and monitored through use of clinical signs and symptoms improvements (e.g., blood sugar reductions). Korlym has been approved in the United States to control hyperglycemia secondary to hypercortisolism in patients with endogenous Cushing’s syndrome who also have diabetes mellitus. About one-third of patients with endogenous Cushing syndrome have diabetes. Korlym is contraindicated in pregnant women and in women with a history of unexplained vaginal bleeding, as its side effects include termination of pregnancy, endometrial thickening and vaginal bleeding. It is also frequently associated with hypokalemia. Mitotane is an adrenolytic agent (i.e., it destroys the adrenal gland at higher doses) that inhibits steroidogenesis non-selectively at low doses, mainly at 20,22-desmolase (cholesterol side-chain cleavage). It seems to be used primarily in adrenocortical cancer, where it had an FDA indication. There are no prospective clinical trials describing the use of mitotane in non-malignant endogenous CS, and it is not approved for that use. We believe that the efficacy and usage limitations and safety concerns associated with other currently available drug therapies for endogenous Cushing’s syndrome are an important reason why a significant unmet medical need exists among endogenous Cushing’s syndrome patients with persistent or recurrent disease post-surgery. In a survey we commissioned in 2019 of 253 U.S. physicians treating patients with Cushing’s syndrome. When asked what percentage of their endogenous Cushing’s patients currently receiving pharmacological therapy, they would consider have symptoms controlled vs. uncontrolled by their medication(s) for CS, the surveyed physicians indicated that approximately 39% of patients were uncontrolled vs. 61% were controlled. We believe that our potential addressable market for Recorlev includes diagnosed endogenous Cushing’s syndrome patients that at any time are eligible for drug therapy, including patients for whom surgery or radiation is not feasible, is contraindicated or has been unsuccessful. Recorlev Clinical Trials Program The Phase 3 program for Recorlev included SONICS and LOGICS, two multinational studies designed to evaluate the safety and efficacy of Recorlev when used to treat endogenous Cushing’s syndrome. The SONICS study met its primary and secondary endpoints, significantly reducing and normalizing mean urinary free cortisol concentrations without a dose increase. The LOGICS study, which met its primary endpoint and key secondary endpoint, was a double-blind, placebo-controlled randomized-withdrawal study of Recorlev that was designed to supplement the efficacy and safety information provided by SONICS. The ongoing open-label OPTICS study will gather further useful information related to the long-term use of Recorlev. The key secondary efficacy endpoint the LOGICS study was the proportion of patients with mUFC normalization, defined as a patient with mUFC at or below the upper limit of normal reference range (ULN) at the end of randomized withdrawal phase without meeting a requirement for early rescue during the randomized withdrawal phase. Out of the 79 patients who entered the dose titration and maintenance phase, 37 (47%) patients who met the requirement to be on a stable therapeutic dose for at least 4 weeks and established normal mUFC at the end of the dose titration and maintenance phase, and 2 patients who did not meet the requirement due to abnormal mUFC, continued to the randomized-withdrawal phase. Out of 5 patients from the SONICS study who were enrolled directly in the randomized withdrawal phase, 2 patients had normal mUFC. Among the 39 patients who had normal mUFC at the randomized withdrawal phase baseline, 21 were randomized to the Recorlev group and 18 to the placebo group. The number and percent of patients who had normal mUFC at the end of the randomized withdrawal phase was 11/21 (52.4%) in Recorlev group and 1/18 (5.6%) in placebo group, and the treatment difference (CI) was 46.8% (16.5%, 70.2%). Out of 11 patients with normal mUFC at the end of the randomized-withdrawal phase, 7 patients in the Recorlev group had normal mUFC throughout the randomizedwithdrawal phase. The primary efficacy endpoint of the SONICS study was the proportion of patients with normalization of mUFC at the end of the 6month maintenance phase. Normalization of mUFC was defined as mUFC at or below the ULN based on central laboratory result without requiring a dose increase during the maintenance phase. At the end of the maintenance phase, 29 of 94 patients (30.9%, 95% exact confidence interval 21.7%, 41.2%) met the primary endpoint. The most common adverse reactions (incidence > 20%) for LOGICS and SONICS were nausea/vomiting, hypokalemia, hemorrhage/ contusion, systemic hypertension, headache, hepatic injury, abnormal uterine bleeding, erythema, fatigue, abdominal pain/dyspepsia, arthritis, upper respiratory infection, myalgia, arrhythmia, back pain, insomnia/sleep disturbances, and peripheral edema. Elevations in AST or ALT post baseline were reported in patients treated with Recorlev who had AST or ALT≤ ULN at baseline in LOGICS and SONICS. There were 11 out of 166 patients who had an AST or ALT above the ULN to ˂3 x ULN at baseline. Of these patients, 3 had increases above 3 x ULN, and none had increases above 5 x ULN. Liver test abnormalities improved with cessation of medication. In the LOGICS and SONICS studies combined, there were 4 (2.4%) patients who experienced QTcF>500 msec, and 23 (14.7%) patients who experienced change-from-baseline QTcF >60 msec, respectively. Adverse reactions reported around the same time that may have been associated with QT prolongation included fatigue, hypertension, nausea/vomiting, and ventricular extrasystoles. The FDA-approved labeling for Recorlev includes a boxed warning for hepatotoxicity and QT prolongation Recorlev has been associated with serious hepatotoxicity and dose-related QT interval prolongation. OPTICS Phase 3 Clinical Trial In 2018, we initiated a long-term, open-label extension trial with Recorlev (“OPTICS”) to capture longer-term safety, tolerability and efficacy data from patients who complete either SONICS or LOGICS and who chose to continue therapy with Recorlev. OPTICS will continue to accrue data on each enrolled patient for a minimum of three years or until Recorlev has become available in their own country, whichever comes first. 14
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