Cushing’s disease is a progressive pituitary disorder in which there is an excess of cortisol in the body. While the disease can be treated surgically, this option is not possible for all patients. This is one of the approved medications that assist in controlling cortisol levels in people with Cushing’s disease.
Recorlev was approved by the FDA in December 2021 to treat those Cushing’s patients for whom surgery is not a choice or has failed to lower cortisol levels. The medication is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms.
Recorlev (levoketoconazole) is a treatment that Strongbridge Biopharma — now acquired by Xeris Pharmaceuticals — developed for endogenous Cushing’s syndrome. Endogenous Cushing’s is a form of the disease in which symptoms occur because the body produces too much cortisol.
Abnormally high cortisol levels in Cushing’s syndrome may be primarily due to a tumor in the brain’s pituitary gland — a type of the condition called Cushing’s disease . The first treatment option is surgery to remove those tumors. However, in some patients, this procedure is not an option or is ineffective at lowering cortisol levels.
How does Recorlev works?
Cortisol plays several important roles in the body, including regulating salt and sugar levels, blood pressure, inflammation, breathing, and metabolism. Too much cortisol, however, throws the body off balance, causing a wide range of symptoms, such as obesity, high blood sugar levels, bone problems, and fatigue.
Recorlev is an oral cortisol synthesis inhibitor that prevents the adrenal glands — sitting atop the kidneys — from producing too much cortisol, thereby easing Cushing’s symptoms.
Recorlev in clinical trials
Recorlev’s approval was mainly supported by data from two Phase 3 clinical trials: one called SONICS (NCT01838551) and the other LOGICS (NCT03277690).
SONICS was a multicenter, open-label, three-part trial that evaluated the safety and effectiveness of Recorlev in 94 patients with endogenous Cushing’s syndrome who were not candidates for radiation therapy or surgery, and whose cortisol levels in the urine were at least 1.5 times higher than normal.
Top-line data from SONICS revealed that nearly a third of patients saw their urinary cortisol levels drop to a normal range after six months of maintenance treatment with Recorlev, without requiring any dose increments in that period of time.
A subgroup analysis of the study also showed Recorlev helped control cortisol and blood sugar levels in patients with both Cushing’s and diabetes. The study also showed that Recorlev was able to lessen symptoms, ease depression, and improve patients’ quality of life.
LOGICS was a double-blind, randomized, withdrawal and rescue study that assessed the safety, efficacy, and pharmacological properties of Recorlev in patients with endogenous Cushing’s syndrome who had previously participated in SONICS, or who had never been treated with Recorlev.
After a period of taking Recorlev, some participants were switched to a placebo while others remained on the medication. This design allowed researchers to assess the effects of treatment withdrawal.
According to patients who stopped using Recorlev and moved to a placebo saw their urine cortisol levels rise in response to the lack of treatment, compared with those who remained on Recorlev. Additional data from the study also showed that patients who switched to a placebo lost Recorlev’s cholesterol-lowering benefits.
Safety data from an ongoing open-label Phase 3 extension study called OPTICS ( NCT03621280 ) also supported Recorlev’s approval. This trial, which is expected to conclude in June 2023, is designed to assess the long-term effects of Recorlev in patients who completed one or both previous studies, for up to three years.
Recorlev’s starting dose is 150 mg twice daily and should be taken orally with or without food. The maximum recommended dose is 1,200 mg per day, given as 600 mg twice daily.
The most common side effects associated with Recorlev include nausea, vomiting, increased blood pressure, abnormally low blood potassium levels, fatigue, headache, abdominal pain, and unusual bleeding.
Liver enzymes should be monitored before and during the treatment since this therapy can cause hepatotoxicity, or liver damage, in some individuals. For this reason, it is contraindicated in people with liver diseases such as cirrhosis. Recorlev should be immediately stopped if signs of hepatotoxicity are observed.
Recorlev also can influence heartbeat. As such, patients with certain heart conditions should be closely monitored before and during treatment.
Hypocortisolism, or lower-than-normal levels of cortisol, also may occur during treatment with Recorlev. For this reason, patients should have their cortisol levels closely monitored, and lessen or interrupt treatment if necessary.
Recorlev interacts with medicines on which certain liver enzymes act, such as CYP3A4. Treatment also is an inhibitor of P-gp, OCT2, and MATE1, which are transporters of certain medicines. The use of Recorlev with these medicines may increase the risk of adverse reactions.