Recorlev Leads to Sustained Improvements in Cortisol Control in Cushing’s Syndrome, Phase 3 Trial Shows

The oral investigational treatment Recorlev (levoketoconazole) leads to sustained improvements in the control of cortisol among patients with endogenous Cushing’s syndrome, a Phase 3 trial shows.

The trial’s findings were reported in the study “Efficacy and safety of levoketoconazole in the treatment of endogenous Cushing’s syndrome (SONICS): a phase 3, multicentre, open-label, single-arm trial,” which was published in The Lancet Diabetes & Endocrinology.

The treatment’s developer, Strongbridge Biopharma, launched the Phase 3 trial (NCT01838551), known as SONICS, to evaluate the safety and efficacy of Recorlev, also called COR-003, to treat patients with Cushing’s syndrome, a medical condition in which the hormone cortisol rises to unhealthy levels, resulting in a series of complications.

The non-randomized study enrolled a total of 94 adults with a confirmed diagnosis of Cushing’s syndrome, who were recruited from 60 clinical centers spread across 19 countries.

During the dose-escalation phase of the trial, participants received increasing doses of oral Recorlev starting at 150 mg twice-a-day, with 150-mg increments until the optimal dose was reached (the dose at which the levels of cortisol in the urine are normalized).

This was followed by a six-month maintenance phase in which patients received Recorlev at the optimal dose (found to be 600 mg twice-a-day in the previous phase).

The trial’s primary outcome was to assess the percentage of patients whose levels of cortisol in the urine had normalized after six months of maintenance therapy with Recorlev.

Secondary outcomes included measuring the levels of heart disease biomarkers (such as fasting glucose, LDL-cholesterol, body weight), evaluating other clinical symptoms and signs of the disease, taking patient-rated quality of life assessments, and testing safety.

From the 94 patients who were enrolled in SONICS and received at least one dose of Recorlev, 80 (85%) had a tumor in the pituitary gland (a pea-sized gland in the brain that controls the production of hormones of other glands in the body), which led to an excessive production of cortisol by the adrenal glands that sit atop of the kidneys.

At baseline, the mean level of cortisol found in the patients’ urine was 243.3 μg/24 hours, which was nearly five times that of the normal upper limit.

From the 77 patients who received maintenance therapy with Recorlev, 61 completed the entire six-month maintenance phase of SONICS.

Key findings from the trial showed that:

• SONICS met its primary outcome, with 31% of the patients initially enrolled in the trial achieving normalization of their urine cortisol levels by the end of the maintenance phase, without requiring any dose increment of Recorlev.
• From the 77 patients who participated in the maintenance phase, 62 (81%) achieved normalization of their urine cortisol levels by the end of the initial dose-escalation phase.
• During the maintenance phase, 36% of the patients initially enrolled in SONICS achieved normalization of their urine cortisol levels, and 46% saw their urine cortisol levels drop by 50% or more, regardless of whether they required dose increments.
• Several biomarkers of heart disease, including fasting glucose and LDL-cholesterol, all showed clinically meaningful improvements from baseline until the end of the maintenance phase.
• Recorlev was generally safe and well-tolerated by patients during both phases of SONICS; no sudden or unexpected safety concerns were reported during the trial.
• The most common adverse events observed during the trial included nausea (32%) and headaches (28%).
• Adverse events that required patients to discontinue treatment were reported in 12 participants of the 94 initially enrolled (13%).
• Four patients experienced serious adverse events that were likely associated with Recorlev. One of the patients died from colon cancer, which was found to be unrelated to Recorlev treatment.

“Importantly, treatment with Recorlev was shown to be effective for reducing and normalizing mUFC [mean urinary free cortisol] concentrations and biomarkers of cardiovascular [heart disease] risk, as well as improving clinical signs and quality of life in patients with endogenous Cushing’s syndrome,” Maria Fleseriu, MD, FACE, professor of medicine and neurological surgery, and director of the Oregon Health Sciences University Northwest Pituitary Center and principal investigator of the study, said in a news release.

“These data are highly encouraging given medical needs remain very high for this rare endocrine disorder, despite the availability of approved treatments,” Fleseriu said.

Fredric Cohen, MD, chief medical officer of Strongbridge, added: “We look forward to continuing to advance our clinical development program for Recorlev with top-line data expected from LOGICS, our second Phase 3 trial, at the end of the first quarter of 2020, and [New Drug Application] submission at the end of the third quarter of 2020.”