An Open-Label Extension Study of the Safety of Relacorilant (CORT125134) in the Treatment of the Signs and Symptoms of Endogenous Cushing Syndrome

Endogenous Cushing syndrome is a rare multisystem disorder that results from
overproduction of the glucocorticoid hormone cortisol. In both adults and
children, Cushing syndrome is most commonly caused by an ACTH-secreting
pituitary tumor (Cushing disease). Other forms of Cushing syndrome result from
autonomous production of cortisol from adrenal cortical tumors or
overproduction of ACTH from non-pituitary tumors (ectopic ACTH syndrome). The
only curative treatment is resection of the tumor source responsible for the
excess cortisol.

Currently, three medical therapies are approved by the United States (US) Food
and Drug Administration (FDA) for treatment of endogenous Cushing syndrome: (1)
mifepristone (Korlym®), approved for the control of hyperglycemia secondary to
hypercortisolism in adult patients with endogenous Cushing syndrome who have
type 2 diabetes mellitus (DM) or glucose intolerance and have failed surgery or
are not candidates for surgery, (2) pasireotide (Signifor), a somatostatin
receptor agonist approved for the treatment of adult patients with Cushing
disease for whom pituitary surgery is not an option or has not been curative
and (3) osilodrostat (Isturisa), a cortisol-synthesis inhibitor approved for
the treatment of adult patients with Cushing*s disease for whom pituitary
surgery is not an option or has not been curative. In Europe, drugs approved
for the treatment of Cushing syndrome include aminoglutethimide (Orimeten),
ketoconazole (Nizoral), metyrapone (Metopirone), osilodrostat (Isturisa),
mitotane (Lysodren), and pasireotide (Signifor).

Relacorilant is a potent, selective GR antagonist. The mechanism of action of
relacorilant is similar to that of mifepristone, with the exception that
relacorilant does not bind to the progesterone receptor. The potential
advantage of relacorilant compared with mifepristone is its selective and
potent GR antagonism, without anti progesterone effects, including endometrial
hypertrophy and the potential for irregular vaginal bleeding.

This protocol is designed to allow therapy with relacorilant (CORT125134), a
potent, selective glucocorticoid receptor (GR) antagonist, in patients with
endogenous Cushing syndrome who meet the entry criteria for this extension
study, who complete their last treatment visit in a Corcept-sponsored study of
relacorilant (referred to as the *parent* study) , and who, in the
Investigator*s opinion, will benefit from relacorilant treatment.

Primary Objectives: Safety Assessments: Effect of Administration of
Relacorilant on:

• Incidence of TEAEs (assessed monthly): TEAEs, SAEs, treatment-related TEAEs,
TEAEs leading to early discontinuation of study treatment
• Clinical laboratory tests (hematology and chemistry panels)
• Physical examinations and vital sign measurements
• ECGs (12-lead) (including QTcF interval, QRS complex, PR interval, and heart
rate) at Baseline and End-of-treatment.
• Pituitary tumors based on MRI scans in patients with Cushing disease.

Exploratory Objectives : Assessments of Treatment Effect
• Effect of administration of relacorilant on the following:

- HbA1c and insulin resistance indices in patients with DM or glucose
intolerance at Baseline in the parent study.
- Blood pressure (BP) by ambulatory BP measurements (ABPM) in patients with
uncontrolled hypertension (HTN) at Baseline in the parent study
and in patients with controlled HTN taking >=1 anti-HTN medication(s).
- Body weight and waist circumference.
- Quality-of-life (CushingQoL) questionnaire.
- Biochemical markers of bone remodeling: serum osteocalcin.
- HPA axis markers: plasma ACTH and serum cortisol.
- Cortisol concentration: 24-hour UFC test with creatinine (for patients who
completed the CORT125134-455 GRACE study only) and late-night
salivary-cortisol test.
- Lipid-metabolism panel: total cholesterol, low-density lipoprotein
cholesterol, high density lipoprotein cholesterol, very low density
lipoprotein-
cholesterol, and triglycerides).
- Sex-steroid hormone and gonadotropin levels: estradiol, total and free
testosterone, follicle-stimulating hormone, luteinizing hormone.
- Menstrual-cycle assessments (premenopausal women not taking hormonal
contraceptive medication): age at menarche, current pattern of
menses, duration of vaginal bleed.
- DXA scans.
-Coagulation markers.
- Clinical appearance (based on review of patient photographs): Cushingoid
appearance and striae (Patient photographs will be collected for
patients who completed the CORT125134-455 GRACE study only.).

• Measurement of mRNA expression of GR-activity biomarkers (e.g.
glucocorticoid-induced gene panel).

This is an open-label, single-arm, extension study designed to evaluate the
long-term safety and therapeutic effect of orally administered relacorilant in
patients with endogenous Cushing syndrome.

Study drug is defined as relacorilant.

Patients will be dosed at the level of the last dosing visit in their parent
Corcept-sponsored study as tolerated. If the last dose of relacorilant was >4
weeks from Day 1 of this study, or the patient enters from a blinded,
placebo-controlled parent study, dosing will be titrated starting with 100 mg.
The titration schedule will follow the titration schedule of the parent
protocol. Suggested titration is as follows: Begin with 100 mg once daily.
After 2 weeks, the dose of relacorilant will be increased to 200 mg and then
increased every 4 weeks by 100 mg until the maximum tolerated dose from the
parent study is achieved (not to exceed 400 mg), at the discretion of the
investigator based on tolerability. Faster dose escalation for patients whose
Cushing syndrome deteriorates during the study may be allowed on a case-by-case
basis after discussion and approval by the medical monitor.
A patient*s relacorilant dose may be maintained, reduced, or increased at the
discretion of the Investigator based on individual response and tolerability.
Doses are increased and decreased in 100-mg increments.


Please refer to the protocol section 5 (page 40) Study Treatments and
Management.

Glucocorticoid receptor antagonism is a proven mechanism of action for the
treatment of the diabetes mellitus/impaired glucose tolerance (DM/IGT)
secondary to hypercortisolism in adult patients with Cushing syndrome (Fleseriu
et al. 2014). Because the mechanism of action of relacorilant is similar to
that of mifepristone, with the exception that it does not bind the PR,
relacorilant is expected to effectively treat Cushing syndrome, without the
drawbacks of progesterone receptor antagonism that may result in untoward
reproductive effects and/or interruption of therapy.

In the Phase 2 study (Study CORT125134-451) in patients with endogenous Cushing
syndrome, relacorilant showed evidence of clinical benefit based on improvement
of cortisol-excess*related comorbidities. The drug was generally well
tolerated, with the upper bound on dosing being typically musculoskeletal
complaints, a tolerability issue that patients can report.

Compared with the predecessor drug mifepristone, relacorilant offers two key
safety advantages: lack of affinity for the PR, and lack of significant
cortisol rise (a driver of hypokalemia in the marketed GR antagonist
mifepristone).

Based on the mechanism of action of relacorilant, there is a theoretical risk
of excessive GR antagonism, which could manifest by weakness, tiredness,
dizziness, hypoglycemia, dehydration, weight loss, nausea, vomiting, diarrhea,
and muscle aches. Since relacorilant does not affect the mineralocorticoid
receptor, it is unlikely that hypotension would occur in the absence of
concurrent treatment with antihypertensive medication. Because plasma
glucocorticoid levels are not decreased with relacorilant administration, a
biochemical diagnosis of excessive GR antagonism is not possible; diagnosis
must rely on clinical assessment. In cases of suspected excess GR antagonism,
study drug will be interrupted for 3 days and supplemental glucocorticoid will
be given in high doses to overcome the GR antagonism.

The safety profile of relacorilant in study patients will be monitored by AE
reporting, safety laboratory tests, physical examinations, vital signs,
concomitant medication reviews, and pregnancy tests. ECGs will be performed at
Screening, Baseline, and End-of-treatment (ECG at follow-up only if clinically
indicated).

In vitro data indicate that relacorilant is metabolized by multiple CYP enzymes
(CYP3A4, CYP2C8, and CYP3A5) and by carbonyl reductases. Data also indicate the
potential for relacorilant to perpetuate drug drug interactions via inhibition
of CYP3A and transporter pathways. Patients taking any prohibited medication
are excluded from this study (refer to Section 5.3). If a concomitant
medication is required to treat an AE, in selecting the appropriate concomitant
medication, the Investigator must consider the risk of drug-drug interaction.
The Medical Monitor should approve all concomitant medications required to
treat an AE if there is a potential for drug-drug interaction. If necessary,
the patient will be withdrawn from the study.

Study procedures include venous blood sampling and noninvasive procedures,
including ECG recording, imaging, and vital-sign measurement. The total volume
of blood collected will not exceed 50 mL per visit, unless the Investigator or
designee considers additional unplanned collection(s) are required for safety
laboratory tests.

More information on the risks and benefits of relacorilant is provided in the
Investigator*s Brochure