About ISTURISA

How ISTURISA Works

ISTURISA is a potent cortisol synthesis inhibitor that blocks the enzyme 11beta-hydroxylase to interrupt the last step of the pathway1-5

ACTH, adrenocorticotropic hormone.

ISTURISA Was Assessed in the 48-Week, Multicenter LINC 3 Study1

The first pivotal, randomized, double-blind, PLACEBO-CONTROLLED withdrawal study for a Cushing’s disease drug.1,6,7

Patients enrolled in the study had confirmed persistent, recurrent, or de novo Cushing’s disease.

KEY ENTRY CRITERIA AND BASELINE CHARACTERISTICS1,8

  • 18-75 years old
    • Mean age = 41 years
  • mUFC > 1.5 x ULN at screening
    • mUFC at baseline = 1006 nmol/24 hr (approximately 7 x ULN)*
    • Median UFC = 476 nmol/24 hr (approximately 3.5 x ULN)*
  • Those with history of pituitary surgery had to be at least 30 days postsurgery
    • 88% enrolled had previous surgery

*Common values for ULN are 138 nmol/24 hr, which is equivalent to 50 mcg/24 hr.

LINC 3 Study Design:

a unique 4-period study well suited to assess a rare disease therapy1,6,7

12-week, open-label ISTURISA dose titration period determined each patient’s effective dose during the 12-week period 1 (N=137)1

12-week, open-label ISTURISA treatment maintenance period measured the ability of ISTURISA to achieve and maintain mUFC ≤ ULN without a dose increase during the 12-week period 2 (N=130)1

8-week, double-blind, placebo-controlled, randomized withdrawal period among patients with normal mUFC following periods 1 and 2 and who did not require a dose increase during period 2 (N=71)1

14-week or 24-week open-label ISTURISA treatment period documented efficacy and safety of ISTURISA over the course of the 48-week trial1

Titration occurred at no greater than 2-week intervals to achieve a mean UFC (mUFC) within the normal range. Individual dose adjustments were based on mUFC.

mUFC, mean urinary free cortisol; ULN, upper limit of normal.

Lowering Cortisol With ISTURISA

ISTURISA effectively normalized and sustained mUFC in the majority of patients1

PRIMARY ENDPOINT1‡ - Complete responder rate at week 34 (end of period 3)

  • Statistically, more patients maintained mUFC ≤ ULN with ISTURISA than placebo, following randomized withdrawal (P<0.001)1

Complete responder rate in period 3 = % who maintained normal mUFC without a dose increase during the 8-week randomized withdrawal period.

SECONDARY ENDPOINT - COMPLETE RESPONDER RATE AT WEEK 24 (END OF PERIOD 2)

§Complete responder rate in period 2 = % who maintained normal mUFC without a dose increase from weeks 12-24.

48-WEEK STUDY ENDPOINT1 PATIENTS WHO HAD NORMAL mUFC AT STUDY ENDPOINT (END OF PERIOD 4)

Overall, improvements were observed from baseline for metabolic parameters, including1:

  • Body weight (kg)
  • Waist circumference (cm)
  • HbA1c (%)
  • Systolic/diastolic blood pressure (mmHg)

Because the study allowed initiation of anti-hypertensive and anti-diabetic medications and dose increases in patients already receiving such medications and there was absence of a control group, the individual contribution of ISTURISA or of anti-hypertensive and anti-diabetic medication adjustments cannot be clearly established.

HbA1c, hemoglobin A1c; mUFC, mean urinary free cortisol; ULN, upper limit of normal.

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. ISTURISA® (osilodrostat) [prescribing information]. Lebanon, NJ: Recordati Rare Diseases Inc.; 2020. 2. Bertagna X, Pivonello R, Fleseriu M, et al. LCI699, a potent 11β-hydroxylase inhibitor, normalizes urinary cortisol in patients with Cushing’s disease: results from a multicenter, proof-of-concept study. J Clin Endocrinol Metab. 2014;99(4):1375-1383. 3. Menard J, Watson C, Rebello S, et al. Hormonal and electrolyte responses to the aldosterone synthase inhibitor LCI699 in sodium depleted healthy subjects. J Am Coll Cardiol. 2010;55(10):A61.E583. 4. Fleseriu M, Castinetti F. Updates on the role of adrenal steroidogenesis inhibitors in Cushing’s syndrome: a focus on novel therapies. Pituitary. 2016;19(6):643-653. 5. Data on file. Recordati Rare Diseases Inc. Lebanon, NJ. 6. Ferriere A, Tabarin A. Cushing’s syndrome: treatment and new therapeutic approaches. Best Pract Res Clin Endocrinol Metab. 2020;101381. doi:10.1016/j.beem.2020.101381. 7. Biller BMK, Newell-Price J, Fleseriu M, et al. OR16-2 Osilodrostat treatment in Cushing’s disease (CD): results from a phase III, multicenter, double-blind, randomized withdrawal study (LINC 3). Abstract. J Endocr Soc. 2019;3(Suppl 1):OR16-2. 8. ClinicalTrials.gov. Safety and efficacy of LCI699 for the treatment of patients with Cushing’s disease. https://clinicaltrials.gov/ct2/show/NCT02697734. Updated February 17, 2020. Accessed April 7, 2020.