Clinical Insights from Cushing's Syndrome Trial: How Patient Disease Severity Shapes Levoketoconazole Treatment Outcomes

Xeris Biopharma unveiled fresh perspectives on the therapeutic impact of levoketoconazole (Recorlev) in managing Cushing’s syndrome, with findings suggesting that baseline disease severity plays a pivotal role in determining treatment response. The company shared these insights at ENDO 2024 in Boston during June 1-4, 2024, drawing from data gathered in the SONICS study.

Understanding the Disease Severity Factor

The core finding challenges a one-size-fits-all approach to Cushing’s syndrome management. Patients presenting with lower baseline mean urine free cortisol (mUFC) levels demonstrated notably higher rates of achieving cortisol normalization compared to those with more pronounced disease manifestations. This relationship held true across multiple clinical parameters, suggesting that individualizing treatment protocols based on initial disease burden could optimize patient outcomes.

According to James Meyer, PharmD and Senior Director of Publications and Medical Communications at Xeris, “These results indicate that stratifying patients by baseline severity allows clinicians to better predict response patterns and tailor dosing strategies more effectively. Patients with less severe presentations may normalize cortisol at substantially higher rates while requiring lower maintenance doses.”

Research Design and Patient Stratification

The exploratory analysis examined 92 patients from the SONICS cohort who received levoketoconazole treatment. Researchers divided participants into three tiers based on baseline mUFC measurements:

• Lower severity group: mUFC ≤ 2.5x upper limit of normal (ULN), baseline level 498.7 nmol/day
• Moderate severity group: mUFC >2.5x to ≤5x ULN, baseline level 267.9 nmol/day
• Higher severity group: mUFC >5x ULN, baseline level 1672.8 nmol/day

Cortisol Normalization and Dosing Requirements

The stratification revealed a clear inverse correlation between baseline cortisol burden and treatment response. The moderate-severity cohort achieved the highest normalization rate at 36.4% (12 of 33 patients), with a 95% confidence interval of 0.20 to 0.54. The lower-severity group followed at 31.6% (12 of 38 patients, 95% CI 0.16-0.47), while the most severely affected patients achieved only 23.8% normalization (5 of 21 patients, 95% CI 0.01-0.55).

Maintenance levoketoconazole dosing requirements aligned with disease intensity. Patients in the higher-severity category required average daily doses of 631 mg during maintenance, escalating to 741 mg at the final dose assessment. In contrast, less severely affected patients needed only 475 mg daily, reaching 545 mg at endpoint. The moderate group fell between these ranges at 548 mg and 611 mg respectively.

Safety Profile Across Disease Severity Levels

A critical clinical observation emerged regarding hepatic safety monitoring. Higher-severity patients experienced elevated rates of liver-related adverse events of special interest—reaching 14% compared to 7.9% in lower-severity patients and just 3.0% in the moderate group. Discontinuations due to adverse events also varied substantially, occurring in 24% of the highest-severity cohort versus 12-16% in lower-severity populations.

Abnormalities in liver function tests, including elevated ALT, AST, and GGT levels, demonstrated a dose-response relationship aligned with baseline disease severity. The data underscore the necessity for vigilant hepatic monitoring, particularly in patients requiring higher levoketoconazole doses.

About Cushing’s Syndrome: Clinical Context

Endogenous Cushing’s syndrome represents a rare but life-threatening endocrine disorder characterized by sustained cortisol overproduction, frequently stemming from pituitary adenomas. The condition predominantly affects adults between ages 30-50, with women experiencing three times the incidence compared to men.

Clinical manifestations extend across multiple organ systems. Women often report menstrual irregularities, fertility challenges, and androgenic symptoms including hirsutism and acne. The systemic complications prove particularly concerning: metabolic derangements such as diabetes and hypertension, vascular fragility, musculoskeletal deterioration, and psychiatric sequelae including depression and anxiety. Without intervention, five-year survival approximates only 50%.

Levoketoconazole: Mechanism and Clinical Development

Recorlev represents the pure 2S,4R enantiomer of ketoconazole, functioning as a selective cortisol synthesis inhibitor. This formulation targets patients with endogenous hypercortisolemia when surgical intervention proves infeasible or unsuccessful.

The development program encompassed two pivotal Phase 3 trials. The SONICS study demonstrated levoketoconazole’s capacity to significantly reduce mean urinary free cortisol while normalizing levels without requiring dose escalation—meeting both primary and secondary endpoints. The LOGICS trial, a double-blind placebo-controlled randomized-withdrawal study, confirmed efficacy and safety findings through its own primary and key secondary endpoint achievements. An ongoing open-label OPTICS study continues gathering long-term safety and efficacy data.

The FDA granted approval in December 2021, along with orphan drug designations from both the FDA and European Medicines Agency, reflecting the unmet medical need in this rare disease population.

Safety Considerations and Monitoring Requirements

Critical Safety Information:

Recorlev carries a boxed warning addressing two major concerns: hepatotoxicity and QT prolongation.

Hepatotoxicity cases, including fatal outcomes and liver transplantation requirements, have been documented with oral ketoconazole formulations. Some affected patients lacked obvious liver disease risk factors. Clinicians must evaluate liver enzymes before treatment initiation and throughout the therapeutic course.

QT interval prolongation occurs in a dose-dependent manner with levoketoconazole exposure. This electrical cardiac abnormality carries potential for life-threatening arrhythmias including torsades de pointes. Baseline electrocardiography and correction of electrolyte abnormalities precede treatment, with ongoing cardiac and electrolyte monitoring required during therapy.

Contraindications include:

• Advanced liver disease, baseline transaminase elevation >3x ULN, or prior azole-induced hepatic injury
• Concurrent QT-prolonging medications
• Baseline QTcF >470 msec, arrhythmia history, or long QT syndrome
• Hypersensitivity to levoketoconazole or ketoconazole
• Sensitive CYP3A4 substrate medications

Adverse Reaction Profile:

Most frequently reported reactions (>20% incidence) encompass nausea/vomiting, electrolyte disturbances (hypokalemia), bleeding manifestations, hypertension, headache, liver injury, abnormal uterine bleeding, dermatologic findings, fatigue, gastrointestinal symptoms, joint pain, respiratory infections, muscle soreness, cardiac arrhythmias, back discomfort, sleep disruption, and fluid retention.

Recorlev-induced cortisol reduction may precipitate hypocortisolism with potential adrenal insufficiency—manifesting as nausea, fatigue, abdominal pain, and potentially life-threatening hypotension. Testosterone lowering in both sexes may produce sexual dysfunction and mood changes. Lactating women should avoid breastfeeding during treatment and for one day post-therapy.

Implications for Clinical Practice

This exploratory analysis reinforces the concept of precision medicine in rare endocrine disease management. The demonstrated relationship between baseline disease burden and multiple clinical outcomes—spanning efficacy, dosing, and safety—suggests that pre-treatment stratification could enhance individualized patient management strategies.

The inverse relationship between baseline mUFC and adverse event rates particularly warrants attention from safety monitoring perspectives. Clinicians might reasonably anticipate more intensive pharmacovigilance requirements in severely affected populations while potentially streamlining monitoring protocols for milder disease presentations, provided rigorous assessment continues.

About Xeris Biopharma Holdings, the Chicago-based biopharmaceutical organization maintains a portfolio including Gvoke (glucagon formulation), Keveyis (periodic paralysis therapy), and Recorlev. The company leverages proprietary XeriSol and XeriJect formulation technologies supporting ongoing pipeline expansion and long-term commercial sustainability.