Safety and Efficacy of LCI699 in Cushing's Disease Patients

This exploratory study is a proof of concept study to determine whether LCI699 can safely reduce the level of urinary free cortisol in patients with Cushing's disease.

In addition, this study evaluated the long term efficacy and safety of LCI699 including an additional 12 week of treatment followed by a 12 month long term optional extension.

A second extension provided patients who were clinically benefitting from LCI699 an opportunity to continue to have access to the drug until LCI699 was commercially available and reimbursed or through the availability of a local access program.

The Primary objective of this study was to assess the effect of 10-week treatment osilodrostat on 24 hour urine free cortisol (UFC) in patients with Cushing's disease.

The study consisted of a screening period of up to 60 days (to allow an adequate washout period for any medications that modified cortisol levels), a 10-14-day baseline period, a 10-week sequential dose escalation treatment period and a 14-day washout period followed by a Study Completion evaluation approximately 14 days after the last drug administration. Twelve patients were recruited and completed Part l of the study.

Eligible patients were dosed at 2 mg b.i.d for the first two weeks, the dose could then be increased every two weeks as necessary (to doses of 5, 10, 20 and 50 mg b.i.d). If at anytime, the subject's UFC was \< Upper Limit of Normal (ULN), dose escalation was halted and the subject remained on the current, efficacious dose through Week 10, with continued monitoring of UFC responses every 2 weeks to allow continued dose adjustments if necessary. If at any time the subject experienced side effects which were either intolerable or met dose adjustment criteria, the prescribed dose was adjusted.

The primary endpoint (UFC ≤ ULN or ≥50% decrease at Day 70) was achieved by all patients. Subsequently, in order to confirm these observations, protocol was amended (Protocol amendment 4) and new patients were enrolled and investigated for a longer treatment period.

Following Protocol amendment 4, the study design was modified to include patients in Part II of the study for evaluating the long-term efficacy and safety of osilodrostat treatment for 22 weeks. Nineteen patients (15 who were treated in the expansion cohort in Part ll and 4 who participated in Part l) with Cushing's disease were enrolled as part of the Expansion cohort in Part II of the study. The 12 patients who had entered the study in Part I, were allowed to re-enter the study as the Core proof of concept (PoC) Follow-up cohort. At Day 70 ± 2 days (Week 10), all patients (both patients entering for the first time and those reentering the study) entered the 12-week assessment period. At Day 154, patients completed the End of Treatment-Core visit.

On Day 154 (Week 22), patients had the option to enter the 12-month extension phase (long-term extension 1). On Day 490, patients who continued in the study had the option to enter a second long term extension phase (extension-2) at the Investigator's discretion, provided they did not meet any of the study discontinuation criteria.

Eligibility Criteria:
Inclusion Criteria:

* Patients with a confirmed diagnosis of Cushing's Disease (persistent or recurrent) as evidenced by increased 24-hour urine free cortisol (UFC), normal or increased morning plasma Adrenocorticotropic Hormone (ACTH), and pituitary origin of excess ACTH.
* Patients with de novo Cushing's disease can be included only if they are not considered candidate for surgery

Exclusion Criteria:

* Patients treated with mitotane 6 months prior to Visit 1
* Patients with compression of the optic chiasm
* Patients with a known inherited syndrome as the cause for hormone over secretion
* Patients with Cushing's syndrome due to ectopic ACTH secretion or adrenal Cushing's syndrome
* Patients with pseudo-Cushing's syndrome
* Patients who are not biochemically euthyroid
* Diabetic patients with poorly controlled diabetes (HbA1c \>9%)
* 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.
* Patients who have received pituitary irradiation within five years prior to Visit 1.
* Patients with risk factors for QTc prolongation or Torsade de Pointes.