Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as LCI699
osilodrostat · 10 trials · 14 indications
A complete responder at week 12 is defined as a participant who had a mean urine free cortisol ≤ upper limit of normal (mUFC ≤ ULN) at Week 12. Participants who had a missing mUFC assessment at Week 12 were counted as non-responders for the primary endpoint.
To compare the complete response rate at the end of the 8-week period of randomized withdrawal between randomized patients.A primary efficacy responder is defined as a randomized patient who has mUFC ≤ ULN at Week 34 and who was neither discontinued (study or RW treatment) nor had osilodrostat dose increase above the level at Week 26 during the RW Period of the study. mUFC: mean urinary free cortisol; ULN: Upper Limit of Normal
Percent change from baseline in the mUFC at the individual patient level
A patient was considered to be a responder if his/her mean UFC level from the three 24-hour urine samples collected at Week 10 was ≤ Upper Limit of Normal (ULN), as defined by the local laboratories, or represented a ≥50% decrease from baseline. Patients who discontinued for a disease or treatment related reason (e.g. death, adverse event, clinical disease progression etc.), or whose mean Week 10 24-hour UFC levels were higher than the normal limit and experienced \<50% decrease in UFC were classified as non-responders.
As per the protocol, MTD is the dose at which 4 participants exhibited ACTH-stimulated cortisol results \<400 nanomoles per liter (nmol/L). The change in the distribution across the treatments were analyzed using 1- way analysis of variance (ANOVA) for continuous variables.
Arterial blood pressure (BP) determinations were made after the participant was in the sitting position for 5 minutes according to the American Heart Association guidelines using a calibrated standard aneroid or mercury sphygmomanometer or a calibrated standard sphygmomanometer. The change in the MSSBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from Baseline in MSSBP was analyzed using an analysis of covariance model (ANCOVA) with treatment and country as factors and Baseline MSSBP as a covariate.
Automated arterial BP determinations were made after the participant was in the sitting position for 5 minutes according to the Guidelines for management of hypertension: report of the 4th working party of the British Hypertension Society, 2004-BHS IV, using an automated BP device (such as the Omron BP monitor). The change in the MSDBP was calculated comparing the Week 8 readings to the readings taken at Baseline. The change from baseline in MSDBP was analyzed using an analysis of covariance model (ANCOVA) with treatment and region as factors and baseline MSDBP level as a covariate.
To assess the influence of renal impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of renal impairment compared to subjects with normal renal function.
To assess the influence of renal impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of renal impairment compared to subjects with normal renal function.
To assess the influence of renal impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of renal impairment compared to subjects with normal renal function.
To assess the influence of renal impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of renal impairment compared to subjects with normal renal function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
To assess the influence of hepatic impairment on the pharmacokinetics (PK) of LCI699i in subjects with varying degrees of hepatic impairment compared to subjects with normal hepatic function.
| Arm | Type | Description |
|---|---|---|
| osilodrostat Group | EXPERIMENTAL | Participants in this arm were randomized to receive the study drug, osilodrostat followed after Week 12 by open-label osilodrostat at the starting dose (with a second dose titration) |
| osilodrostat Placebo Group | PLACEBO_COMPARATOR | Participants in this arm were randomized to receive osilodrostat placebo followed after Week 12 by open-label osilodrostat at the starting dose (with a dose titration) |
| osilodrostat (LCI699) | EXPERIMENTAL | Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then osilodrostat during a double-blind, placebo controlled RW Period. |
| LCI699 Placebo | PLACEBO_COMPARATOR | Consisted of a single-arm, open-label, osilodrostat dose-titration in individual patients and then placebo during a double-blind, placebo controlled RW Period. |
| Osilodrostat | EXPERIMENTAL | Patients in this arm took the study drug, osilodrostat. |
| Part l: Core cohort | EXPERIMENTAL | Participants took an ascending dose of LCI699 (osilodrostat) from 2mg bid or 5 mg bid, up to 30 mg bid and participated in Part I of this study. 4 patients in this cohort moved to Part II of the study |
| Part II Core: Expansion cohort | EXPERIMENTAL | Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Expansion of this study. These patients were all newly enrolled into the phase II part of the study |
| Part II Core: Follow-up cohort | EXPERIMENTAL | Participants took an ascending dose from 2mg bid or 5 mg bid, up to 30 mg bid and participated in the Part II Core Follow-up of this study. These patients were patients who transferred from Part I Core phase of the study |
| Cohort A: LCI699 0.5 mg QD | EXPERIMENTAL | Participants received LCI699 0.5 mg, capsules, orally, once daily (QD), with or without food for up to 6 weeks. |
| Cohort A: LCI699 1.0 mg QD | EXPERIMENTAL | Participants received LCI699 1.0 mg, capsules, orally, QD, with or without food for up to 6 weeks. |
| Cohort B1: LCI699 1.0 mg BID | EXPERIMENTAL | Participants received LCI699 1.0 mg, capsules, orally, twice daily (BID), with or without food for up to 6 weeks. |
| Cohort B1: LCI699 2.0 mg QD | EXPERIMENTAL | Participants received LCI699 2.0 mg, capsules, orally, QD, with or without food for up to 6 weeks. |
| Placebo | PLACEBO_COMPARATOR | Participants received LCI699-matching placebo, capsules, orally, QD or BID, with or without food for up to 6 weeks. |
| LCI699 0.25 mg BID | EXPERIMENTAL | Following a 2-week placebo run-in period, participants received LCI699 0.25 mg, capsules, orally, twice daily (BID), with or without food for up to 8 weeks. |
| LCI699 1 mg QD | EXPERIMENTAL | Following a 2-week placebo run-in period, participants received LCI699 1 mg, capsules, orally, once daily (QD), with or without food for up to 8 weeks. |
| LCI699 0.5 mg followed by LCI699 1 mg BID | EXPERIMENTAL | Following a 2-week placebo run-in period, participants received LCI699 0.5 mg, capsules, orally, BID, with or without food for up to 4 weeks, followed by LCI699 1 mg, capsules, orally, BID with or without food for up to 4 weeks. |
| Eplerenone 50 mg BID | ACTIVE_COMPARATOR | Following a 2-week placebo run-in period, participants received eplerenone 50 mg, capsules, orally, BID, with or without food for up to 8 weeks. |
| Core Period: LCI699 0.25 mg QD | EXPERIMENTAL | Participants received LCI699 0.25 mg capsules, orally, once daily (QD), with or without food for up to 8 weeks. |
| Core Period: LCI699 0.5 mg QD | EXPERIMENTAL | Participants received LCI699 0.5 mg capsules, orally, QD, with or without food for up to 8 weeks. |
| Core Period: LCI699 1.0 mg QD | EXPERIMENTAL | Participants received LCI699 1 mg capsules, orally, QD, with or without food for up to 8 weeks. |
| Core Period: LCI699 0.5 mg BID | EXPERIMENTAL | Participants received LCI699 0.5 mg capsules, orally, twice daily (BID), with or without food for up to 8 weeks. |
| Core Period: Eplerenone 50 mg BID | ACTIVE_COMPARATOR | Participants received eplerenone 50 mg capsules, orally, BID, with or without food for up to 8 weeks. |
| Core Period: Placebo | PLACEBO_COMPARATOR | Participants received LCI699-matching placebo or eplerenone-matching placebo, capsules, orally, QD or BID, with or without food for up to 8 weeks. |
| Withdrawal Period: LCI699 0.25 mg QD | EXPERIMENTAL | Participants received LCI699 0.25 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 0.25 mg QD Placebo | PLACEBO_COMPARATOR | Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 0.5 mg QD | EXPERIMENTAL | Participants received LCI699 0.5 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 0.5 mg QD Placebo | PLACEBO_COMPARATOR | Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 1.0 mg QD | EXPERIMENTAL | Participants received LCI699 1 mg capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 1.0 mg QD Placebo | PLACEBO_COMPARATOR | Participants received LCI699 matching placebo capsules, orally, QD, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 0.5 mg BID | EXPERIMENTAL | Participants received LCI699 0.5 mg capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: LCI699 0.5 mg BID Placebo | PLACEBO_COMPARATOR | Participants received LCI699 matching placebo capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: Eplerenone 50 mg BID | ACTIVE_COMPARATOR | Participants received eplerenone 50 mg capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: Eplerenone 50 mg BID Placebo | PLACEBO_COMPARATOR | Participants received eplerenone matching placebo capsules, orally, BID, with or without food for up to 1 week (Week 8 to Week 9). |
| Withdrawal Period: Placebo | PLACEBO_COMPARATOR | Participants received LCI699-matching placebo or eplerenone-matching placebo, capsules, orally, QD or BID, with or without food for up to 1 week (Week 8 to Week 9). |
| LCI696 1mg bid | EXPERIMENTAL | - |
| osilodrostat ( LCI699) | EXPERIMENTAL | Each participant will undergo a 28 day screening /baseline period (day-28 to Day -1), followed by a 4 day treatment period ( a single 30 mg dose of LCI699 (Day 1) with 4 days of PK smple collection |
| Name | Type | Description |
|---|---|---|
| osilodrostat | DRUG | In the form of filmcoated tablets for oral administration, in the following dose strengths: 1 mg, 5 mg, 10 mg, and 20 mg. |
| osilodrostat Placebo | DRUG | Matching Placebo in the form of filmcoated tablets for oral administration |
| LCI699 matching placebo | DRUG | Osilodrostat placebo comes in the form of film-coated tablets for oral administration, in the following strengths: 1 mg, 5 mg, 10 mg, and 20 mg. The maximum dose of osilodrostat placebo was 30 mg bid. |
| LCI699 | DRUG | Osilodrostat 1 mg and 5 mg capsules, was prepared by Novartis and supplied to the Investigator. The capsule formulation of osilodrostat was later changed to tablets and this change was implemented in the study with Protocol amendment 6. Osilodrostat was open labeled 1 mg, 5 mg, 10 mg and 20 mg tablets. |
| LCI699-matching placebo | DRUG | LCI699-matching placebo oral capsules |
| Eplerenone | DRUG | Eplerenone oral capsules |
| Eplerenone-matching Placebo | DRUG | Eplerenone-matching placebo oral capsules |
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 wash...
Osilodrostat is being studied for the treatment of Cushing's syndrome and Cushing's disease, including cases caused by ectopic corticotropin syndrome, adrenal adenoma, adrenal carcinoma, AIMAH, and PPNAD. It is also being evaluated in people with hepatic impairment and renal impairment. It is an investigational therapy and has not been approved for these uses.
Osilodrostat targets CYP11B1, an enzyme involved in cortisol synthesis, and acts as an inhibitor. By inhibiting CYP11B1, osilodrostat is designed to reduce excessive cortisol production, which is the underlying problem in Cushing's syndrome and Cushing's disease.
Osilodrostat is being developed by Novartis AG, which trades under the ticker NVS. Novartis is the sponsor of the clinical trials evaluating the drug in Cushing's syndrome, Cushing's disease, hepatic impairment, and renal impairment.
Osilodrostat is in Phase 2 development according to the overall program status, although individual completed trials have reached Phase 3 and Phase 1. It is an investigational drug and is not approved for any indication. The clinical program includes both Phase 2 and Phase 3 studies that have been completed.
Osilodrostat has been studied in completed trials including NCT02697734, a Phase 3 trial in Cushing's disease with 73 participants, and NCT02468193, a Phase 2 trial in Cushing's syndrome and related conditions with 9 participants in Japan. Phase 1 trials NCT02399202 and NCT02372084 evaluated the drug in renal and hepatic impairment, respectively.
Yes, osilodrostat is also known as LCI699. The alternative name LCI699 appears in the titles of the Phase 1 trials NCT02399202 and NCT02372084, which studied osilodrostat in healthy volunteers and subjects with impaired renal or hepatic function.