Phase 3 trial confirms the effectiveness of osilodrostat in Cushing's disease
This is the first phase 3 study of any medical therapy (osilodrostat) to include a placebo-controlled period in patients with Cushing's disease.
Osilodrostat is a potent novel steroidogenesis inhibitor that inhibits 11-beta-hydroxylase, the enzyme that catalyses the final step of cortisol synthesis in the adrenal cortex.
It is approved worldwide for the treatment of patients with Cushing's disease who are candidates for medical therapy.
LINC-3 is a prospective, multi-centre phase 3 study with a double-blind, randomised withdrawal phase.
The study had an open-label, single-arm stage for 24 weeks to titrate and determine the therapeutic dose of osilodrostat. Patients who met criteria were then randomly assigned, in a double-blind manner, to continue osilodrostat at the same therapeutic dose or to receive a matching placebo for 8 weeks (withdrawal phase; weeks 26 to 34). In the final stage (weeks 35 to 48), all participants were given open-label osilodrostat.
The primary endpoint was the proportion of participants who had been randomly assigned to treatment or placebo with a complete response (i.e., mean 24-hour urinary free cortisol concentration at or below the upper limit of normal) at the end of the randomised stage (week 34).
137 patients were enrolled to receive open-label osilodrostat.
71 (52%) patients were eligible for the randomised stage at week 26
placebo (n=35); 1 patient in this group discontinued due to an adverse event.
At week 34, significantly more patients who continued osilodrostat treatment maintained a complete response, without a dose increase above the level at week 26, versus those who were on placebo
31 (86%) of 36 vs. 10 (29%) of 34 (odds ratio [OR] 13.7, 95% CI 3.7 to 53.4; P <0.0001).
Secondary endpoints included the proportion of participants who had a complete response at the end of week 24 and week 48, cardiovascular-related parameters, and patient-reported outcomes. At the end of week 48, 91 (66%) enrolled patients had a complete response. Most patients (82%) completed the 48-week study, and the rate of discontinuations due to adverse events was low (13%).
Hypocortisolism-related adverse events were reported in 70 (51%) of patients during the study (mostly occurring and resolved during the dose-titration period). Other commonly reported adverse events were nausea (57 [42%]), headache (46 [34%]), and fatigue (39 [28%]).
The study concluded that osilodrostat rapidly reduces mean UFC concentrations and cortisol production and sustains this reduction alongside improvements in clinical signs of hypercortisolism without unexpected side-effects.
Osilodrostat is the only steroidogenesis inhibitor approved in both Europe and the US for use in patients with Cushing's disease. This paper confirmed its efficacy as first-line medical therapy after surgery in most patients with this disease.
Original source of updateexternal link opens in a new window
Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause.
Exogenous corticosteroid exposure is the most common cause of Cushing syndrome. Cushing's disease, which is hypercortisolism caused by an adrenocorticotrophic hormone (ACTH)-secreting pituitary adenoma, is the most common cause of endogenous Cushing syndrome, and is responsible for 70% to 80% of cases.
It may be difficult to distinguish patients with mild Cushing syndrome from those with the metabolic syndrome (central obesity with insulin resistance, and hypertension). Features more specific to Cushing syndrome include proximal muscle weakness, supraclavicular fat pads, facial plethora, violaceous striae, easy bruising, and premature osteoporosis.
After exclusion of exogenous corticosteroid use, patients with suspected Cushing syndrome should be tested for hypercortisolism with 1 of 4 high-sensitivity tests (late-night salivary cortisol; 1 mg overnight low-dose dexamethasone suppression testing, 24-hour urinary free cortisol; or 48-hour 2 mg dexamethasone suppression testing).
At least one additional test should be used to confirm hypercortisolism in patients with a positive initial screening test.
Once endogenous hypercortisolism is confirmed, plasma ACTH should be measured. If ACTH is suppressed, diagnostic testing should focus on the adrenal glands. If ACTH is not suppressed, pituitary or ectopic disease should be sought.
In the vast majority of cases of endogenous Cushing syndrome, surgical resection of the pituitary adenoma or adrenal adenoma that is causing hypercortisolism is the primary treatment of choice.
Cushing syndrome is the clinical manifestation of pathological hypercortisolism from any cause. Patients often display weight gain with central obesity, facial rounding and plethora, proximal muscle weakness, and thinning of the skin. They also develop metabolic complications including diabetes mellitus, dyslipidaemia, metabolic bone disease, and hypertension. Cushing syndrome can be caused by adrenocorticotrophic hormone (ACTH)-secreting pituitary tumours (termed Cushing's disease), by autonomous adrenal cortisol overproduction, and, rarely, by ectopic ACTH-secreting tumours.
History and exam
- female sex
- glucose intolerance or diabetes mellitus
- premature osteoporosis or unexplained fractures
- weight gain and central obesity
- psychiatric symptoms
- decreased libido
- easy bruisability
- facial rounding
- dorsocervical fat pads
- unexplained nephrolithiasis
- venothrombolic event
- plasma dehydroepiandrosterone sulphate (DHEAS) level
- morning plasma adrenocorticotrophic hormone (ACTH)
- high-dose dexamethasone suppression test
- pituitary MRI
- adrenal CT
- inferior petrosal sinus sampling
- CT of chest, abdomen, and pelvis
- MRI chest
- octreotide scanning
- gallium-68 DOTATATE PET/CT
Professor of Medicine (Endocrinology) and Neurological Surgery
Oregon Health & Science University
MF is the Pituitary Society's President and sits on its Board of Directors. She holds a research grant to the University for Clinical Studies as Principal Investigator for Novartis, Millendo, and Strongbridge, and is an occasional Scientific Consultant for Novartis and Strongbridge. MF is an author of several references cited in this topic.
Dr Maria Fleseriu would like to gratefully acknowledge Dr Ty Carroll and Dr James Findling, previous contributors to this topic.
TC is an author of a number of references cited in this topic. He is an investigator in clinical trials sponsored by Corcept. JF is an author of a number of references cited in this topic. He is a consultant for, and investigator in, clinical trials sponsored by Corcept and Novartis.
Professor of Medicine
Director of Research
College of Medical and Dental Sciences
University of Birmingham
Honorary Consultant Physician
Queen Elizabeth Hospital
PMS declares that he has no competing interests.
Department of Endocrinology
University Hospital of Bordeaux
AT declares that he has no competing interests.
Endocrine Research Department
Instituto de Investigaciones Médicas A. Lanari
University of Buenos Aires and IDIM-CONICET
LC declares that she has no competing interests.
Professor of Medicine
Division of Endocrinology, Diabetes & Metabolism
University of Texas Medical School
PRO declares that he has no competing interests.
Department of Endocrine Neoplasia and Hormonal Disorders
Division of Internal Medicine
University of Texas MD Anderson Cancer Center
MAH declares that he has no competing interests.
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