Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease

Key inclusion criteria:

- Confirmed CD that is persistent or recurrent as evidenced by all of the following
criteria being met (i.e., a, b and c):

1. mUFC > 1.3 x ULN (Mean of three 24-hour urine samples collected preferably on 3
consecutive days, during screening after washout of prior medical therapy for CD
(if applicable), confirmed by the central laboratory and available before Day 1),
with ≥2 of the individual UFC values being > 1.3 x ULN.

2. Morning plasma ACTH above Lower Limit of Normal

3. Confirmation (based on medical history) of pituitary source of excess

ACTH as defined by any one or more of the following three criteria:

i. Histopathologic confirmation of an ACTH-staining adenoma in patients who have had
prior pituitary surgery. OR ii. MRI confirmation of pituitary adenoma > 6 mm OR iii.
Bilateral inferior petrosal sinus sampling (BIPSS) with either CRH or DDAVP
stimulation for patients with a tumor ≤ 6mm. The criteria for a confirmatory BIPSS
test are any of the following: Pre-dose central to peripheral ACTH gradient > 2;
Post-dose central to peripheral ACTH gradient > 3 after either CRH or DDAVP
stimulation

- Patients that received glucocorticoid replacement therapy must have discontinued such
therapy for at least seven days or 5 half-lives prior to screening, whichever is
longer.

- Patients with de novo CD can be included only if they are not considered candidates
for surgery (e.g., poor surgical candidates due to co-morbidities, inoperable tumors,
patients who refuse to have surgical treatment, or surgical treatment is not
available).

Key exclusion criteria:

- Patients with pseudo-Cushing's syndrome. This may be diagnosed by a normal late night
salivary cortisol value collected during the screening period and after washout of
prior CD medication.

- Patients with risk factors for QTc prolongation or Torsade de Pointes, including:

patients with a baseline QTcF > 450 ms for males and QTcF > 460 ms for females; personal or
family history of long QT syndrome; concomitant medications known to prolong the QT
interval; patients with hypokalemia, hypocalcaemia, or hypomagnesaemia, if not corrected
before pre-dose Day 1.

- Patients likely to require adrenalectomy, pituitary surgery, or radiation therapy
during the placebo-controlled period (Weeks 1-12) for the treatment of severe
hypercortisolism or pituitary tumor growth causing compression of the optic chiasm.

- Patients with compression of the optic chiasm due to a macroadenoma or patients at
high risk of compression of the optic chiasm (tumor within 2 mm of optic chiasm).

- Patients who have a known inherited syndrome as the cause for hormone over secretion
(i.e. Carney Complex, McCune-Albright syndrome, MEN-1, AIP).

- Patients with Cushing's syndrome due to ectopic ACTH secretion or ACTH independent
(adrenal) Cushing's syndrome. Pregnant or nursing (lactating) women. 8. Women of
child-bearing potential, defined as all women physiologically capable of becoming
pregnant, unless they are using highly effective methods of contraception during
dosing and for 1 week after completion of dosing. Highly effective contraception
methods include: A. Total abstinence (when this is in line with the preferred and
usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation,
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of
contraception. B. Female sterilization (have had surgical bilateral oophorectomy with
or without hysterectomy) or tubal ligation at least six weeks before taking study
drug. In case of bilateral oophorectomy, documentation is required (e.g. operative
report, pelvic ultrasound or other reliable imaging method). C. Male sterilization (at
least 6 months prior to screening). For female subjects on the study the vasectomized
male partner should be the sole partner for that subject.

D. Combination of any two of the following (a+b or a+c, or b+c):

1. Use of oral*, injected, or implanted hormonal methods of contraception or other forms
of hormonal contraception that have comparable efficacy (failure rate <1%), for
example hormone vaginal ring or transdermal hormone contraception

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS)

3. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or cervical/vault
caps) with spermicidal foam/gel/film/cream/vaginal suppository. *In the case of use of
oral contraception, women should have been stable on the same pill for a minimum of 3
months before taking study drug. Women are considered post-menopausal and not of child
bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with
an appropriate clinical profile (i.e., age appropriate, history of vasomotor symptoms)
or have had surgical bilateral oophorectomy (with or without hysterectomy), total
hysterectomy, or tubal ligation at least six weeks ago. In the case of oophorectomy
alone, only when the reproductive status of the woman has been confirmed by follow-up
hormone level assessment is she considered not of child bearing potential. Other
protocol-defined inclusion/exclusion criteria may apply.