What is the function, pharmacological effect, and potential side effects of Vicadrostast (LCI699) in treating Cushing's syndrome?

Vicadrostat (Osilodrostat): Function, Pharmacological Effects, and Side Effects

Vicadrostat (osilodrostat) is a potent oral medication that blocks cortisol production by inhibiting the enzyme 11β-hydroxylase in the adrenal glands, making it highly effective for rapidly lowering dangerously high cortisol levels in patients with Cushing's syndrome. 1

How Vicadrostat Works (Basic Mechanism)

Enzyme Blockade: Vicadrostat works by blocking a specific enzyme called 11β-hydroxylase (also called CYP11B1) in your adrenal glands 1, 2. Think of this enzyme as a key worker on an assembly line that makes cortisol—when you block this worker, cortisol production drops significantly.

Dual Action: The drug also inhibits aldosterone synthase, another enzyme involved in hormone production, though the primary therapeutic benefit comes from cortisol reduction 1, 2.

Speed of Action: Unlike some other medications for Cushing's syndrome, vicadrostat acts rapidly—it's one of the fastest-acting oral medications available for this condition 1, 3.

Pharmacological Effects (What It Does in the Body)

Cortisol Normalization

• 77% of patients achieve normal cortisol levels within 12 weeks of starting treatment, compared to only 8% with placebo 1, 4
• 86% maintain normal cortisol levels when continuing treatment long-term (34 weeks) 1
• The medication produces sustained cortisol reduction that persists with ongoing therapy 3, 4

Clinical Improvements Beyond Cortisol

By 48 weeks of treatment, patients experience: 1

• Significant weight loss and reduction in body fat
• Lower blood pressure (important since Cushing's causes hypertension)
• Improved blood sugar control and decreased HbA1c levels
• Reduced total and LDL cholesterol
• Better quality of life scores
• Improvement in depression symptoms

These improvements occur because normalizing cortisol reverses the metabolic chaos that Cushing's syndrome creates. 3

Potential Side Effects

Common Side Effects (Occur in More Than 10% of Patients)

Hypocortisolism-Related Effects (Too Little Cortisol): 1, 3

• Nausea (31% of patients)
• Fatigue and weakness
• Decreased appetite (38% of patients)
• These occur in approximately 27-50% of patients, mostly during the initial dose-adjustment period
• Critical point: These are manageable with dose reductions or temporary treatment interruptions; about 36% may need temporary cortisol replacement 1

Effects from Steroid Precursor Accumulation: 1, 3

• Hypokalemia (low potassium)—occurs in 42% of patients due to mineralocorticoid precursor buildup
• Hypertension (paradoxically, despite treating Cushing's)
• Edema (fluid retention)

Other Common Effects: 1, 3, 4

• Headache (8-11% of patients)
• Arthralgia (joint pain)—35% of patients
• Anemia (8-11% of patients)
• Dizziness

Gender-Specific Side Effects

In Women: 1, 3

• Hirsutism (excessive hair growth)—occurs in 11% of women
• Acne
• These result from accumulation of androgen precursors when the enzyme is blocked

In Men: 1

• Unlike ketoconazole (another Cushing's medication), vicadrostat does NOT cause hypogonadism

Serious Side Effects Requiring Monitoring

QT Prolongation: 3, 4

• The medication can prolong the QT interval on ECG (heart rhythm abnormality)
• Requires: Baseline ECG before starting, periodic monitoring during treatment
• Avoid: Combining with other QT-prolonging medications

Adrenal Insufficiency: 1, 3

• Can occur if cortisol drops too low
• Requires careful dose titration and monitoring
• May necessitate temporary glucocorticoid replacement

Important Clinical Considerations

Dosing Schedule: Vicadrostat is taken twice daily, making it more convenient than metyrapone (which requires dosing every 4 hours) 3.

Drug Interactions: Careful review of all medications is essential, particularly those that prolong QT interval 3.

Monitoring Requirements: 3

• Regular cortisol level checks (24-hour urinary free cortisol)
• Electrolyte monitoring (especially potassium)
• ECG monitoring for QT prolongation
• Blood pressure checks

Pitfall to Avoid: Starting at too high a dose can cause severe hypocortisolism; slower up-titration minimizes adverse effects 3.

When Vicadrostat Is Used

Primary Indication: Approved for adult patients with Cushing's disease who have failed surgery or are not surgical candidates 2, 3, 5.

Pediatric Use: Currently being evaluated in children (Phase II trial ongoing), but not yet approved for pediatric patients 1, 5.

Advantage Over Alternatives: Vicadrostat achieves higher rates of cortisol normalization (77%) compared to metyrapone (47%) or ketoconazole, with a more favorable dosing schedule 1, 4.