Efficacy and Safety Evaluation of Osilodrostat in Cushing's Disease

A Phase III, Multi-center, Randomized, Double-blind, 48 Week Study With an Initial 12 Week Placebo-controlled Period to Evaluate the Safety and Efficacy of Osilodrostat in Patients With Cushing's Disease

The purpose of this study was to confirm efficacy and safety of osilodrostat for the treatment of patients with Cushing's disease who are candidates for medical therapy.

The study LCI699C2302 (LINC-4) is a multi-center, randomized, double-blind study to evaluate the safety and efficacy of osilodrostat in patients with Cushing's disease.

Enrolled patients were initially randomized to either osilodrostat or placebo, in a 2:1 ratio, for a 12-week double-blind period (Period 1). Randomization was stratified by history of pituitary radiation. After Week 12, all patients received open-label osilodrostat until the end of the Core phase at Week 48 (Period 2).

After Week 48, patients could join an optional 48 week extension period.

Key inclusion criteria:

• Confirmed Cushing's Disease (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 Adrenocorticotropic hormone (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. Magnetic resonance imaging (MRI) confirmation of pituitary adenoma > 6 mm OR iii. Bilateral inferior petrosal sinus sampling (BIPSS) with either corticotropic-releasing hormone (CRH) or desmopressin (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 QT corrected (QTc) prolongation or Torsade de Pointes, including:

patients with a baseline QT corrected (Fridericia QT formula) (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.