Study of SPR001 in Adults With Classic Congenital Adrenal Hyperplasia

This is a 6-week, multiple-dose, dose escalation study of SPR001 for the treatment of adults with classic CAH. After screening, eligible patients will be enrolled into a 6-week treatment period followed by a 4-week washout/safety follow-up period.

It is initially planned that up to approximately 18 patients in 2 dose cohorts will be enrolled. Additional patients or dose groups may be considered based upon specific safety, PK/PD, and/or efficacy findings, or if an active dose has not yet been reached.

SPR001 will be administered as an oral daily dose. Patients will undergo titration of SPR001 through three escalating dosage strengths at 2-week intervals. Patients will have overnight PK/PD assessments performed at baseline, which include an pre-dose overnight assessment and a post-dose overnight assessment for PK/PD following administration of the first dose. At the end of each 2-week dosing period, patients will return for single overnight visits for steady-state PK/PD assessments.

A follow-up outpatient visit will occur 30 days after their last dose.

• SPR001 (Drug): SPR001 Capsules

Primary outcomes

• Safety of SPR001 in Patients With CAH [6 weeks]: Incidence of treatment-emergent adverse events, changes from Baseline to End-of-study in clinical laboratory parameters, physical examination findings, vital signs, ECG parameters
• Change in 17-hydroxyprogesterone [Cohort A: Baseline/2a (Day -1-0), First dose/2b (Day 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41-42). Cohort B and Cohort C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 14-15), Visit 5 (Last dose +30d)]: Change in 17-hydroxyprogesterone from Baseline to End-of-study. Results are expressed as mean percent change from baseline. Reductions in 17-OHP are indicators of better disease control.

Secondary outcomes

• Changes in Pharmacodynamic (PD) Markers [Cohort A: Visit 2a (Day -1 to 0), Visit 2b (Days 0-1), Visit 3 (Day 13-14), Visit 4 (Day 27-28), Visit 5 (Day 41 to 42). Cohorts B+C: Visit 2 (Day 0-1), Visit 3 (Day 8), Visit 4 (Day 27-28), Visit 5 (+30 days after last dose)]: Changes in adrenocorticotropic hormone (ACTH) and androstenedione (A4) from Baseline to End-of-study are measured in patient serum. Results are expressed as a mean percentage change from baseline. A negative change indicates improvement.
• Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) [Serial PK sampling was performed at the end of the 2 weeks for all cohorts and dose levels]: To evaluate the pharmacokinetic (PK) parameter of maximum plasma concentration (Cmax) of SPR001 in patients with CAH.
• Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) [For Cohort A, serial blood collections were made for PK measurements on Day 1 for 200 mg SD and at Week 2 for all QD dose levels. In Cohorts B and C, serial blood samples were drawn for PK measurements at the end of the 2-week treatment period.]: To evaluate the PK parameter of area under the concentration-time curve (AUC) of SPR001 in patients with CAH

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Male and female patients age 18 or older.
* Documented diagnosis of classic CAH due to 21-hydroxylase deficiency
* Elevated 17-OHP at screening
* On a stable glucocorticoid replacement regimen for a minimum of 30 days

Exclusion Criteria:

* Clinically significant unstable medical condition, illness, or chronic disease
* Clinically significant psychiatric disorder.
* Clinically significant abnormal laboratory finding or assessment
* History of bilateral adrenalectomy or hypopituitarism
* Pregnant or nursing females
* Use of any other investigational drug within 30 days
* Unable to understand and comply with the study procedures, understand the risks, and/or unwilling to provide written informed consent.

Participant flow

Outcome results

• Safety of SPR001 in Patients With CAH (Primary), Count of participants, Participants: Cohort A 6; Cohort B 5; Cohort C 4
• Change in 17-hydroxyprogesterone (Primary), Mean, percentage of mean change from baseline: Cohort B -47.79 +/- 63.300; Cohort C -33.19 +/- 41.604; Cohort A - Dose A 22.16 +/- 172.298; Cohort A - Dose B -23.71 +/- 64.146; Cohort A - Dose C -13.79 +/- 74.742
• Changes in Pharmacodynamic (PD) Markers (Secondary), Mean, percentage of mean change from baseline: PD Population Cohort B -26.05 +/- 54.807; PD Population Cohort C 16.66 +/- 120.211; PD Population - Cohort A Dose A -28.53 +/- 53.834; PD Population Cohort A - Dose B -67.60 +/- 32.100; PD Population - Cohort A - Dose C -36.83 +/- 48.510
• Pharmacokinetic Parameter - Maximum Plasma Concentration (Cmax) (Secondary), Mean, ng/dL: PK Population Cohort B 411.25 +/- 130.107; PK Population Cohort C 200.96 +/- 132.262; PK Population - Cohort A Dose A 283.69 +/- 150.116; PK Population Cohort A - Dose B 719.30 +/- 325.056; PK Population - Cohort A - Dose C 892.56 +/- 289.272; PK Population Cohort A - Dose A (After single dose) 96.35 +/- 86.1
• Pharmacokinetic Parameter - Area Under the Concentration-time Curve (AUC) (Secondary), Mean, ng*hr/dL: PK Population Cohort B 2975.968 +/- 970.6; PK Population Cohort C 1425.582 +/- 941.9188; PK Population - Cohort A Dose A 1474.162 +/- 642.6; PK Population Cohort A - Dose B 4449.263 +/- 1826.4801; PK Population - Cohort A - Dose C 6212.983 +/- 2051.9077; PK Population Cohort A - Dose A (After single dose) 421.539 +/- 331.54

Adverse events

Time frame: 6-week treatment period followed by a 4-week washout/safety follow-up period

Other adverse events by term

• Results publication: Sarafoglou K, Barnes CN, Huang M, Imel EA, Madu IJ, Merke DP, Moriarty D, Nakhle S, Newfield RS, Vogiatzi MG, Auchus RJ. Tildacerfont in Adults With Classic Congenital Adrenal Hyperplasia: Results from Two Phase 2 Studies. J Clin Endocrinol Metab. 2021 Oct 21;106(11):e4666-e4679. doi: 10.1210/clinem/dgab438. PMID 34146101

• Study Protocol (PDF, 2018-08-23)
• Statistical Analysis Plan (PDF, 2019-05-03)

• Spruce Chief Medical Officer, MD, Study director, Spruce Biosciences
• Richard Auchus, MD, PhD, Principal investigator, University of Michigan