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Osilodrostat therapy was found to be effective in improving blood pressure parameters, health-related quality of life, depression, and other signs and symptoms in patients with Cushing disease, regardless of the degree of cortisol control, according to study results presented at the 30th Annual Scientific and Clinical Congress of the American Association of Clinical Endocrinologists (ENVISION 2021). Investigators of the LINC 3 study (ClinicalTrials.gov Identifier: NCT02180217), a phase 3, multicenter study with a double-blind, randomized withdrawal period, sought to assess the effects of twice-daily osilodrostat (2-30 mg) on signs, symptoms, and health-related quality of life in 137 patients with Cushing disease. Study endpoints included change in various parameters from baseline to week 48, including mean urinary free cortisol (mUFC) status, cardiovascular-related measures, physical features, Cushing Quality-of-Life score, and Beck Depression Inventory score. Participants were assessed every 2, 4, or 12 weeks depending on the study period, and eligible participants were randomly assigned 1:1 to withdrawal at week 24. The median age of participants was 40.0 years, and women made up 77.4% of the cohort. Of 137 participants, 132 (96%) achieved controlled mUFC at least once during the core study period. At week 24, patients with controlled or partially controlled mUFC showed improvements in blood pressure that were not seen in patients with uncontrolled mUFC; at week 48, improvement in blood pressure occurred regardless of mUFC status. Cushing Quality-of-Life and Beck Depression Inventory scores, along with other metabolic and cardiovascular risk factors, improved from baseline to week 24 and week 48 regardless of degree of mUFC control. Additionally, most participants reported improvements in physical features of hypercortisolism, including hirsutism, at week 24 and week 48. The researchers indicated that the high response rate with osilodrostat treatment was sustained during the 48 weeks of treatment, with 96% of patients achieving controlled mUFC levels; improvements in clinical signs, physical features, quality of life, and depression were reported even among patients without complete mUFC normalization. Disclosure: This study was sponsored by Novartis Pharma AG; however, as of July 12, 2019, osilodrostat is an asset of Recordati AG. Please see the original reference for a full list of authors’ disclosures. Visit Endocrinology Advisor‘s conference section for complete coverage from the AACE Annual Meeting 2021: ENVISION. Reference Pivonello R, Fleseriu M, Newell-Price J, et al. Effect of osilodrostat on clinical signs, physical features and health-related quality of life (HRQoL) by degree of mUFC control in patients with Cushing’s disease (CD): results from the LINC 3 study. Presented at: 2021 AACE Virtual Annual Meeting, May 26-29, 2021. From https://www.endocrinologyadvisor.com/home/conference-highlights/aace-2021/osilodrostat-improves-blood-pressure-hrqol-and-depression-in-patients-with-cushing-disease/
Data from LINC3 and LINC4 provide insight into the impact of dosing titration schedules on risk of hypocortisolism-related adverse events associated with osilodrostat use in patients with Cushing's disease. Data from a pair of phase 3 studies presented at the American Academy of Clinical Endocrinology’s 30th Annual Meeting (AACE 2021) is providing insight into the effect of dose titration schedules with use of osilodrostat (Isturisa) in patients with Cushing’s disease. Presented by Maria Fleseriu, MD, of Oregon Health and Science University, the analysis of the LINC3 and LINC4 demonstrated the more gradual titration occurring in LINC4 resulted in a lower proportion of hypocortisolism-related adverse events, suggesting up-titration every 3 weeks rather than every 2 weeks could help lower event risk without compromising mean urinary free cortisol (mUFC) control. “For patients with Cushing’s disease, osilodrostat should be initiated at the recommended starting dose with incremental dose increases, based on individual response/tolerability aimed at normalizing cortisol levels,” concluded investigators. With approval from the US Food and Drug Administration in March 2020 for patients not eligible for pituitary surgery or have undergone the surgery but still have the disease, osilodrostat became the first FDA-approved therapy address cortisol overproduction by blocking 11β-hydroxylase. Based on results of LINC3, data from the trial, and the subsequent LINC4 trial, provide the greatest available insight into use of the agent in this patient population. The study presented at AACE 2021 sought to assess whether slow dose up titration might affect rates of hypocortisolism-related adverse events by comparing titration schedules from both phase 3 trials. Median osilodrostat exposure was 75 (IQR, 48-117) weeks and 70 (IQR, 49-87) weeks in LINC3 and LINC4, respectively. The median time to first mUFC equal to or less than ULN was 41 (IQR, 30-42) days in LINC3 and 35 (IQR, 34-52) days in LINC4. Adverse events potentially related to hypocortisolism were more common among patients in LINC3 (51%, n=70) than LINC4 (27%, n=20). Upon analysis of adverse events, investigators found the most commonly reported type of adverse event was adrenal insufficiency, which included events of glucocorticoid deficiency, adrenocortical insufficiency, steroid withdrawal syndrome, and decreased urinary free cortisol. Results incited the majority of hypocortisolism-related adverse events occurred during the dos titration periods of each trial. In LINC3, 54 of the 70 (77%) hypocortisolism-related adverse events occurred by week 26. In comparison, 58% of hypocortisolism-related adverse events occurring in LINC4 occurred prior to week 12. Investigators noted most of events that occurred were mild or moderate and managed with dose interruption or reduction of osilodrostat or concomitant medications. This study, “Effect of Dosing and Titration of Osilodrostat on Efficacy and Safety in Patients with Cushing's Disease (CD): Results from Two Phase III Trials (LINC3 and LINC4),” was presented at AACE 2021. From https://www.endocrinologynetwork.com/view/fda-panels-votes-to-support-teplizumab-potential-for-delaying-type-1-diabetes