Recorlev Lessens Cushing’s Symptoms, Eases Depression, SONICS Trial Data Show

Recorlev (levoketoconazole), Strongbridge Biopharma’s oral investigational therapy, lessens disease symptoms and depression, and improves quality of life among people with endogenous Cushing’s syndrome, according to data from the Phase 3 SONICS trial.

Notably, the therapy was found to particularly ease symptoms among female patients.

“People with Cushing’s syndrome often experience a variety of problematic signs, symptoms, and [simultaneous conditions] related to excess cortisol, testosterone or both,” Fredric Cohen, MD, Strongbridge’s chief medical officer, said in a press release.

“The SONICS study provided important evidence that Recorlev treatment was associated with durable improvements in several of the more common and bothersome signs and symptoms of the syndrome, including those that most commonly affect women, such as hirsutism [excess of body and facial hair] and acne, which are related to increases in testosterone produced by the adrenal glands,” Cohen said.

The results of the trial (NCT01838551) were reported in a study titled “Levoketoconazole improves clinical signs and symptoms and patient-reported outcomes in patients with Cushing’s syndrome,” published in the journal Pituitary.

These findings, concerning most of the trial’s secondary goals, add to previously reported SONICS’ data showing the therapy effectively normalized urine cortisol levels among patients, meeting the trial’s main goal.

Notably, SONICS’ data and similar findings from a second Phase 3 trial called LOGICS (NCT03277690) will be the foundation of Strongbridge’s request to the U.S. Food and Drug Administration (FDA) for Recorlev’s approval. That request is planned for early next year.

Recorlev, also known as COR-003, is a small molecule that works by blocking an enzyme involved in the final step of cortisol production in the adrenal glands, which sit atop of the kidneys. As such, Recorlev has the potential to lower or even normalize the abnormally high cortisol levels that underly Cushing’s syndrome.

Of note, the therapy also may suppress the activity of enzymes involved in the production of other steroid hormones by the adrenal glands, including testosterone.

The therapy received orphan drug designation from the FDA and the European Medicines Agency for the treatment of endogenous Cushing’s syndrome. This designation is meant to accelerate Recorlev’s clinical development by providing regulatory support and financial benefits, as well as a marketing exclusivity period of seven years in the U.S. and 10 years in Europe, upon approval.

SONICS evaluated the safety and effectiveness of Recorlev in 94 adults with endogenous Cushing’s syndrome, who were recruited at 60 clinical sites across 19 countries in North America, Europe, and the Middle East.

Following a dose-titration phase to establish a therapeutic dose for trial, 77 (81.9%) of the study’s participants — 61 women and 16 men — entered its maintenance phase. These patients received Recorlev’s therapeutic dose, found to be 600 mg twice per day, for six months.

A total of 61 patients completed the six-month treatment period and were allowed to continue on Reclorlev for an additional six months for long-term safety and effectiveness assessments (extended evaluation).

The trial’s main goal was to assess whether Recorlev was superior to a placebo at normalizing cortisol levels in the patients’ urine after six months of maintenance therapy, without any dose increase during that period.

Secondary goals included changes in the levels of heart disease biomarkers, which are often high among Cushing’s patients, clinical symptoms and signs of the disease, safety measures, and patient-reported quality of life and depression. Quality of life was assessed with the CushingQoL questionnaire, while depression was determined using the Beck Depression Inventory II.

SONICS’ top-line data, announced in August 2018, showed the trial met its main goal and the key secondary goal of lowering heart disease risk. Findings from the extended evaluation, reported in March 2019, demonstrated that Recorlev continued to be well-tolerated and to promote clinically meaningful improvements in the long-term.

The newly published results concerned the other secondary goals of the trial, as well as changes in blood testosterone levels, which were analyzed separately in men and women. These goals were all set for the maintenance phase of the study.

These results showed that Recorlev significantly and consistently lessened three Cushing’s symptoms: acne, hirsutism — assessed only in women — and peripheral edema, or swelling in the legs, feet, or ankles.

These beneficial effects were observed as early as day 1 of maintenance treatment for hirsutism, end of the first month for acne, and end of the fourth month for peripheral edema.

Consistent with the observed reductions in clinical signs associated with abnormally high levels of testosterone in women (acne and hirsutism), the female patients’ testosterone levels showed a significant drop from day one of treatment.

Conversely, Recorlev treatment in men led to a mild increase in testosterone levels, similar to what was previously reported in some case studies with ketoconazole, a medication used for treating Cushing’s syndrome.

Of note, ketoconazole — under the brand name Ketoconazole HRA, by HRA Pharma — is approved in Europe for treating Cushing’s syndrome. In the U.S., it has been used off-label for this indication.

In addition, reductions in other clinical signs and symptoms were found in 38.1% to 66.7% of participants after six months of treatment.

Significant improvements in patients’ quality of life were observed from the third month onward, and depressive symptoms were significantly reduced by the end of the maintenance treatment period.

Recorlev was generally well-tolerated, with nausea (32%), and headaches (28%) as the most commonly reported adverse events (side effects).

“In conclusion, [Recorlev] provides sustained improvements in relevant investigator-assessed signs and symptoms and patient-reported [quality of life] and depression outcomes for patients with [Cushing’s syndrome],” the researchers wrote.

They also noted that these improvements were associated with changes in disease biomarkers, including blood testosterone and cortisol levels.

Recorlev’s longer-term safety and effectiveness will be assessed in the OPTICS study (NCT03621280), which is currently enrolling patients who completed either the SONICS study, the LOGICS trial, or both. In this open-label extension trial, patients will continue Recorlev treatment for up to three more years.