Last reviewed: 25 Oct 2020
Last updated: 17 Nov 2020
17 Nov 2020

Phase 3 trial confirms the effectiveness of osilodrostat in Cushing disease

This is the first phase 3 study of any medical therapy (osilodrostat) to include a placebo-controlled period in patients with Cushing 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 disease who are candidates for medical therapy.

LINC-3 is a prospective, multicenter phase 3 study with a double-blind, randomized 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 randomized stage (week 34).

  • 137 patients were enrolled to receive open-label osilodrostat.

  • 71 (52%) patients were eligible for the randomized stage at week 26

    • osilodrostat (n=36)

    • 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 disease. This paper confirmed its efficacy as first-line medical therapy after surgery in most patients with this disease.

See Management: approach

See Management: treatment algorithm

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Summary

Definition

History and exam

Key diagnostic factors

  • facial plethora
  • supraclavicular fullness
  • violaceous striae
  • absence of pregnancy
  • menstrual irregularities
  • absence of malnutrition
  • absence of alcoholism
  • absence of physiologic stress
  • linear growth deceleration in children

Other diagnostic factors

  • female sex
  • hypertension
  • glucose intolerance or diabetes mellitus
  • premature osteoporosis or unexplained fractures
  • weight gain and central obesity
  • acne
  • psychiatric symptoms
  • decreased libido
  • easy bruisability
  • weakness
  • facial rounding
  • dorsocervical fat pads
  • unexplained nephrolithiasis
  • venothrombolic event
  • hirsutism

Risk factors

  • exogenous corticosteroid use
  • pituitary adenoma
  • adrenal adenoma
  • adrenal carcinoma
  • neuroendocrine tumors
  • thoracic or bronchogenic carcinoma

Diagnostic investigations

1st investigations to order

  • urine pregnancy test
  • serum glucose
  • late-night salivary cortisol
  • 1 mg overnight dexamethasone suppression test
  • 24-hour urinary free cortisol
  • 48-hour 2 mg (low-dose) dexamethasone suppression test
More 1st investigations to order

Investigations to consider

  • plasma dehydroepiandrosterone sulfate (DHEAS) level
  • morning plasma adrenocorticotropic 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
More investigations to consider

Treatment algorithm

Contributors

Professor of Medicine (Endocrinology) and Neurological Surgery

Director

Pituitary Center

Oregon Health & Science University

Portland

OR

Disclosures

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.

Disclosures

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.

Peer reviewersVIEW ALL

Professor of Medicine

Director of Research

College of Medical and Dental Sciences

University of Birmingham

Honorary Consultant Physician

Queen Elizabeth Hospital

Birmingham

UK

Disclosures

PMS declares that he has no competing interests.

Head

Department of Endocrinology

University Hospital of Bordeaux

Pessac

France

Disclosures

AT declares that he has no competing interests.

Chief

Endocrine Research Department

Instituto de Investigaciones M├ędicas A. Lanari

University of Buenos Aires and IDIM-CONICET

Buenos Aires

Argentina

Disclosures

LC declares that she has no competing interests.

Professor of Medicine

Director

Division of Endocrinology, Diabetes & Metabolism

University of Texas Medical School

Houston

TX

Disclosures

PRO declares that he has no competing interests.

Assistant Professor

Department of Endocrine Neoplasia and Hormonal Disorders

Division of Internal Medicine

University of Texas MD Anderson Cancer Center

Houston

TX

Disclosures

MAH declares that he has no competing interests.

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