ISTURISA® Was Assessed in Two Phase 3 Clinical Trials
NEW STUDY, NEW DATA
KEY RESULTS FROM LINC 4:
A Phase 3 Clinical Trial of ISTURISA1
Abstract presented at ENDO Society 2021
Abstract 7065—Osilodrostat is an effective and well-tolerated treatment for Cushing’s disease (CD): results from a Phase III study with an upfront, randomized, double-blind, placebo-controlled phase (LINC 4)1
Gadelha M, Bex M, Feelders RA, Heaney AP, Auchus RJ, Gilis-Januszewska A, Witek P, Belaya Z, Liao Z, Ku CHC, Carvalho D, Roughton M, Wojna J, Hofstetter G, Pedroncelli AM, Snyder PJ.
LINC 4 is a randomized, double-blind, parallel, placebo-controlled study to evaluate the safety and efficacy of ISTURISA among 73 patients with Cushing’s disease (mUFC >1.3 × ULN)1
*Patients started on ISTURISA 2 mg twice daily (baseline median mUFC was 2.5 × ULN) or matching placebo (baseline median mUFC was 2.2 × ULN). Dose adjustments to normalize mUFC or to address safety issues were permitted at week 2, week 5, and week 8 (range 1–20 mg bid) based on efficacy and tolerability.
†Starting at week 12, all patients received open-label ISTURISA, with dose adjustments permitted (range 1–30 mg bid).
DOUBLE-BLIND PERIOD: 12-week, double-blind, parallel, placebo-controlled period (N=73)
Isturisa Rapidly Normalized mUFC Levels1
PRIMARY ENDPOINT:
Significantly more patients had mUFC ≤ ULN with ISTURISA at week 12 (P<0.0001)1*
Dose adjustments were made at 2-to-3–week intervals based on patient response and tolerability*
*Patients started on ISTURISA 2 mg twice daily (baseline median mUFC was 2.5 × ULN) or matching placebo (baseline median mUFC was 2.2 × ULN). Dose adjustments to normalize mUFC or to address safety issues were permitted at week 2, week 5, and week 8 (range 1–20 mg bid) based on efficacy and tolerability.
Note: Adverse events (AEs) related to hypocortisolism occured in 15% of ISTURISA patients and 0% in placebo patients.
OPEN-LABEL PERIOD: 36-week treatment with open-label ISTURISA (week 12 through 48) (N=73)
Improvements in mUFC With ISTURISA Were Sustained Over 36 Weeks of Treatment1
SECONDARY ENDPOINT:
A large majority of ISTURISA patients had mUFC ≤ ULN at week 361
81%
of ISTURISA patients had mUFC ≤ ULN1†
Among patients who received blinded ISTURISA (n=48) or blinded placebo (n=25) for 12 weeks followed by open-label ISTURISA for 24 weeks1†
†Starting at week 12, all patients received open-label ISTURISA, with dose adjustments permitted (range 1–30 mg bid).
The most common AEs observed during the overall study with osilodrostat were arthralgia (45%), decreased appetite (45%), fatigue (38%), and nausea (37%).
KEY LEARNINGS FROM LINC 4 STUDY1:
Isturisa provides rapid and sustained normalization of cortisol
ISTURISA is well tolerated and has a manageable safety profile
Response and tolerability may be managed with discretionary dose management
CI, confidence interval; mUFC, mean urinary free cortisol; OR, odds ratio; ULN, upper limit of normal.
LINC 3: The Pivotal Clinical Study for Isturisa
The first Phase 3 trial of any medical therapy for Cushing’s disease that included a randomized, double-blind, placebo-controlled withdrawal period2
INDICATIONS AND USAGE
ISTURISA (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions
-
Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.
Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA. Please see section 5.1 of full Prescribing Information.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
- QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring. Please see section 5.2 of full Prescribing Information.
- Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur. Please see section 5.3 of full Prescribing Information.
Adverse Reactions
- Most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
- To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
- CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
- CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.
Use in Specific Populations
- Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
INDICATIONS AND USAGE
ISTURISA (osilodrostat) is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease for whom pituitary surgery is not an option or has not been curative.
IMPORTANT SAFETY INFORMATION
Warnings and Precautions
-
Hypocortisolism: ISTURISA lowers cortisol levels and can lead to hypocortisolism and sometimes life-threatening adrenal insufficiency. Lowering of cortisol can cause nausea, vomiting, fatigue, abdominal pain, loss of appetite, and dizziness. Significant lowering of serum cortisol may result in hypotension, abnormal electrolyte levels, and hypoglycemia.
Hypocortisolism can occur at any time during ISTURISA treatment. Evaluate patients for precipitating causes of hypocortisolism (infection, physical stress, etc). Monitor 24-hr urine free cortisol, serum or plasma cortisol, and patient’s signs and symptoms periodically during ISTURISA treatment.
Decrease or temporarily discontinue ISTURISA if urine free cortisol levels fall below the target range, there is a rapid decrease in cortisol levels, and/or patients report symptoms of hypocortisolism. Stop ISTURISA and administer exogenous glucocorticoid replacement therapy if serum or plasma cortisol levels are below target range and patients have symptoms of adrenal insufficiency. After ISTURISA discontinuation, cortisol suppression may persist beyond the 4-hour half-life of ISTURISA. Please see section 5.1 of full Prescribing Information.
Educate patients on the symptoms associated with hypocortisolism and advise them to contact a healthcare provider if they occur.
- QTc Prolongation: ISTURISA is associated with a dose-dependent QT interval prolongation which may cause cardiac arrhythmias. Perform an ECG to obtain a baseline QTc interval measurement prior to initiating therapy with ISTURISA and monitor for an effect on the QTc interval thereafter. Correct hypokalemia and/or hypomagnesemia prior to ISTURISA initiation and monitor periodically during treatment with ISTURISA. Use with caution in patients with risk factors for QT prolongation and consider more frequent ECG monitoring. Please see section 5.2 of full Prescribing Information.
- Elevations in Adrenal Hormone Precursors and Androgens: ISTURISA blocks cortisol synthesis and may increase circulating levels of cortisol and aldosterone precursors and androgens. This may activate mineralocorticoid receptors and cause hypokalemia, edema and hypertension. Hypokalemia should be corrected prior to initiating ISTURISA. Monitor patients treated with ISTURISA for hypokalemia, worsening of hypertension and edema. Inform patients of the symptoms associated with hyperandrogenism and advise them to contact a healthcare provider if they occur. Please see section 5.3 of full Prescribing Information.
Adverse Reactions
- Most common adverse reactions (incidence >20%) are adrenal insufficiency, fatigue, nausea, headache, and edema.
- To report SUSPECTED ADVERSE REACTIONS, contact Recordati Rare Diseases Inc. at 1-888-575-8344, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
Drug Interactions
- CYP3A4 Inhibitor: Reduce the dose of ISTURISA by half with concomitant use of a strong CYP3A4 inhibitor.
- CYP3A4 and CYP2B6 Inducers: An increase of ISTURISA dosage may be needed if ISTURISA is used concomitantly with strong CYP3A4 and CYP2B6 inducers. A reduction in ISTURISA dosage may be needed if strong CYP3A4 and CYP2B6 inducers are discontinued while using ISTURISA.
Use in Specific Populations
- Lactation: Breastfeeding is not recommended during treatment with ISTURISA and for at least one week after treatment.
References: 1. Gadelha M, Bex M, Feelders RA, et al. Abstract presented at: ENDO 2021; March 20-23, 2021; virtual. Abstract 7065. 2. Pivonello R, Fleseriu M, Newell-Price J, et al; LINC 3 investigators. Efficacy and safety of osilodrostat in patients with Cushing's disease (LINC 3): a multicentre phase III study with a double-blind, randomised withdrawal phase. Lancet Diabetes Endocrinol. 2020 Sep;8(9):748-761.