Positive Top-Line Results Announced from the Pivotal Phase 3 SONICS Study of Levoketoconazole for the Treatment of Endogenous Cushing’s Syndrome

Positive top-line results this week were announced from the multinational, pivotal Phase 3 SONICS study evaluating levoketoconazole for the treatment of endogenous Cushing’s syndrome. Strongbridge Biopharma is marketing the drug as RECORLEV™ .

The open-label, single-arm SONICS study achieved statistical significance of its pre-specified primary endpoint, with 30 percent of patients achieving normalization of mean urinary free cortisol (UFC) following six months of maintenance treatment with RECORLEV without a dose increase (p<.025). Sensitivity analyses as well as secondary and exploratory endpoints of UFC response were supportive of the primary endpoint.

For key secondary endpoints of cardiovascular risk, including fasting blood glucose, hemoglobin A1C, total cholesterol, low density lipoprotein (LDL)-cholesterol, body weight and body mass index (BMI), RECORLEV demonstrated statistically significant and clinically meaningful improvements from baseline (p<.0001 for each).

Safety and tolerability findings based upon data collected through the six-month maintenance phase indicate that RECORLEV was generally well tolerated.

  • 12 patients (12.8 percent) discontinued treatment with RECORLEV due to adverse events (AEs). For the two most commonly reported AEs, no patients discontinued treatment due to nausea and one patient discontinued treatment due to headache.
  • 14 patients (14.9 percent) reported one or more serious adverse events (SAEs), of whom four had SAEs deemed drug related by investigators.
  • One patient death was reported and not considered drug related (colon cancer).

The following tables represent the SONICS liver-related findings and the most commonly reported treatment-emergent AEs:

SONICS Liver-Related Findings

Liver-Related FindingsN=94
Liver-related AEs defined in protocol as AE of special interest7.4%*
>3X Upper Limit of Normal (ULN) (includes those > 5x ULN)10.6%
>5x ULN3.2%
Bilirubin values > 1.5x ULN0%

*No severe drug-induced liver injury; no Hy’s law; no transaminases >20x ULN; no obvious dose relationship (exposure relationships analyses pending).

SONICS Treatment-Emergent Adverse Events (≥15%)

Treatment-Emergent AESubjects ≥ 1 AE% of Enrolled (N=94)
Peripheral edema1819%
Alanine Aminotransferase (ALT) increased**1415%

**Includes all ALT increases reported as an adverse event regardless of level or relationship to drug. A subset of these ALT increased events was also reported as AEs of special interest.

“Given the prospective design and rigorous nature of the SONICS primary endpoint, which required patients to maintain normalized mean 24-hour UFC (2 to 4 samples) without a dose increase for six months, a 30 percent intent-to-treat response rate has significant clinical relevance. The robust effect of RECORLEV in normalizing or decreasing UFC levels was complemented by key secondary endpoint data showing significant improvements in multiple markers for cardiovascular risk,” says Maria Fleseriu, MD, FACE, professor of Neurological Surgery and Medicine, and director of the Oregon Health Sciences University Northwest Pituitary Center. “SONICS efficacy and safety results, including a low frequency (3.2 percent) of significant ALT elevations (more than five times above the upper limit of normal) without clinical sequalae and fully reversible, positions RECORLEV, if approved, to play an important role in individualized medical therapy for Cushing’s syndrome, including consideration as a first-line treatment.”

“Strongbridge would like to thank the many patients and investigators who have and are participating in the SONICS trial. The data generated from this study has and will continue to provide important insights into the understanding of Cushing’s syndrome and the use of RECORLEV. Strongbridge looks forward to working with healthcare professionals and patients to raise awareness of Cushing’s syndrome and to potentially provide a new treatment option for this disease,” says Matthew Pauls, president and chief executive officer of Strongbridge Biopharma.

Fred Cohen, MD, chief medical officer of Strongbridge Biopharma says, “The impressive top-line results of the SONICS study suggest that RECORLEV, the 2S,4R enantiomer of ketoconazole, is an effective and well tolerated cortisol synthesis inhibitor in Cushing’s syndrome. Based on these compelling data, we look forward to discussing the potential for accelerated approval of RECORLEV with the FDA and to continuing our discussions with regulators around the world.”

About the SONICS Study:

SONICS is an open-label, Phase 3 study of RECORLEV as a treatment for endogenous Cushing’s syndrome that enrolled 94 patients at centers in North America, Europe and the Middle East. Following a screening phase, SONICS has three treatment phases:

(1) Dose Titration Phase: Patients started RECORLEV at 150 mg twice daily (300 mg total daily dose) and titrated in 150 mg increments with the goal of achieving a therapeutic dose – a dose resulting in UFC normalization – at which point titration was stopped;

(2) Maintenance Phase: The dose was fixed and should not have been changed other than for safety reasons or loss of efficacy. At the end of the six-month maintenance phase, the UFC response rate was measured; and

(3) Extended Evaluation Phase: Patients continue for another six months.

In order to be considered a UFC responder for the primary efficacy analysis, a patient must have met either three or four criteria, as applicable: (1) have completed the six-month maintenance phase; (2) have normal (at or below the ULN) mean 24-hour UFC on the basis of at least two (and up to four) adequate 24-hour urine samples; (3) must not have increased the dose of RECORLEV used during the entire maintenance phase and; (4) for patients with a recent history of pituitary radiation must have exhibited a rebound increase in mean UFC above the ULN following a two-week minimum withdrawal of RECORLEV at the end of maintenance phase.