Recorlev Normalizes Cortisol Levels in LOGICS Trial: Results Published
More than 95% of participants who switched to a placebo saw cortisol increases above nomal
Recorlev (levoketoconazole) outperformed a placebo at normalizing urine cortisol levels among people with endogenous Cushing’s syndrome in the Phase 3 LOGICS trial.
Top-line data from the study were announced in 2020. Full results have now been published in Pituitary in the study, “Levoketoconazole in the treatment of patients with endogenous Cushing’s syndrome: a double-blind, placebo-controlled, randomized withdrawal study (LOGICS).”
The work was funded by Recorlev’s developer Strongbridge Biopharma, which was recently acquired by Xeris Pharmaceuticals.
A feature of endogenous Cushing’s syndrome is abnormally high levels of the stress hormone cortisol, which leads to symptoms such as weight gain and skin problems. Cushing’s disease is a specific form of the syndrome where excessive cortisol production is driven by a tumor in the brain’s pituitary gland.
Recorlev is designed to block cortisol production in the body. It was approved by the U.S. Food and Drug Administration (FDA) late last year to treat adults with endogenous Cushing’s for whom surgery is either ineffective or not an option and has been available in the U.S. since early 2022.
The FDA’s approval was supported in part by data from the Phase 3 LOGICS trial (NCT03277690) along with an open-label study called SONICS (NCT01838551).
LOGICS enrolled 79 adults with Cushing’s at sites in the U.S., Europe, and Israel. In the first part of the study, all participants were treated with Recorlev starting at 150 mg twice daily. Cortisol levels were monitored and doses were regularly adjusted to find normalized hormone levels.
During this phase, 15 patients discontinued treatment due to side effects. Researchers noted patients with higher initial cortisol levels generally required a higher dose for normalization.
After this, 39 patients who achieved normal levels, as well as five who had achieved normal levels with Recorlev in SONICS, entered the placebo-controlled part of the study. Here, patients were randomly assigned to continue taking Recorlev or switch to a placebo for eight weeks.
Results showed that nearly all (95.5%) patients who switched had increased urine free cortisol levels above 1.5-times the upper normal value, as compared with less than half (40.9%) of those who remained on Recorlev.
Consistently, half (50%) of Recorlev-treated patients had cortisol levels in the normal range at the end of this part of the study, compared with just one (4.5%) in the placebo group.
Recorlev helped reduce cholesterol levels, analyses indicated. Patients on Recorlev also tended to report better outcomes on measures of quality of life, depression, and symptom severity, though the difference from the placebo group was not statistically significant.
After the eight-week placebo-controlled withdrawal phase, all were treated with Recorlev for another eight weeks. By the end, more than half (58%) had cortisol levels in the normal range, including 52% of those taking Recorlev during the withdrawal phase and 64% in the placebo group. Mean urinary cortisol levels, as well as the effect on cholesterol, were comparable in both groups by the study’s end.
“Primary results from LOGICS demonstrate a difference between continuing masked active treatment versus switching to matching placebo following establishment of [cortisol] control,” the researchers wrote. “Furthermore, restoration of active therapy was largely successful in reversing therapy withdrawal to placebo… Therefore, the effect of [Recorlev] to normalize [cortisol] is shown to be drug-specific, reversible upon drug withdrawal, and restorable upon drug reintroduction.”
While results show short-term cortisol normalization with Recorlev treatment leads to long-term normalization for most patients, researchers noted that “sustained [cortisol] normalization should not be assumed to result from an initial [cortisol] normalization demonstration,” since findings indicate that “a minority of patients will lose [cortisol] control” in the short term and won’t get it back with Recorlev alone.
Recorlev was well tolerated overall in the study, with no remarkable new findings related to its safety profile. The most commonly reported side effects included nausea, headache, high blood pressure, and low potassium levels (hypokalemia). Tests showed abnormal electrical activity in the heart of a few patients on Recorlev, but these were not associated with clinical problems. Abnormalities in liver tests were somewhat common, but rarely led to symptoms.
Investigators concluded Recorlev “was generally well tolerated and had a safety profile that was manageable with appropriate close monitoring.”
“Together these findings support the use of levoketoconazole as a treatment option for adult patients with [Cushing’s syndrome]”, they wrote, noting the study was limited by its relatively small size and short duration, as well as a somewhat homogeneous population of patients of European descent.