1. Cushing’s syndrome Update and issue In-Kyung Jeong, MD, PhD Department of Endocrinology & Metabolism Kyung Hee University, Graduate school of Medicine Satellite symposium 1

2.  History of Cushing’s syndrome  Classification & prevalence  Case discussion  Diagnosis  Treatment  New drugs Discussion Point

3. History of Cushing’s syndrome Harvey Cushing (1869-1939) J Royal Soc Med 84:363:1991

4.  정의 : 만성적인 당질코르티코이드의 과잉  원인에 따른 분류 Hypothalamus Pituitary gland Adrenal gland CRH ACTH Cortisol Aldosteron Androgen Ectopic site (CRH, ACTH producing tumor) EndogenousExogenous Prolonged Use of Glucocorticoid Cushing’s syndrome

5. Arnaldi G et al. J Clin Endocrinol Metab 2003;88:5593–5602 대한내분비학회 증례연구위원회 대한내분비학회지 15:31-45:2000 Pituitary Adenoma 43.3% Ectopic ACTH Syndrome 0.6% 국외 자료국내 자료

6.  Very rare disease : Limited information on the incidence and prevalence  Annual incidence - Spain, 1 Italy 2 and Denmark 3 : 0.7–2.4 per million population - Korea : 0.84 new case/million population. Prevalence of Cushing’s syndrome

7. Clinical manifestation’s of Cushing’s syndrome  특정 부위의 지방 조직 침착 중심성 비만, moon face, buffalo hump, 안면홍조, 체중증가  말초 지지조직의 catabolic response 근력 저하, 피로감, 골다공증 weakening of collagen fibers in dermis: 자색 선조, 쉽게 멍듬  간의 gluconeogenesis 증가 및 인슐린 저항성  고혈압  정신적 장애 irritability, 우울, psychosis  안드로젠 분비 증가 여드름, 조모증, 과소월경, 무월경,  적혈구 증다증, 과립구증다증, 임파구 및 호산구 감소증

8. Clinical manifestation’s of Cushing’s syndrome 대한내분비학회 증례연구위원회, 대한내분비학회지 15:31-45:2000

9.  Insulin resistance or Insulin secretion  Which is more important to development of diabetes in Cushing syndrome ? Is it reversible ? Cushing’s syndrome & diabetes Jeong IK, J Kor Soc Endocrinol 18:392-403, 2003 Insulin resistance Insulin secretion

10. Consequence of Cushing’s syndrome Increased co-morbidities Increased cardiovascular co-morbidities Cushing’s syndrome 5.5-fold higher mortality Increased morbidity Cardiovascular complications Coronary heart disease Heart failure Cerebro-vascular events Osteoporotic fractures Diabetes/ hyperlipidemia Opportunistic infections Impaired health-related quality of life Etxabe J & Vazquez JA. Clin Endocrinol (Oxf) 1994;40:479–484 van der Eerden AW et al. Neth J Med 2007;65:137–141 Faggiano A et al. J Clin Endocrinol Metab 2003;88:2076–2080 Bakker RC et al. J Endocrinol Invest 1998;21:329–333 Webb SM et al. Eur J Endocrinol 2008;158:623–630 Clayton RN et al. J Clin Endocrinol Metab 2011;96:632–642 These issues can be present if the patient is left untreated or uncontrolled

11. Clinical Practice Guideline Diagnosis of Cushing’s syndrome 2010 : 2008 :

12. Case 1.  45 세 여자  주소 : 체중 증가, 안면 부종  현병력 : 6 개월전부터 얼굴이 붓고 체중이 증가하는 증상 심해져서 내원  과거력 : 고혈압 (+) : 10 년전, 고지혈증 (+) : 1 년전부터 약물치료중  가족력 : 아버지 – 고혈압 (+)

13. Case 1. 체중증가, 부종의 45 세 여자  75 gram OGTT  24 hr urine free cortisol/cr : 220.3 ( μg/1g cr/ day)  1mg overnight dexamethasone suppression test cortisol : 18.2 (μg/dl) Time(m)0306090120 Glucose (mg/dl)106216318298273 Insulin5.66.3

14.  Testing for Cushing’s syndrome, after excluding exogenous glucocorticoid use, is recommended  Patients with multiple and progressive features compatible with syn., (e.g. facial plethora, easy bruising, striae, and proximal myopathy)  Patients with unusual features for age (e.g. osteoporosis, hypertension, and type 2 diabetes)  Patients with adrenal incidentaloma  Children with decreasing height percentile and increasing weight Who should be tested for Cushing’s syndrome ? Guignat L et al, European Journal of Endocrinology, 2010

15.  24 hr urine free cortisol (at least two measurements)  1 mg overnight dexamethasone suppression test(DST) - abnormal: cortisol > 50 nmol/l (18 ng/ml or 1.8 μg/dl)  Midnight Salivary cortisol (two measurements)  Low dose DST : 2 ND step confirm test 에 더 합당. How to test for Cushing’s syndrome ? 1 st step : Screening test 선별검사로 부적합한 검사  Random serum cortisol, or plasma ACTH levels  Urinary 17-KS  Insulin tolerance test, or loperamide test  Pituitary and adrenal imaging or 8 mg DST

16. How to test for Cushing’s syndrome ? Special condition Recommended test Reason PregnancyUFCDST – False positive in pregnancy EpilepsyUFC, midnight cortisol Antiepileptic drug : enhance the dexa clearance Renal failure1mg DST Cyclic Cushing’s syndrome UFC, midnight cortisol Adrenal incidentaloma 1mg DST midnight cortisol UFC : less sensitive in this population

17.  Low dose dexa. Supp. Test (2-mg 48-h Dex Supp. Test)  Dex-CRH (dexamethasone-corticotrophin-releasing hormone) test USA : ovine-CRH, Europe : human CRH (Lower stimulatory effect)  Serum midnight cortisol Abnormal : > 7.5 μg/dl (specificity 87%) Precatheterization is needed. How to test for Cushing’s syndrome ? 2 nd step : Confirm test 확진 검사로 부적합한 검사  Desmopression test

18. Case 1. 체중증가, 부종의 45 세 여자 Basal state Low dose dexa supp test High dose dexa supp test Cortisol (μg/dl)3317.514.3 ACTH (pg/ml)11310344.7 24 hr u-free cortisol (μg/1g cr/ day) 223.334.620.6 Midnight cortisol (μg/dl) 18.5

19. Case 1. 체중증가, 부종의 45 세 여자

20. IPSS data Time (min) peripheral ACTH (pg/ml) Rt IPS ACTH (pg/ml ) Lt IPS ACTH (pg/ml ) -151855264 - 54625459 0521042246 240183689 5586482849 10784015253 151524008250 Intra Petrosal Sinus Sampling (IPSS) CRH Peak petrosal / peripheral ACTH >3 at 2-5 min : Pituitary ACTH secreting tumor Case 1. IPSS

21. Case 1. OP  Trans-sphenoidal approach : Right hemiphysectomy  Pathology : ACTH- producing pituitary adenoma with crook’s hyaline change

22. Case 1. Post-op pituitary function test Time0306090120 Glucose (mg/dl)9834859699 Cortisol (pg/ml)11.710.58.16.65.6 ACTH (pg/ml)3420272522 GH (ng/ml)0.050.030.570.170.05 TSH (μIU/ml)0.145.675.663.52.3 PRL (ng/ml)1023281813 LH (mIU/ml)27.76.85.34.4 FSH (mIU/ml)3.25.26.96.77.2 IGF-1 (ng/ml)98 FT 4 (ng/dl)1.7 E 2 (pg/ml)1

23. Case 1. OPD f/u serum cortisol (ug/dl) serum ACTH (pg/dl) 1 mg dexa supp test Postop 1 month6.242 Postop 6 month2298 Postop 1 yearcortisol: 24 ACTH: 78 Postop 1.2 year3581

24. Case 1. Postop 1.2 yr Basal state Low dose dexa supp test High dose dexa supp test Cortisol (μg/dl)432616.7 ACTH (pg/ml)887646 24 hr u-free cortisol (μg/1g cr/ day) 31513528 Midnight cortisol (μg/dl) 16.7

25. Case 1. Postop 1.2 yr

26. peripheral ACTH (pg/ml) Rt IPS ACTH (pg/ml ) Lt IPS ACTH (pg/ml ) -15min23451264 - 538225559 05672237 136103288 3615583963 5805014348 101255422311 151794211376 301332362315

27. Case 1. Postop 1.2 yr  혈압약, 당뇨병약, 고지혈증약 복용  퇴원후 gamma-knife surgery 예정으로 입원대기중  갑자기 hemorragic cerebral infarction 발생되어 응급실 내원  쿠싱병이 재발한 이 환자에게 가장 적합한 치료는 무엇이었을까 ?

28.  Adrenal tumor : (1) surgical removal of the tumor (2) large, or malignancy : medical adrenalectomy metyrapone, ketoconazole, mitotane, etomidate  Pituitary corticotrope tumor (1) surgical removal of tumor : initial cure rate (70-80%) (2) relapse : second op, radiotherapy, medical therapy stereotactic radiosurgery, bilateral adrenalectomy Treatment of Cushing’s syndrome

29. Treatment response of Cushing’s syndrome 대한내분비학회 증례연구위원회, 대한내분비학회지 15:31-45:2000

30. Second Surgery Surgical resection Surgery for Cushing’s disease If unsuccessful or relapse, further surgical resection Success rate for patients receiving repeat surgery : lower than that for first surgery Significant risk of pituitary insufficiency Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462 First line therapy for Cushing’s disease Remission rate - microadenoma : 65–90% - macroadenoma : <65%

31. Radiation therapy Persistent disease or relapsed Cushing’s disease after transsphenoidal surgery  Provides immediate control of hypercortisolism  Results in permanent hypoadrenalism  life-long glucocorticoid & mineralocorticoid replacement  Risk of developing Nelson’s syndrome Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462; Losa M et al. Neuroendocrinology 2010;92(Suppl 1):107–110  Achieves control in 50–60% of patients after 3–5 years  Long-term follow-up is necessary to detect relapse  Hypopituitarism : 50% of patients (more than 20% treated with gamma knife) Bilateral adrenal- ectomy

32. Medical Adrenalectomy (Steroidogenesis-targeted medical therapy) Biller BMK et al. J Clin Endocrinol Metab 2008;93:2454–2462 Steroido- genesis inhibitors  Mitotane, metyrapone, ketoconazole, etomidate  Reduce cortisol levels via inhibition of steroid synthe sis in the adrenal gland  Temporary, palliative treatment  Adverse events : GI reactions, fatigue, ataxia, hyperc holesterolemia, gynecomastia, adrenal insufficiency  Does not target the ACTH producing tumor

33. Glucocorticoid-receptor-targeted medical therapy Glucocorticoid receptor antagonist  Mifepristone  Blocks the action of cortisol by binding to the GR-II (cortisol) receptor 18-fold higher affinity than cortisol  Phase III study of mifepristone showed clinical improv ements in patients with refractory Cushing’s syndrome  Increases in ACTH and UFC levels  Adverse effects : hypokalemia (44%), endometrial thi ckening (20%)  Does not target the underlying ACTH producing tumor or restore normal HPA secretory dynamics Fleseriu M et al. Endocrinol Rev 2011;32:OR09-5 Korlym (mifepristone) tablets prescribing information. Corcept Therapeutics Inc 2012

34. Dopamine-receptor-targeted medical therapy 1 Pivonello R et al. J Clin Endocrinol Metab 2004;89:2452–2462 2 Godbout A et al. Eur J Endocrinol 2012;163:709–716 Cabergoline  Potent dopamine type 2 receptor (DR 2 ) agonist  Approximately 80% of ACTH-secreting adenomas e xpress the dopamine D 2 receptor 1  Small studies (n=20–27) have demonstrated the effective use of cabergoline in a subset of patients 1,2  The phenomenon of escape has been described  Studies in larger patient populations are required t o establish efficacy and safety

35. Ideal treatment for Cushing’s disease Normalize/reduce ACTH secretion – Determines subsequent normalization – reduction of plasma cortisol levels Restore normal HPA axis Inhibit tumor growth

36. Pasireotide  Pasireotide (SOM230) is a multireceptor-targeted somatostatin analogue with highest affinity for sst 5, as well as activating sst 1, sst 2 and sst 3 Bruns C et al. Eur J Endocrinol 2002;146:707–716

37. Pasireotide sc Phase II trial (CSOM230B2208)  Phase II, proof-of-concept, open-label, single-arm, 15-day multicenter trial in patients with de n ovo, persistent or recurrent Cushing’s disease  Patients self-administered pasireotide 600 µg sc twice daily for 15 days  UFC levels decreased in 76% of patients (22/29)  5 (17%) patients: normalization of mean UFC; 11 (38%) patients: decrease of >50% Boscaro M et al. J Clin Endocrinol Metab 2009;94:115–122 Change from baseline in UFC level (%) Day 15 UFC responders –100 –80 –60 –40 –20 0 20 40 60 80 100 120 Day 15 UFC reducers Day 15 increased UFC levels

38. CSOM230B2305 – the largest Phase III study in Cushing’s disease 38 | Pasireotide Cushing’s Disease July 2011 | Business Use Only 38                                                          Argentina, Belgium, Brazil, Canada, China, Denmark, Finland, France, Germany, Greece, Isra el, Italy, Mexico, Poland, Portugal, Spain, Turkey, United States              329 patients screened 162 patients randomized 62 sites 18 countries

39. Pasireotide sc Phase III trial: Key inclusion and exclusion criteria  Key inclusion criteria  Male or female patients aged ≥18 years  Confirmed persistent/recurrent or de novo Cushing’s disease (baseline UFC ≥1.5xULN) –Mean UFC based on four collections  De novo Cushing’s disease if not candidates for pituitary surgery –Poor surgical candidates, surgically unapproachable tumors, refused surgery  Key exclusion criteria  Pituitary irradiation within the last 10 years  Mitotane within the last 6 months  Compression of the optic chiasm  Poorly controlled diabetes mellitus (HbA 1c >8%)  Risk factors for torsades de pointes –QTc >480 ms, hypokalemia, family history of long QT syndrome, concomitant medications known to prolong QT interval Colao A et al. N Engl J Med 2012;366:914–924 ULN, upper limit of normal

40. Study design Core study 900 μ g bid (unblinded)* 1200 μ g bid (unblinded)* Month 12 Open label Extension Day 1 Screening Month –1 Screening Washout of other meds Partially blind Month 6 Primary efficacy (Normalization of UFC without dose uptitration before 6 months) 600 μ g bid 900 μg bid *For patients who had a mean baseline UFC ≥2xULN with a 3-month UFC >2xULN OR For patients who had a mean baseline UFC 1.5–2xULN with a 3-month UFC above their baseline UFC ↓↑ dose titration per investigator Optional extension ph ase Randomization (n=162) Pasireotide 900 μ g sc bid Pasireotide 600 μ g sc bid Month 3 Double blind n=80 n=82 Patients with UFC ≤2xULN and less than baseline at month 3 continued at their randomize d dose, double blind, until month 6 All other patients were unblinded and the dose was increased by 300 μg bid until month 6, and they were considered non-responders for the primary efficacy analysis

41. Pasireotide sc Phase III trial: Baseline demographics by randomized dose Overall n=162 600 μg bid n=82 900 μg bid n=80 Mean age (years)40.240.539.9 Female, n (%)126 (77.8)62 (75.6)64 (80.0) Time since diagnosis (months)54.053.454.5 Cushing’s disease status Persistent/recurrent, n (%)135 (83.3)67 (81.7)68 (85.0) De novo, n (%)27 (16.7)15 (18.3)12 (15.0) Previous surgery, n (%)128 (79.0)64 (78.0)64 (80.0) Previous medication, n (%)78 (48.1)36 (43.9)42 (52.5) Previous pituitary irradiation, n (%)7 (4.3)3 (3.7)4 (5.0) Mean UFC level, nmol/24h (range) 970 (195–22,944) 1156 (220–22,944) 781 (195–6123) Colao A et al. N Engl J Med 2012;366:914–924

42. Overall n=162 600 μg bid n=82 900 μg bid n=80 Dispositionn (%) Completed month 6107 (66.0)54 (65.9)53 (66.3) Completed month 1278 (48.1)39 (47.6)39 (48.8) Reason for discontinuation Unsatisfactory therapeutic effect41 (25.3)19 (23.2)22 (27.5) Adverse event(s)28 (17.3)13 (15.9)15 (18.8) Subject withdrew consent24 (14.8)13 (15.9)11 (13.8) Protocol deviation4 (2.5)4 (4.9)0 Pasireotide sc Phase III trial: Patient disposition Colao A et al. N Engl J Med 2012;366:914–924

43. Change in UFC from baseline to month 6 in the 103 patients with baseline and month-6 UFC measurements ULN † 7000 UFC (nmol/24h) 0 500 1000 1500 2000 4000 600 µg bid 900 µg bid Baseline UFC Month 6 UFC Month 6 UFC ≤ULN * Median percentage UFC change from baseline was –47.9% in both groups Colao A et al. N Engl J Med 2012;366:914–924 † Reference line is the ULN UFC, which is 145 nmol/24h

44. Significant reduction in mean UFC over time Similar trends seen for: Serum and salivary cortisol Plasma ACTH Statistically significant (P<0.001) decrease from baseline to month 6 and month 12 for both do se groups Colao A et al. N Engl J Med 2012;366:914–924 Time (month) Mean UFC ± SE (nmol/24 h) 036912 1500 1300 1100 900 700 500 300 100 900 µg bid 600 µg bid n =1531441321311231161119377 21

45. Pasireotide sc Phase III trial: Primary efficacy analysis 600 µg bid (n=82) 900 µg bid (n=80) Overall (n=162) 6 months Response,* n (%) [95% CI] 12 (14.6) [7.0, 22.3] 21 (26.3) [16.6, 35.9] 33 (20.4) [14.2, 26.6] 12 months Fully controlled, n (%)11 (13.4)20 (25.0) 31 (19.1) Partially controlled, n (%)13 (15.9)2 (2.5)15 (9.3) Uncontrolled, n (%)58 (70.7)58 (72.5)116 (71.6) *Note: Responder was a patient with UFC ≤ULN who did not require uptitration Fully controlled: UFC ≤ULN; partially controlled: UFC >ULN, but had ≥50% reduction from baseline; Uncontrolled: UFC >ULN and <50% reduction from baseline Predetermined criterion for the primary efficacy endpoint was that the lower bound of the 95% CI had to be gre ater than 15% for at least one of the dose groups: this was met for the 900 µg group

46. Pasireotide sc Phase III trial: Early prediction of uncontrolled patients at 6 and 12 months Early non- responders Month 6 responseMonth 12 response UCFCPCUCFCPCUC Month 1 + 2, n (%) 72 (100.0) 4 (5.6) 2 (2.8) 66 (91.7) 6 (8.3) 2 (2.8) 64 (88.9) Month 1 + 2 + 3, n (%) 63 (100.0) 2 (3.2) 1 (1.6) 60 (95.2) 5 (7.9) 1 (1.6) 57 (90.5) Fully controlled (FC): UFC ≤ULN Partially controlled (PC): UFC >ULN, but had ≥50% reduction from baseline Uncontrolled (UC): UFC >ULN and <50% reduction from baseline, or missing values Colao A et al. N Engl J Med 2012;366:914–924 Within 1–2 months, patients who will remain uncontrolled can be identified

47. Pasireotide sc Phase III trial: Baseline UFC level and response at 6 months Higher rate of UFC normalization with lower baseline UFC 600 µg bid (n=82) 900 µg bid (n=80) Baseline UFC shown as fold elevations above ULN Patients achieving normal UFC at month 6 (%) 0102030405060 >1.5 to ≤2x >2x to ≤5x >5x 1/22 4/39 10/40 7/26 7/14 1/12 Colao A et al. N Engl J Med 2012;366:914–924

48. Pasireotide sc Phase III trial: Significant decrease in blood pressure and UFC Note: Changes in antihypertensive medicines were allowed Significant (P=0.03) change from baseline to month 12 was observed for: SBP –6.1 mmHg (95% CI: –9.8, –2.4) DBP –3.7 mmHg (95% CI: –6.2, –1.2) Colao A et al. N Engl J Med 2012;366:914–924 1250 1000 750 500 250 0 Time (month) Mean SBP 135 133 131 129 127 125 123 121 Mean UFC ± SE (nmol/24h) Mean BP ± SE (mmHg) Systolic blood pressure (SBP) 1250 1000 750 500 250 0 88 87 86 85 84 83 82 81 80 B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 Mean DBP Mean UFC Diastolic blood pressure (DBP) Mean UFC B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

49. 49 | Pasireotide Cushing’s Disease March 2012 | Business Use Only Pasireotide sc Phase III trial: Significant decrease in weight and UFC Significant (P<0.001) decrease in weight of 6.7 kg from baseline to month 12 (95% CI: –8.0, –5.4) Colao A et al. N Engl J Med 2012;366:914–924 84 82 80 78 76 74 72 1250 1000 750 500 250 0 B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 Time (month) Mean UFC ± SE (nmol/24h) Mean weight ± SE (kg) Mean UFC Mean weight

50. Pasireotide sc Phase III trial: Significant decrease in LDL-cholesterol and UFC Significant (P<0.001) decrease in LDL-cholesterol of 0.4 mmol/L from baseline to month 12 (95% CI: –0.6, –0.2) Colao A et al. N Engl J Med 2012;366:914–924 Time (month) 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9 Mean LDL-cholesterol ± SE (mmol/L) 1250 0 500 1000 750 250 The ULN for LDL-cholesterol is 3.3 mmol/L [129 mg/dL]; changes in lipid-lowering medicines were allowed LDL, low-density lipoprotein B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 Mean UFC ± SE (nmol/24h) Mean UFC Mean LDL-cholesterol

51. Pasireotide sc Phase III trial: Significant improvement in HRQoL and UFC 51 | Pasireotide Cushing’s Disease March 2012 | Business Use Only Measured via Cushing QoL Significant (11.1 points) improvement from baseline to month 12 (95% CI: 6.8, 15.5) Colao A et al. N Engl J Med 2012;366:914–924 Time (month) HRQoL score ± SE 1250 1000 750 500 250 0 52 50 48 46 44 42 40 HRQoL, health-related quality of life B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12 54 Mean UFC ± SE (nmol/24h) Mean UFC Mean HRQoL score

52. Pasireotide sc Phase III trial: Safety profile (I) Overall (N=162) AE All grades n (%) Grades 3 or 4 (%) Hyperglycemia related118 (72.8)40 (24.7) Diarrhea related95 (58.6)5 (3.1) Nausea related85 (52.5)4 (2.5) Gallbladder and biliary related54 (33.3)4 (2.5) Liver chemistry related26 (16.0)7 (4.3) Bradycardia related23 (14.2)3 (1.9) Hypocortisolism related13 (8.0)4 (2.5) QT prolongation related13 (8.0)4 (2.5) Hypothyroidism related7 (4.3)0 Grading (1–4) of AEs follows the US HHS Common Terminology Criteria for Adverse Events (CTCAE) 2009 Common AE terms were pooled, for example, all terms relating to elevations in blood glucose or terms relating to diarrhea 52 | Pasireotide Cushing’s Disease March 2012 | Business Use Only

53. Pasireotide sc Phase III trial: Safety profile (II)  Safety of pasireotide : similar to other somatostatin analogues, except for hyperglycemia  Most frequently reported AEs were gastrointestinal  12% of patients had ≥1 SAE suspected to be drug related  No deaths during treatment  Hypocortisolism (8%)  Responded to dose reduction and/or temporary corticosteroid substitution  Hyperglycemia-related AE (72.8% of patients had at least one time)  6% of patients discontinued treatment because of a hyperglycemia-related adverse event Colao A et al. N Engl J Med 2012;366:914–924 AE, adverse event; SAE, serious AE

54. Pasireotide sc Phase III trial: Changes in glycemia Colao A et al. N Engl J Med 2012;366:914–924 Mean fasting plasma glucose (mg/dL) 600 µg bid (n=82) 900 µg bid (n=80) 90 100 110 120 130 140 150 BaselineDay 15Month 3Month 6Month 12 Of the 67 patients who were normoglycemic at baseline, 14 (21%) remained normal, 29 (43%) became pre-diabetic and 23 (34%) became diabetic during treatment 5 6 7 8 BaselineMonth 2Month 6Month 12 Mean HbA 1c (%) Note: Treatment of diabetes mellitus was allowed but not protocol specified

55. Evaluating the underlying mechanism of pasireotide-induced hyperglycemia Two studies conducted to assess the mechanism(s) responsible for pasireotide-related hyperglycemia Double-blind, randomized, single-center trial in healthy male volunteers evaluating the mechanism responsible for pasireotide-related hyperglycemia (SOM230B2216) Randomized, open-label, single-center study evaluating the effects of the co-administration of antihyperglycemic agents and pasireotide, compared with pasireotide alone, on glucose metabolism in healthy male volunteers (SOM230B2124)

56. Summary and conclusion  Cushing’s syndrome is a state of excess glucocorticoids.  Early diagnosis of Cushing’s syndrome is crucial, because of high morbidity & mortality.  Surgery is the first-line treatment, but Cushing’s disease is associated with high relapse rates.  The Phase III SOM230B2305 study showed that pasireotide is the first pituitary-targeted medical therapy to rapidly decrease urinary free cortisol and improve signs and symptoms in Cushing’s disease.  Although some currently available second-line therapeutic options can result in cure, they are associated with variable response rates and significant risks.