Long-term Recorlev Found Safe, Effective for Endogenous Cushing’s

Most side effects were considered mild or moderate in severity

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Long-term treatment with Recorlev (levoketoconazole) safely leads to sustained reductions in cortisol levels, disease signs and symptoms, and improvements in quality of life in adults with endogenous Cushing’s syndrome, according to nearly two years of data from the Phase 3 SONICS trial.

Treatment benefits were generally maintained or deepened in the six months following the trial’s dose-escalation and six-month maintenance phases, and no new safety signals were identified.

These findings support the favorable long-term safety and efficacy profile of Xeris BioPharma’s oral therapy in this patient population.

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“The results from this extended evaluation of the SONICS study provide important new evidence in support of Recorlev and will help inform clinicians’ decisions and individualization of medical therapy for patients with endogenous [Cushing’s syndrome],” Ken Johnson, Xeris’ senior vice president of global development and medical affairs, said in a company press release.

Trial findings were detailed in a company-funded study, “Levoketoconazole treatment in endogenous Cushing’s syndrome: extended evaluation of clinical, biochemical, and radiologic outcomes,” published in the European Journal of Endocrinology.

Cushing’s syndrome results from abnormally high levels of cortisol, the body’s major stress hormone. It is mainly caused by prolonged exposure to cortisol-like steroid medications and less commonly by excessive production of cortisol by the body — in which case it is called endogenous Cushing’s.

The most common cause of endogenous Cushing’s syndrome is a tumor in the brain’s pituitary gland, a condition known as Cushing’s disease. Surgery to remove the tumor is usually the first-line treatment option for these patients, while medications are considered when surgery is not possible or is ineffective.

Recorlev designed to block cortisol production

Recorlev, which works by blocking the production of cortisol, was approved in the U.S. late last year for adults with endogenous Cushing’s syndrome for whom surgery was ineffective or isn’t an option.

Its recommended starting dose is 150 mg twice a day, which can be increased up to a maximum of 600 mg twice a day, or a total daily dose of 1,200 mg.

The approval was based mainly on positive findings from two international Phase 3 clinical trials, SONICS (NCT01838551) and LOGICS (NCT03277690), which collectively enrolled 166 adults with endogenous Cushing’s.

The results from this extended evaluation of the SONICS study provide important new evidence in support of Recorlev

The open-label SONICS trial enrolled 94 patients and was conducted in three parts. The first was a dose-escalation phase (2–21 weeks) to determine the optimal Recorlev dose, which was followed by a maintenance phase in which patients received the established dose for six months.

Participants were then invited to continue their maintenance dose in a six-month extended evaluation period, with evaluations performed at three and six months — corresponding to nine and 12 months of maintenance treatment.

Previously reported top-line trial data demonstrated that six months of Recorlev treatment in the maintenance phase led to significant drops in urinary cortisol levels without the need for a dose increase, meeting the trial’s main goal. Specifically, about 30% of patients achieved cortisol levels within a normal range.

Treatment also eased Cushing’s symptoms, lessened depression, and improved life quality, while controlling blood sugar levels in a subgroup of patients with diabetes.

New data show the long-term safety and efficacy of Recorlev in 60 patients

Newly published results concern up to nearly two years of safety and efficacy data from the 60 patients who completed the maintenance phase and entered the extension phase.

These participants received Recorlev for a median of about 15 months (range of 7.9–22 months) throughout the trial, with 46 of them (77%) completing the entire study, representing 49% of all trial participants.

Most (65%) of the 60 patients entering the extension had received total daily doses of 600 mg or less, and received a median daily dose of 569 mg (range of 202 mg–1,190 mg) during the extension.

Results showed that urinary cortisol levels were significantly reduced after six months of maintenance treatment, and that these reductions were maintained up to 12 months.

Cortisol levels were normalized in 61% of patients after six months of maintenance treatment, 55% after nine months, and 41% after a year.

Moreover, up to 22 months of Recorlev treatment led to significant reductions in multiple cardiovascular risk markers, including cholesterol levels, blood sugar, body weight, body mass index (a measure of body fat), and abdominal girth compared to the start of the study.

Women experienced a significant decrease in excessive hair growth and acne throughout treatment, which was associated with a significant drop in mean testosterone levels. This finding differs from that seen with other suppressors of cortisol production, which tend to increase testosterone and exacerbate hair growth and acne in women, the team noted.

Recorlev treatment was also associated with statistically significant and clinically meaningful improvements in quality of life and reductions in depression.

Importantly, observed changes in all these measures at six months of maintenance treatment were generally sustained or even more pronounced during the extension phase.

Also, no notable change in tumor size was observed for most (87%) of the 31 patients with tumor measurements available, while the tumor shrank in one patient and grew in three.

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Side effects, mostly mild or moderate in severity, reported in 67% of patients

Adverse events were reported in 67% of patients, and most were mild or moderate in severity. Four patients (6.7%) discontinued treatment due to side effects. The most common side effects were joint stiffness, headache, low blood potassium levels, and mild heart rhythm abnormalities (6.7% each).

“Overall, the incidence of treatment-emergent [adverse events] was substantially lower in the [extension] phase than in the first 2 phases of the study,” the researchers wrote.

Side effects which may be of concern for this class of treatment, including signs of liver damage and heart problems, were not observed during the extension phase.

Nonetheless, “continued periodic monitoring during long-term treatment is advisable to mitigate these potential risks,” the team wrote.

“I would like to extend our gratitude to all the investigators, study coordinators and patients who participated in the SONICS trial program,” Johnson said. “Their contributions are integral in our mission to improve outcomes for patients with this rare, debilitating, and life-threatening condition.”