DUBLIN & TREVOSE, Pa.—Strongbridge Biopharma plc announced in March top-line findings from the extended evaluation phase of the pivotal Phase 3 SONICS study of Recorlev (levoketoconazole) for the potential treatment of endogenous Cushing’s syndrome. The purpose of the six-month extended evaluation phase was to evaluate the long-term safety, tolerability and benefit-risk of chronic use of Recorlev.
“We are encouraged by the top-line results from the SONICS extended evaluation phase. Recorlev (levoketoconazole) treatment was associated with no new clinically relevant liver-related findings or other new safety signals, while demonstrating long-term efficacy to reduce mean urinary free cortisol, or mUFC, as well as key cardiovascular risk markers such as weight and LDL-cholesterol,” says Dr. Fredric Cohen, chief medical officer of Strongbridge Biopharma. Recorlev was generally well tolerated during the extended evaluation phase, and no new drug-related safety signals were observed. Sixty out of 61 study participants who completed the maintenance phase elected to participate in the extended evaluation phase. Of the 60 patients that entered the extended evaluation phase, 46 patients completed it.
Data were collected twice at three-month intervals, which is common practice for long-term follow-up of chronic medical therapy for endogenous Cushing’s syndrome. Four patients (6.7 percent) discontinued due to adverse events. No patients experienced an increase in either alanine aminotransferase or aspartate aminotransferase greater than three times the upper limit of normal, and there were no reported adverse events of special interest related to liver injury or dysfunction.
The most commonly reported (≥5 percent) treatment-emergent adverse events in the extended evaluation phase were arthralgia (7 percent), QTc prolongation (7 percent), headache (7 percent), hypokalemia (7 percent) and nasopharyngitis (5 percent); QTc prolongation greater than 460 milliseconds was not observed in the extended evaluation phase. Nausea (2 percent) and headache (7 percent) were reported at lower rates compared to the previously reported aggregate rates of 32 percent (nausea) and 28 percent (headache) from the dose titration and maintenance phases.
“Recorlev (levoketoconazole) is the pure 2S,4R single enantiomer of ketoconazole, a steroidogenesis inhibitor, which over the years has been used off-label in Cushing’s syndrome based on its believed cortisol control properties. We believe that Recorlev, if approved, may have favorable efficacy, safety and tolerability for patients with endogenous Cushing’s syndrome,” Cohen explains. “The need for a safe and effective next-generation cortisol synthesis inhibitor such as Recorlev in the treatment of Cushing’s syndrome remains substantial. Current treatment options either have limited indications or are difficult to dose since they do not reduce cortisol, have significant negative side effects, especially for women, or are off-label and have never been rigorously studied in Cushing’s.”
“Last year, we announced positive results from the pivotal Phase 3 SONICS study, which evaluated the safety and efficacy of Recorlev in patients with endogenous Cushing’s syndrome. The study met its primary endpoint, with mUFC—a surrogate endpoint that predicts clinical outcomes—confirmed normal among 30 percent of the intent-to-treat population, without a preceding dose increase following six months of maintenance therapy (one-sided P=0.0154). Safety and tolerability findings based upon data collected through the six-month maintenance phase indicate that Recorlev was generally well tolerated,” continues Cohen. “In addition, the exploratory responder analyses indicate that Recorlev provided clinical benefit across the spectrum of baseline comorbidities in Cushing’s syndrome, including hypercholesterolemia and diabetes. Many markers of cardiovascular risk, an important cause of morbidity and mortality in Cushing’s syndrome, also improved significantly.”
In this exploratory evaluation, an observed-case analysis of completers was used to evaluate mUFC responders. At the end of the extended evaluation phase, normalization of mUFC was observed in 41 percent of patients, and normalization of or at least 50-percent improvement in mUFC was observed in 68 percent of patients. Clinically meaningful improvements in key cardiovascular risk markers (hemoglobin A1c, fasting glucose, total and LDL-cholesterol) were observed throughout the extended evaluation phase. Weight loss and reduction in body mass index continued throughout the extended evaluation phase.
“We continue to advance Recorlev, and will be conducting a Type C meeting with FDA in the first quarter of 2019 to seek guidance on the regulatory path forward to obtain marketing approval for Recorlev for the treatment of endogenous Cushing’s syndrome,” Cohen points out. “We plan to provide a market update on our FDA meeting outcomes in the second quarter, and look forward to working with healthcare professionals and patients to raise awareness of Cushing’s syndrome and to potentially provide a new treatment option for this disease.”
“We are most excited about the opportunity to develop curative or significant life-saving treatments for patients in areas where there is a tremendous unmet need, like in Cushing’s syndrome. Our focus on rare diseases—a strategy that welcomes and nurtures products that may be too large for smaller biotechs, and yet too small for larger firms—allows us to bring research, education and resources to niche communities, which would continue to be largely underserved without our involvement,” he adds. “We are excited and proud to continue serving those rare disease communities that are often overlooked and underserved in the drug development and commercialization process.”