Randomized Trial of Osilodrostat for the Treatment of Cushing Disease

European Journal of Endocrinology

Newell‐Price

Pivonello

et al. 2022

Self Cite

Objective: To investigate the long-term efficacy and tolerability of osilodrostat, a potent oral 11β-hydroxylase inhibitor, for treating Cushing’s disease (CD). Design/methods: 137 adults with CD and mean 24-hour urinary free cortisol (mUFC) >1.5x upper limit of normal (ULN) received osilodrostat (starting dose 2 mg bid; maximum 30 mg bid) during the prospective, Phase III, 48-week LINC 3 (NCT02180217) core study. Patients benefiting from osilodrostat at week 48 could enter the optional extension (ending when all patients had received ≥72 weeks of treatment or discontinued). Efficacy and safety were assessed for all enrolled patients from core study baseline. Results: Median osilodrostat exposure from core study baseline to study end was 130 weeks (range 1–245) and median average dose 7.4 mg/day (range 0.8–46.6). The reduction in mean mUFC achieved during the core was maintained during the extension and remained ≤ULN. 86/106 (81%) patients who entered the extension had mUFC ≤ULN at week 72. Improvements in cardiovascular/metabolic-related parameters, physical manifestations of hypercortisolism (fat pads, central obesity, rubor, striae, and hirsutism in females), and quality of life in the core study were also maintained or improved further during the extension. No new safety signals were reported; 15/137 (10.9%) and 12/106 (11.3%) patients discontinued for adverse events during the core and extension, respectively. Mean testosterone in females decreased towards baseline levels during the extension. Conclusions: Data from this large, multicentre trial show that long-term treatment with osilodrostat sustains cortisol normalisation alongside clinical benefits in most patients with CD and is well tolerated.

Section: Introductionmentioning

confidence: 99%

Long-term outcomes of osilodrostat in Cushing's disease: LINC 3 study extension

European Journal of Endocrinology

Newell‐Price

Pivonello

et al. 2022

Self Cite

“…In the LINC 3 study, prescheduled dose up-titration steps within the first 3 months of treatment were mandated per study design, with a 2 mg BID starting dose of osilodrostat and up-titration occurring every 2 weeks until week 12 (with 5-, 10-, 20-, and 30-mg BID escalation) if 24-h mean UFC (mUFC) was greater than ULN. In contrast, in LINC 4, the starting dose of osilodrostat remained 2 mg BID, but it was up-titrated by central independent endocrinologists (used in this double-blind study) less rapidly at weeks 2, 5, and 8 on the basis of efficacy and tolerability [ 6 , 9 ]. In LINC 3, for all patients, the median osilodrostat exposure was 130 weeks (range, 7–245 weeks) and median dose was 7.4 mg/d, which consistently decreased and normalized UFC [ 33 ].…”

Section: Choice Of Dose and Titration Speedmentioning

confidence: 99%

“…In LINC 3, for all patients, the median osilodrostat exposure was 130 weeks (range, 7–245 weeks) and median dose was 7.4 mg/d, which consistently decreased and normalized UFC [ 33 ]. In LINC 4, for all patients, the median osilodrostat exposure was 70.0 weeks (range, 2.0–112.7 weeks) and median dose was 5.0 mg/d, which maintained mUFC within normal range in most patients up to week 48 [ 6 ]. In LINC 4, increasing osilodrostat dose at 3-week intervals instead of every 2 (as in LINC 3) resulted in fewer hypocortisolism-related AEs (LINC 4 vs LINC 3: 27% vs 51%, respectively) without delaying the time to first mUFC normalization (LINC 4 vs LINC 3: 35 vs 41 days, respectively) [ 33 , 34 ].…”

Section: Choice Of Dose and Titration Speedmentioning

confidence: 99%

“…Hypocortisolism-related AEs in LINC 3 and LINC 4 were predominantly of mild or moderate severity and were effectively managed via dose reduction, interruption, and/or concomitant glucocorticoid administration [ 34 ]. Only 3% of participants permanently discontinued osilodrostat because of these AEs in LINC 3 (4/137) and LINC 4 (2/73) [ 6 , 9 ]. Together, these clinical data demonstrate that gradual up-titration of osilodrostat can mitigate the incidence of hypocortisolism-related AEs in many patients without affecting rates of UFC control.…”

Section: Choice Of Dose and Titration Speedmentioning

confidence: 99%

“…Osilodrostat is a potent, oral, reversible inhibitor of both 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, and aldosterone synthase, which catalyzes conversion of 11-deoxycorticosterone to aldosterone [2]. Clinical evidence from the LCI699 in Cushing's (LINC) studies have demonstrated the efficacy and safety of osilodrostat [6][7][8][9]. This medication is approved in the United States for the treatment of CD in adults for whom pituitary surgery is not an option or has not been curative [10], and it is approved for the treatment of all causes of endogenous CS in Europe and Japan.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Treatment of Cushing’s syndrome with osilodrostat: practical applications of recent studies with case examples

2022

Pituitary

Endogenous Cushing’s syndrome (CS) is a rare endocrine condition frequently caused by a tumor resulting in elevated cortisol levels. Cushing’s disease (CD) caused by an adrenocorticotropic hormone–secreting pituitary adenoma is the most common form of endogenous CS. Medical therapy for CD is mostly used as second-line treatment after failed surgery or recurrence and comprises several pituitary-directed drugs, adrenal steroidogenesis inhibitors, and a glucocorticoid receptor blocker, some of which are US Food and Drug Administration (FDA)–approved for this condition. The recent Pituitary Society consensus guidelines for diagnosis and management of CD described osilodrostat, an oral inhibitor of 11β-hydroxylase, as an effective, FDA-approved medical therapy for CD. Because clinical experience outside clinical trials is limited, we provide here a review of published data about osilodrostat and offer example case studies demonstrating practical considerations on the use of this medication. Recommendations regarding osilodrostat are provided for the following situations: specific assessments needed before treatment initiation; monitoring for adrenal insufficiency, hypokalemia, and changes in QTc; the potential value of a slow up-titration in patients with mild disease; managing temporary treatment cessation for patients with CD who have acquired coronavirus disease 2019; monitoring for increased testosterone levels in women; exercising caution with concomitant medication use; considering whether a higher dose at nighttime might be beneficial; and managing cortisol excess in ectopic and adrenal CS. This review highlights key clinical situations that physicians may encounter when using osilodrostat and provides practical recommendations for optimal patient care when treating CS, with a focus on CD.

Cushing Syndrome

Reincke

2023

JAMA

ImportanceCushing syndrome is defined as a prolonged increase in plasma cortisol levels that is not due to a physiological etiology. Although the most frequent cause of Cushing syndrome is exogenous steroid use, the estimated incidence of Cushing syndrome due to endogenous overproduction of cortisol ranges from 2 to 8 per million people annually. Cushing syndrome is associated with hyperglycemia, protein catabolism, immunosuppression, hypertension, weight gain, neurocognitive changes, and mood disorders.ObservationsCushing syndrome characteristically presents with skin changes such as facial plethora, easy bruising, and purple striae and with metabolic manifestations such as hyperglycemia, hypertension, and excess fat deposition in the face, back of the neck, and visceral organs. Cushing disease, in which corticotropin excess is produced by a benign pituitary tumor, occurs in approximately 60% to 70% of patients with Cushing syndrome due to endogenous cortisol production. Evaluation of patients with possible Cushing syndrome begins with ruling out exogenous steroid use. Screening for elevated cortisol is performed with a 24-hour urinary free cortisol test or late-night salivary cortisol test or by evaluating whether cortisol is suppressed the morning after an evening dexamethasone dose. Plasma corticotropin levels can help distinguish between adrenal causes of hypercortisolism (suppressed corticotropin) and corticotropin-dependent forms of hypercortisolism (midnormal to elevated corticotropin levels). Pituitary magnetic resonance imaging, bilateral inferior petrosal sinus sampling, and adrenal or whole-body imaging can help identify tumor sources of hypercortisolism. Management of Cushing syndrome begins with surgery to remove the source of excess endogenous cortisol production followed by medication that includes adrenal steroidogenesis inhibitors, pituitary-targeted drugs, or glucocorticoid receptor blockers. For patients not responsive to surgery and medication, radiation therapy and bilateral adrenalectomy may be appropriate.Conclusions and RelevanceThe incidence of Cushing syndrome due to endogenous overproduction of cortisol is 2 to 8 people per million annually. First-line therapy for Cushing syndrome due to endogenous overproduction of cortisol is surgery to remove the causative tumor. Many patients will require additional treatment with medications, radiation, or bilateral adrenalectomy.