Metabolic & Endocrine · Clinical trials
Cushing's Disease Clinical Trials
Approved therapies, the pivotal-trial endpoints they were judged on, the magnitude of benefit — and the drugs that failed their endpoints, and why.
Indication overview
About cushing's disease — and why its trials are hard
Cushing's disease is chronic endogenous hypercortisolism caused by an ACTH-secreting pituitary adenoma, the most common cause of Cushing's syndrome. Untreated, cortisol excess drives central obesity, diabetes, hypertension, osteoporosis, myopathy, psychiatric disturbance and markedly increased mortality. Transsphenoidal surgery is first-line, but persistent or recurrent disease is common, creating a need for medical therapy. Options act at three levels: pituitary-directed pasireotide, adrenal steroidogenesis inhibitors (osilodrostat, levoketoconazole, and off-label ketoconazole and metyrapone), and the glucocorticoid-receptor antagonist mifepristone, which targets hyperglycemia rather than cortisol itself. Osilodrostat (Isturisa, 2020), an 11-beta-hydroxylase inhibitor validated in the LINC-3 randomized-withdrawal trial, and levoketoconazole (Recorlev, 2021) expanded the modern armamentarium, both normalizing mean urinary free cortisol in a substantial share of patients. Treatment is titrated to biochemical control while avoiding adrenal insufficiency; drug-specific risks include QT prolongation and hypocortisolism (osilodrostat), hepatotoxicity (levoketoconazole), hyperglycemia (pasireotide) and endometrial thickening (mifepristone). Long-term durable control and safety remain the central challenges.
Approved therapies & pivotal evidence
What's been approved — and by how much it moved the endpoint
| Drug (brand) | Approved | Setting | Pivotal trial | Primary endpoint | Magnitude of benefit |
|---|---|---|---|---|---|
| Pasireotide (Signifor) | 2012 | Pituitary-directed somatostatin analog for patients not candidates for or not cured by surgery | Phase III B2305 (Colao et al., NEJM 2012) | Normalization of mean urinary free cortisol (mUFC) at month 6 without dose increase | Roughly 15% (600 mcg) and 26% (900 mcg) achieved normal mUFC at month 6 |
| Mifepristone (Korlym) | 2012 | Glucocorticoid-receptor antagonist for hyperglycemia/glucose intolerance in endogenous Cushing's syndrome | SEISMIC | Improvement in oral glucose tolerance (AUC glucose) in the diabetes cohort | 60% of the diabetes/glucose-intolerance group were responders (≥25% reduction in glucose AUC) |
| Osilodrostat (Isturisa) | 2020 | 11-beta-hydroxylase inhibitor for Cushing's disease when surgery is not an option or has not worked | LINC-3 (randomized withdrawal; Lancet Diabetes Endocrinol 2020) | Proportion maintaining normal mUFC at end of the 8-week randomized withdrawal (week 34) | 86% on osilodrostat vs 29% on placebo maintained mUFC normalization |
| Levoketoconazole (Recorlev) | 2021 | Steroidogenesis inhibitor for endogenous hypercortisolemia in Cushing's syndrome | SONICS (open-label) and LOGICS (randomized withdrawal) | Normalization of mUFC without dose increase (SONICS) and maintenance vs withdrawal (LOGICS) | SONICS: 31% normalized mUFC at end of maintenance; LOGICS confirmed loss of control on placebo withdrawal |
| Ketoconazole ((generic; Ketoconazole HRA in EU)) | off-label in US (EU approval 2014) | Adrenal steroidogenesis inhibitor; widely used off-label in the US | Retrospective/observational cohorts (no US pivotal RCT) | Normalization of urinary/serum cortisol | ~50% achieve cortisol normalization in cohorts (unverified against a single pivotal trial) |
Where trials have failed
Drugs that missed their endpoint — and what contributed
The most instructive lessons in cushing's disease development come from programmes that failed the endpoint that mattered.
| Drug / trial | Endpoint outcome | What contributed |
|---|---|---|
| Cabergoline (dopamine agonist) — Off-label investigational cohorts | No successful registrational pivotal program for Cushing's disease; a substantial proportion escape from initial control over time | Loss of response (escape phenomenon), variable efficacy, and absence of an adequately powered prospective pivotal trial (magnitude unverified) |
Choosing the right endpoint
Primary endpoints that matter in cushing's disease trials
- Mean urinary free cortisol (mUFC) — Primary regulatory endpoint; normalization reflects control of cortisol overproduction
- Late-night salivary cortisol — Sensitive marker of disrupted diurnal cortisol rhythm used for monitoring
- Randomized-withdrawal maintenance — Design (LINC-3, LOGICS) demonstrating durable drug effect vs placebo relapse
- Cardiometabolic parameters — Blood pressure, weight, HbA1c/glucose as clinically meaningful secondary endpoints
- Safety: adrenal insufficiency and QT — Hypocortisolism from over-suppression and QT prolongation (osilodrostat) are key safety endpoints
How iNGENū runs cushing's disease trials
Physician-led design, built for FDA submission
Endpoint & biomarker strategy
Board-certified specialists design endpoints and patient selection aligned to current FDA guidance for this indication.
FDA-ready data
Built to ICH-GCP and 21 CFR 312.120, with direct FDA submission — data accepted by the FDA, EMA and MHRA.
Faster, lower-cost delivery
~4-week ethics via the TGA CTN scheme, up to 43.5% R&D rebate, and 80–90% below US CRO cost.
Request a fixed-milestone proposal and a tailored endpoint & feasibility summary for this indication.
Frequently asked questions
Cushing's Disease clinical trials — FAQs
What is the difference between Cushing's disease and Cushing's syndrome?
How do the newer drugs differ?
Is medication a cure?
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