screening to the end of the study; donation or receipt of platelets, white blood cells, or plasma from 30 days before Screening to the end of the study