Steps

Steps to determine a CD diagnosis³

Diagnosis begins with screening^3,4

While some features are more discriminatory to indicate Cushing’s syndrome (CS), diagnosis of CD begins with screening for elevated endogenous cortisol.^3-5

ACTH, adrenocorticotropic hormone; CRH, corticotropin-releasing hormone; CT, computed tomography; DST, dexamethasone suppression test; IPSS, inferior petrosal sinus sampling; MRI, magnetic resonance imaging; UFC, urinary free cortisol.

^aCan also use the 48-hour, 2-mg/d low-dose DST. May deliver more accurate results than other tests when certain psychiatric conditions, morbid obesity, alcoholism, and diabetes are present.⁶

^bConsider psychiatric disorders, alcohol use disorder, pregnancy, severe obesity, polycystic ovary syndrome, uncontrolled diabetes, anorexia, malnutrition, excessive exercise, illness or surgery, high corticosteroid-binding globulin state, glucocorticoid resistance.³

^cOn average, 20% to 50% of pituitary adenomas are not visible on MRI.⁷

^dThere is consensus that all patients with lesions <6 mm in diameter should have IPSS and those with lesions of ≥10 mm do not need IPSS, but expert opinions differ regarding tumors 6 to 9 mm in diameter.³

^eThis option does not have clear consensus and needs further research.³

Tests

Testing options to
determine a CD
diagnosis

Late-night salivary cortisol (LNSC) test

24-hour UFC

Overnight 1-mg DST

48-hour, 2-mg/d DST

IPSS

CRH screening

Desmopressin test

Diagnose CD

As soon as you diagnose CD, it is critical to initiate treatment to minimize further complications⁹. Surgery is the first-line treatment for CD, but may not be curative³

While pituitary surgery is the recommended first-line treatment for CD, recurrence after surgery is common.³

Recurrence rates

The high incidence of CD recurrence necessitates annual clinical and biochemical follow-up, or sooner if there is clinical suspicion for recurrence^3,10

Pharmacologic therapy is a potential treatment choice for patients for whom surgery is not an option or has failed to effectively normalize cortisol³

≈25%

up to 5 years⁹

≈26%

up to 13 years¹⁰

Pharmacologic therapy

May be appropriate for:

Patients who have refused or are ineligible for surgery³

Patients with persistent or recurrent CD³

Patients undergoing radiotherapy who require further control in cortisol levels³

^*Persistent comorbidities despite remission could increase mortality¹¹

Types of Pharmacologictherapy

Therapeutic Area	Therapeutic Class	Efficacy	Possible Side Effects
Pituitary gland	Somatostatin analogues (SSA) e.g. Pasireotide	~40%*	Nausea, diarrhoea, gallstones, hyperglycaemia*
	Dopamine agonist e.g. Cabergoline	28-40%^β	Asthenia, Nausea^β
Adrenal Gland	Steroidal genesis inhibitor e.g Ketoconazole	>50%^§	Elevated liver enzyme, Gastrointestinal disorders, hypogonadism^§
	Metyrapone	>50%	Hirsutism, hypokalaemia and Hypertension (high dose)^π
	Osilodrostat	~86%^€	Nausea, anemia, arthralgia and headache^€
	Adrenolytic drug e.g. Mitotane	72%#	Gastrointestinal disorders, asthenia, rashes, neurological disturbances, increased liver enzymes, hypercholesterolemia and isolated thyrotropic insufficiency#
Serum Cortisol	Glucocorticoid receptor blocker e.g. Mifepristone	38-60%^*	Nausea, asthenia, metrorragia, hypokalemia^¥

#Baudry C, Coste J, Bou Khalil R, et al. Efficiency and tolerance of mitotane in Cushing's disease in 76 patients from a single center. Eur J Endocrinol 2012;167:473e81

*Lacroix A, Gu F, Gallardo W, et al. Efficacy and safety of once-monthly pasireotide in Cushing's disease: a 12 month clinical trial. Lancet Diabetes Endocrinol 2018;6:17e26.

βFerriere A, Cortet C, Chanson P, et al. Cabergoline for Cushing's disease: a large retrospective multicenter study. Eur J Endocrinol 2017;176:305e14.

§Castinetti F, Guignat L, Giraud P, et al. Ketoconazole in Cushing's disease: is it worth a try? J Clin Endocrinol Metabol 2014; 99:1623e30.

πDaniel E, Aylwin S, Mustafa O, et al. Effectiveness of metyrapone in treating Cushing's syndrome: a retrospective multicenter study in 195 patients. J Clin Endocrinol Metabol 2015;100:4146e54.

¥Fleseriu M, Biller BMK, Findling JW, et al. Mifepristone, a glucocorticoid receptor antagonist, produces clinical and metabolic benefits in patients with Cushing's syndrome. J Clin Endocrinol Metabol 2012;97:2039e49.

€Biller BM, Newell-Price J, Fleseriu M, et al. (LINC 3). OR16-2 osilodrostat treatment in Cushing's disease (CD): results from a phase III, multicenter, double-blind, randomized withdrawal study. J Endocr Soc 2019;3

Disclaimer:The information is based on study publications and is not intended to be a substitute for professional advice

Monitoring

Lab tests

a.

UFC level/ LNSC to assess the disease control level

b.

ACTH especially for adrenal targeting agents – tumour growth monitoring

Clinical symptoms improvement
Imaging

a.

MRI if clinically relevant

Publications & Studies

Osilodrostat study: 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 period^1,3

Inclusion criteria^1,3
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 characteristics^1,3
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)

ACTH, adrenocorticotropic hormone; mUFC, mean urinary free cortisol; UFC, urinary free cortisol; ULN, upper limit of normal.

^aDose 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

^bDose adjustments were permitted during Study Period 2.¹

^cPatients 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

^dPatients 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]^1,3

Primary End Point^1,3

Complete responder ratee after 8-week randomized withdrawal period (week 34)

^eComplete 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 levels^1,f. More than half of patients maintained normalized mUFC with ISTURISA at the therapeutic dose established during the titration period¹

Key Secondary End Point^1,3

Complete responder rate at week 24 (end of maintenance period)

Additional Analysis Indicate Other Signs of Improvement with Isturisa¹

The ULN for UFC was defined as 138 nmol/24 h or 50 μg/24 h.1These data were not included in primary or secondary end point analyses and were assessed post hoc; therefore, no definitive conclusions should be drawn.^1,3

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 Point^1,3

ITT analysis, end of open-label period

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/d^5,

^hAmong patients who were ineligible for the randomized withdrawal period, the average daily ISTURISA dose was 11 mg/d.⁵ITT, intention-to-treat; mUFC, mean urinary free cortisol.

ISTURISA was associated with improvements in several secondary end points, including metabolic, health-related QOL (HRQOL), and depression parameters^1,3

Mean Improvements

In patients taking ISTURISA, mean improvements were observed from baseline in the following parameters^1,4,5

BDI-II, Beck Depression Inventory; CushingQoL, Cushing Quality of Life; HbA1c, glycated hemoglobin.

ⁱStudy 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

^jCushing’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.8The 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.⁹

^kImprovements 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

Improvements in cardiovascular-related parameters

were maintained through the open-label extension^1,6,l

BMI, body mass index; HbA1c, glycated hemoglobin.

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

A well-tolerated safety profile demonstrated through 48 weeks¹

Adverse reactions among 137 patients

with Cushing’s disease (CD) who received at least 1 dose of ISTURISA in the study³

^aAdrenal insufficiency includes glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, cortisol free urine decreased, cortisol decreased. One-third of the subjects with this event had low cortisol levels indicative of adrenal insufficiency. The majority of subjects had normal cortisol levels suggesting a cortisol withdrawal syndrome.

^bFatigue includes lethargy, asthenia.

^cHeadache includes head discomfort.

^dEdema includes edema peripheral, generalized edema, localized edema.

^eRash includes rash erythematous, rash generalized, rash maculopapular, rash papular.

Among the 43% of patients who were deemed to have experienced adrenal insufficiency, 1/3 had low cortisol levels indicative of adrenal insufficiency³
Hypocortisolism was reported at a rate of 31% during weeks 1 to 12 and 18% during weeks 12 to 26³
In most cases, hypocortisolism is addressed by reducing the dose of ISTURISA and/or adding low-dose, short-term glucocorticoid therapy³
36% (25/70) of patients with 1 or more hypocortisolism-related event received glucocorticoid supplementation during the duration of the study¹

Hirsutism was observed in 12% (13/106) of female patients.^1,3This adverse event was considered mild to moderate,fand no patient discontinued as a result.¹

^fMild to moderate = severity rated by investigator as 1 or 2 in the LINC 3 clinical trial.⁴

References

Sharma ST, Nieman LK, Feelders RA. Cushing’s syndrome: epidemiology and developments in disease management. Clin Epidemiol. 2015;17(7):281-293. doi:10.2147/CLEP.S44336 2. Lonser RR, Nieman L, Oldfield EH. Cushing’s disease: pathobiology, diagnosis, and management. J Neurosurg. 2017;126(2):404-417. doi:10.3171/2016.1.JNS152119 3. Giuffrida G, Crisafulli S, Ferraù F, et al. Global Cushing's disease epidemiology: a systematic review and meta-analysis of observational studies. Endocrinol Invest. 2022;45(6):1235-1246. doi:10.1007/s40618-022-01754-1 4. Nishioka H, Yamada S. Cushing's disease. Clin Med. 2019;8(11):1951. doi:10.3390/jcm8111951 5. Feelders RA, Pulgar SJ. Kempel A, Pereira AM. The burden of Cushing's disease: clinical and health-related quality of life aspects. Eur J Endocrinol. 2012;167(3):311-326. doi:10.1530/EJE-11-1095 6. Pivonello R, De Leo M, Cozzolino A, Colao A. The Treatment of Cushing's Disease. Endocr Rev. 2015 Aug;36(4):385-486. doi:10.1210/er.2013-1048 7. Nieman LK, Biller BMK, Findling JW. et al. Treatment of Cushing's syndrome: an Endocrine Society clinical practice guideline. Endocrine. 2015;100(8):2807-2831. doi:10.1210/jc.2015-1818 8. Fleseriu M, Auchus R, Bancos I, et al. Consensus on diagnosis and management of Cushing's disease: a guideline update. Lancet Diabetes Endocrinol. 2021;9(12):847-875. doi:10.1016/S2213-8587(21)00235-7 9. Dekkers OM, Biermasz NR, Pereira AM, et al. Mortality in patients treated for Cushing's disease is increased, compared with patients treated for nonfunctioning pituitary macroadenoma. J Clin Endocrinol Metab. 2007;92(3):976-981. doi:10.1210/jc.2006-2112 10. Lacroix A, Feelders RA, Stratakis CA, Nieman LK. Cushing's syndrome. Lancet. 2015;386(9996):913-927. doi:10.1016/S0140-6736(14)61375-1 11. 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. doi:10.1007/s11102-016-0742-1 12. Dekkers OM, Horváth-Puhó E, Jørgensen JOL, et al. Multisystem morbidity and mortality in Cushing’s syndrome: a cohort study. J Clin Endocrinol Metab. 2013;98(6):2277-2284. doi:10.1210/jc.2012-3582 13. van Haalen FM, Broersen LHA, Jørgensen JO, Pereira AM, Dekkers OM. Management of endocrine disease: Mortality remains increased in Cushing’s disease despite biochemical remission: a systematic review and meta-analysis. Eur J Endocrinol. 2015;172(4):R143-R149. doi:10.1530/EJE-14-0556

Treatment
for Cushing's Disease

Treatment for Cushing's Disease

Steps to determine a CD diagnosis³

Diagnosis begins with screening^3,4

Testing options to
determine a CD
diagnosis

Recurrence rates

Pharmacologic therapy

Types of Pharmacologictherapy

Monitoring

Publications & Studies

Treatmentfor Cushing's Disease

Treatment for Cushing's Disease

Steps to determine a CD diagnosis3

Diagnosis begins with screening3,4

Testing options todetermine a CD diagnosis

Recurrence rates

Pharmacologic therapy

Types of Pharmacologictherapy

Monitoring

Publications & Studies

Welcome to P'aware

Treatment
for Cushing's Disease

Steps to determine a CD diagnosis³

Diagnosis begins with screening^3,4

Testing options to
determine a CD
diagnosis