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WHY ISTURISA
Clinical Studies
The efficacy of ISTURISA® (osilodrostat) was assessed in 2 phase 3 clinical studies.1,2 Select a study to review efficacy data.
LINC 3 was a phase 3 clinical trial in patients with Cushing’s disease (CD) (N=137) that included a randomized, double-blind, placebo-controlled withdrawal period1,3
Inclusion criteria1,3
- Patients aged 18 to 75 years with a confirmed diagnosis of persistent, recurrent, or de novo (if not surgical candidates or refused surgery) Cushing’s disease
- Confirmed Cushing’s disease as determined by mean of 3 UFC concentrations of >1.5 x ULN at screening
- Patients with a history of pituitary surgery had to be at least 30 days post surgery
- Evidence of a pituitary source of excess ACTH
Baseline characteristics1,3
- Mean age at enrollment was 41 years
- 77% (106/137) of patients were female
- 88% (120/137) of enrolled patients had previous surgery
- Mean of three 24-hour mUFC at baseline was 365 μg/24 h (≈7 x ULN)
- Median mUFC was 173 µg/24 h (≈3.5 x ULN)
Dose was up- or down-titrated every 2 weeks if mean urinary free cortisol (mUFC) was greater than upper limit of normal (ULN; defined as 138 nmol/24 h or 50 μg/24 h) or if mUFC was lower than lower limit of normal (LLN; defined as 11 nmol/24 h or 4 μg/24 h), respectively.1
Dose adjustments were permitted during Study Period 2.1
Patients who did not require further dose increase, tolerated the drug, and had mUFC levels ≤ULN at week 24 were considered responders and eligible to enter the randomized withdrawal period. Patients whose mUFC became elevated during the maintenance period could have their dose increased further, if tolerated, up to 30 mg twice daily. These patients were considered nonresponders and did not enter the randomized withdrawal period, but continued open-label treatment together with the patients who did not achieve normal mUFC levels at week 12.1
Patients remained on assigned dose throughout the randomized withdrawal period if their mUFC levels were within normal limits (WNL). Blinded dose reduction or temporary discontinuation for safety or tolerability issues were permitted; however, dose increases were not permitted. Patients with mUFC levels >1.5 x ULN or who required a dose increase were considered nonresponders and discontinued from the randomized withdrawal period but allowed to receive open-label treatment during the open-label period.1
ISTURISA maintained normalization of mUFC in a majority of patients in the randomized withdrawal period3
Demonstrated superiority over placebo at maintaining mUFC ≤ULN at the end of the randomized withdrawal period [n=71, Difference 57% (95% CI: 38-76); P<.001]3
CI, confidence internal.PRIMARY END POINT1,3
Complete responder ratee after 8-week randomized withdrawal period (week 34)
Complete responder rate at the end of the randomized withdrawal period was the percentage of patients who had mUFC levels ≤ULN (defined as 138 nmol/24 h or 50 μg/24 h) at the end of the randomized withdrawal period (week 34), and who neither discontinued randomized treatment or the study nor had any dose increase above their week 26 dose.1,3
ISTURISA works to normalize mUFC levels1,f
More than half of patients maintained normalized mUFC with ISTURISA at the therapeutic dose established during the titration period1
Key secondary END POINT1,3
Complete responder rate at week 24 (end of maintenance period)
53%
(72/137) of patients who received ISTURISA maintained mUFC ≤ULN at week 24 without dose up-titration after week 121,3
The lower bound of the 95% CI exceeded 30%, the prespecified threshold for statistical significance and minimum threshold for clinical benefit1
ADDITIONAL ANALYSES INDICATE OTHER SIGNS OF IMPROVEMENT WITH ISTURISA1
Irrespective
of dose increase,
(93/137) of patients achieved
mUFC ≤ULN at
week 24 (prespecified end point)
The median
time to first
complete response
(mUFC ≤ULN)g
was
96%
(132/137) of patients achieved
cortisol normalization
at least once during
the studyg
ISTURISA sustained normal mUFC up to 48 weeks in a majority of patients3
In patients who received ISTURISA, mean mUFC decreased rapidly during the titration period, then remained below baseline through week 484
48-WEEK STUDY END POINT1,3
(ITT analysis, end of open-label period)
66%
of patients who received ISTURISA maintained mUFC levels ≤ULN at week 48 (91/137; 95% CI, 57.9-74.3)3,4
MEAN mUFC AT TIME POINTS UP TO WEEK 48,
among all patients who received treatment in the randomized withdrawal period3
- Average daily ISTURISA dose for all patients through 48 weeks was 10 mg/d5,h
ISTURISA was associated with improvements in several secondary end points, including metabolic, health-related QOL (HRQOL), and depression parameters1,3
In patients taking ISTURISA, mean improvements were observed from baseline in the following parameters1,4,5:
Baseline
Week 24
Week 48
Systolic blood pressure (mm Hg)i
132.2
124.9 (-4.1%)
121.7 (-6.8%)
Diastolic blood pressure (mm Hg)i
85.3
81.0 (-3.8%)
78.9 (-6.6%)
Body weight (kg)
80.8
77.3 (-3.0%)
75.5 (-4.6%)
Waist circumference (cm)
103.5
99.1 (-2.6%)
97.4 (-4.7%)
HbA1c (%)i
6.0
5.6 (-4.6%)
5.6 (-5.4%)
Total cholesterol (mg/dL)
205.0
181.8 (-9.0%)
185.6 (-8.8%)
CushingQoL (total score)j
42.2
52.1 (42.4%)
58.3 (52.4%)
BDI-II (total score)k
16.8
12.9 (-19.2%)
10.7 (-31.8%)
Study limitations: Because the study allowed initiation of antihypertensive and antidiabetic 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 antihypertensive and antidiabetic medication adjustments cannot be clearly established.3
Cushing’s Quality of Life questionnaire (CushingQoL) is proven to be a reliable and valid instrument for measuring health-related quality of life (QOL) in patients with Cushing’s syndrome. Scores correlate with relevant clinical parameters.8 The Beck Depression Inventory-II (BDI-II) is a proven valid and reliable 21-item self-report multiple-choice inventory tool used to evaluate depressive states that occur at high prevalence among the medically ill.9Improvements were maintained during the 72-week open-label extension6
ISTURISA sustained normal mUFC for over a year in the majority of patients who entered the open-label extension (N=106)6
LINC 3 EXTENSION RESULTS6
Complete responder rate at week 72
81%
of patients who took ISTURISA who entered the extension maintained mUFC ≤ULN at week 72
(86/106; 95% CI, 72.4-88.1)6
(86/106; 95% CI, 72.4-88.1)6
- Patients who had mUFC ≤ULN (defined as 138 nmol/24 h or 50 μg/24 h) were classified as complete responders6
Prespecified secondary end point Improvements in cardiovascular-related parameters
were maintained through the open-label extension1,6,l
72 Weeks
Mean change from core baseline
Systolic blood pressure (mm Hg)l
-10.1
Diastolic blood pressure (mm Hg)l
-5.8
HbA1c (%)i
-0.4%
BMI (kg/m2)
-1.8
Because the study allowed initiation of antihypertensive and antidiabetic 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 antihypertensive and antidiabetic medication adjustments cannot be clearly established.3
ISTURISA was well tolerated, with no new safety signals reported during long-term treatment6
- 106 of 137 enrolled patients entered the optional extension6
- Median duration of ISTURISA treatment from baseline to study end for all enrolled patients was 130 weeks with a median dose of 7.4 mg/d6
- Most hypocortisolism-related AEs emerged during the first 26 weeks of treatment and AEs related to adrenal hormone precursor accumulation were less frequent in the extension6
- Mean testosterone levels in women increased upon initiation of ISTURISA but tended to return to baseline levels and within the normal range at 72 weeks (0.8 × ULN)7
LINC 4 was a randomized, double-blind, parallel, placebo-controlled clinical trial to evaluate the safety and efficacy of ISTURISA among 73 patients with Cushing’s disease (mUFC >1.3 x ULN)2
Inclusion criteria2
- Patients aged 18 to 75 years with a confirmed diagnosis of persistent, recurrent, or de novo (if not surgical candidates) CD
- Confirmed CD as determined by mean of 3 UFC concentrations of >1.3 x ULN
- Evidence of a pituitary source of excess ACTH
Baseline characteristics2
- Median age at enrollment was 39 years
- 84% (n=61/73) of patients were female
- 88% (n=64/73) of enrolled patients had previous surgery
- Mean mUFC at baseline was 157 μg/24 h (≈3.1 x ULN)
- Median mUFC at baseline was 123 μg/24 h (≈2.5 x ULN)
Patients started on ISTURISA 2 mg twice daily or matching placebo. Dose adjustments to normalize mUFC or to address safety issues were permitted at week 2, week 5, and week 8 (range 1-20 mg twice a day) based on considerations of all data for each patient, including mUFC level, rate of decrease of mUFC, and tolerability of ISTURISA. ULN was defined as 138 nmol/24 h or 50 μg/24 h and LLN was defined as 11 nmol/24 h or 4 μg/24 h.2
Starting at week 12, all patients received open-label ISTURISA, with dose adjustments permitted (range 1 mg every other day to 30 mg twice a day).2
LLN, lower limit of normal.
ISTURISA normalized cortisol levels in a majority of patients2
Demonstrated superiority over placebo at normalizing cortisol (mUFC ≤ULN) at week 12 (N=73, P<.0001)2
PRIMARY END POINT2
Significantly more patients had mUFC ≤ULN with ISTURISA at week 12 (P<.0001)
12-week, randomized, double-blind, placebo-controlled period (N=73)2
Among patients who received ISTURISA (37/48)
77%
Achieved normal mUFC
Among patients who received placebo (2/25)
8%
Achieved normal mUFC
P<.0001
(OR 43.4;
95% CI, 7.1-343.2)
(OR 43.4;
95% CI, 7.1-343.2)
Dose adjustments were made at weeks 2, 5, and 8 followed by adjustments approximately every 3 weeks based on considerations of all data for each patient, including mUFC level, rate of decrease of mUFC, and tolerability of ISTURISA.2,c
Note: Adverse events related to hypocortisolism occurred in 15% of patients who received ISTURISA vs 0% of patients who received placebo during titration.2
mUFC, mean urinary free cortisol; OR, odds ratio; ULN, upper limit of normal.
ISTURISA effectively sustained cortisol normalization in a majority of patients2
Maintained mUFC ≤ULN for 4 out of 5 patients at week 36 in the open-label period (N=73)2
Key secondary END POINT2
Proportion of patients with mUFC ≤ULN at week 36
81%
of patients who received ISTURISA maintained normalized mUFC (mUFC ≤ULN) at week 36 (n=59/73)2
Median ISTURISA dose from baseline to data cutoff was 5.0 mg per day in patients initially assigned to ISTURISA.2
ISTURISA titration was slower in LINC 4 and did not compromise its ability to normalize cortisol in patients with CD. In LINC 4, decisions to increase dose took into consideration all data for each patient, including mUFC level, rate of decrease of mUFC, and tolerability of ISTURISA.2,3
Patients in LINC 3
received dose increases every
2 weeks1
Patients in LINC 4
received dose increases approximately every
3 weeks2
Key learnings from LINC 4 study2:
ISTURISA provides sustained normalization of cortisol levels
ISTURISA has a generally well-tolerated safety profile
Response and tolerability may be managed with close monitoring and dose adjustments
INDICATION(S) AND IMPORTANT SAFETY INFORMATION
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
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.
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.
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.
The 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.
Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see the full Prescribing Information.
INDICATION(S) AND IMPORTANT SAFETY INFORMATION
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
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.
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.
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.
The 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.
Dosage Interruptions and Modifications: If treatment is interrupted, re-initiate ISTURISA at a lower dose when cortisol levels are within target ranges and patient symptoms have been resolved.
ISTURISA® (osilodrostat) tablets, for oral use, is available as 1 mg and 5 mg tablets.
Please see the full Prescribing Information.
References: 1. 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;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0 2. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882-e2895. doi:10.1210/clinem/dgac178 3. Isturisa. Package insert. Recordati Rare Diseases Inc; 2023. 4. Pivonello R, Fleseriu M, Newell-Price J, et al. 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;8(9)(suppl). doi:10.1016/S2213- 8587(20)30240-0 5. Data on file 1. Recordati Rare Diseases Inc; 2019. 6. Fleseriu M, Newell-Price J, Pivonello R, et al. Long-term outcomes of osilodrostat in Cushing’s disease: LINC 3 study extension. Eur J Endocrinol. 2022;187(4):531-541. doi:10.1530/EJE-22-0317 7. Fleseriu M, Biller B, Pivonello R, et al. Osilodrostat is an effective and well-tolerated treatment option for patients with Cushing’s disease (CD): final results from the LINC3 study. Abstract presented at: European Congress of Endocrinology 2021; May 22-26, 2021; Abstract OC8.2. 8. Webb SM, Badia X, Barahona MJ, et al. Evaluation of health-related quality of life in patients with Cushing’s syndrome with a new questionnaire. Eur J Endocrinol. 2008;158(5):623-630. doi:10.1530/EJE- 07-0762 9. Wang YP, Gorenstein C. Assessment of depression in medical patients: a systematic review of the utility of the Beck Depression Inventory-II. Clinics (Sao Paulo). 2013;68(9):1274-1287. doi:10.6061/clinics/2013(09)15
References: 1. 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;8(9):748-761. doi:10.1016/S2213-8587(20)30240-0 2. Gadelha M, Bex M, Feelders RA, et al. Randomized trial of osilodrostat for the treatment of Cushing disease. J Clin Endocrinol Metab. 2022;107(7):e2882-e2895. doi:10.1210/clinem/dgac178 3. Isturisa. Package insert. Recordati Rare Diseases Inc; 2023. 4. Fleseriu M, Auchus RJ, Snyder PJ, et al. 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). Endocr Pract. 2021;27(suppl 6):S112. Abstract #999926. doi:10.1016/j.eprac.2021.04.707