5. Accreditation Statement The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The Endocrine Society has achieved Accreditation with Commendation. The Endocrine Society designates this live activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

6. Upon completion of this educational activity, learners will be able to: Examine principle recommendations of the latest evidence-based clinical practice guidelines for the diagnosis and management of acromegaly evaluate surgery, radiotherapy, and pharmacological treatments, as well as the use of biochemical control, in the overall management of acromegaly Assess the effect of acromegaly and its comorbidities on patients’ quality of life to better assist and manage these patients Assess novel therapeutic targets and emerging drug formulations for the treatment of acromegaly Learning Objectives

7. The Endocrine Society has reviewed all disclosures and resolved or managed all identified conflicts of interest, as applicable. The following faculty reported relevant financial relationships: Andrea Giustina, MD: Consultant, Ipsen, Novartis Pharmaceuticals, Pfizer, Inc. Shlomo Melmed, MD: Consultant, Genentech, Inc.; Principal Investigator, Ipsen, Pfizer, Inc. Roberto Salvatori, MD: Advisory Board, Novartis Pharmaceuticals, Pfizer, Inc.; Advisory Board and Investigator, Ipsen The following faculty reported no relevant financial relationships: David R. Clemmons, MD The following SPC member who planned and reviewed content for this activity reported relevant financial relationships: Andrea L. Utz, MD, PhD: Advisory Board, Corcept, Ipsen Disclosures

8. The following SPC members reported relevant financial relationships: Benjamin Leder, MD: Consultant and Investigator, Amgen Inc.; Investigator, Eli Lilly & Co. Sarah Berga, MD: Advisory Board, Agile Therapeutics, Noven Pharmaceuticals, Inc., Watson Pharmaceuticals, Teva Pharmaceuticals Industries, Shionogi, Inc.; Consultant, AHC Media, LLC, Shionogi, Inc. Paresh Dandona, MD, PhD, FRCP: Consultant and Speaker, AstraZeneca, Bristol-Myers Squibb, Janssen, Merck, Novo Nordisk Henry Fein, MD: Investigator, Corcept Therapeutics Irl Hirsch, MD: Consultant, Abbott Laboratories, Johnson & Johnson, Roche Diagnostics, Valeritas; Investigator, Sanofi Anton Luger, MD: Advisory Board, Investigator and Speaker, Novo Nordisk; Advisory Board and Speaker, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Ipsen, Merck, Merck, Sharp & Dohme, Novartis, Pfizer, Reckitt Benckiser, Takeda; Investigator, Roche The following SPC members reported no relevant financial relationships: Jeffrey Boord, MD, MPH; Larry Fox, MD; Ann Kearns, MD, PhD; Connie Newman, MD Endocrine Society and Vindico Medical Education staff associated with the development of content for this activity reported no relevant financial relationships Disclosures - continued

9. COMORBIDITIES OF ACROMEGALY Andrea Giustina Chair of Endocrinology University of Brescia Italy

10. Disclosure Consultant: Ipsen, Novartis Pharmaceuticals, Pfizer, Inc.

11. Comorbidities in Acromegaly Hypertension, cardiomyopathy, valvular disease Glucose intolerance/ diabetes mellitus Acromegaly comorbidities Acromegaly comorbidities Hypopituitarism, hypogonadism Colon polyps Respiratory complications, sleep apnea Cerebrovascular events, headache Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44. Osteoarthritis, osteoporotic fractures Craniofacial deformations Soft tissue hypertrophy Na+-fluid retention peripheral vasomotor dysfunction endothelial disturbances Myocardial fibrosis Increased bone resorption Cartilage hypertrophy Osteophytosis Insulin resistance Impairment of insulin secretion

12. Mortality in Acromegaly Biochemical Determinants Holdaway IM, et al. Eur J Endocrinol. 2008;159:89-95.

13. Rajasoorya C, et al. Clin Endocrinol (Oxf). 1994;41:95-102. Mortality in Acromegaly Clinical Determinants

14. Hypertension in Acromegaly Present in ≥40% of patients – Exacerbated by sleep apnea Baseline BP measurement recommended Early, aggressive treatment important Unclear effect of different medical treatments for acromegaly on hypertension Vitale G, et al. Clin Endocrinol (Oxf). 2005;63:470-476. Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44.

15. De Marinis L, et al. Pituitary. 2008;11:13-20. SURGERY NEUROSURGERY + SOMATOSTATIN ANALOGS SURGERY NEUROSURGERY + SOMATOSTATIN ANALOGS Cardiovascular Disease in Acromegaly

16. Sleep Apnea in Acromegaly/1 Underassessed – Prevalence up to 70% All patients require careful assessment – Symptomatic – Laboratory Improved compliance with CPAP and other devices needed Maxillofacial consultation advised SAS only partially reversible with biochemical control of acromegaly Davi' MV, et al. Eur J Endocrinol. 2008;159:533-540. Katznelson L, et al. Endocr Pract. 2011;17 Suppl 4:1-44.

17. PaperType of therapy N° of patients with improved SAS/Total Mean AHI before therapy Mean AHI after therapy Grunstein et al., 1994 SRLsNA3919 Ip et al., 2001 SRLsNA2913 Herrmann et al., 2004 SRLs9/14NA Berg et al., 2009 PEG9/122318 Pekkarinen et al., 1987 S1/320,618,3 Sze et al., 2007 S6/64111,3 Davì et al., 2008 S, SRLs, RT5/631,221,3 Rosenow et al., 1996 S, SRLs, RT, DA 24/32NA Davì MV, et al. Exp Rev Endocrinol Metab. 2012;7:55-62. Sleep Apnea in Acromegaly/2

18. Dreval AV, et al. Endocr Connect. 2014;3:93-98. Diabetes in Acromegaly

19. Skeletal Fragility in Acromegaly Clinical evidence!

20. 1° Author (year)Non vertebral (Clinical)Vertebral (RX) Vestergaard (2002)↓- Vestergaard (2004)↔- Bonadonna (2005)-↑ Mazziotti (2008)-↑ Wassenaar (2011)-↑ Padova (2011)↑ Madeira (2013)↑ All cross-sectional studies Skeletal Fragility in Acromegaly

21. a a,b,c a a, p<0.05 vs. control subjects; b, p<0.05 vs. controlled/cured disease; c, p<0.05 vs. active disease for 1-12 months Skeletal Fragility in Acromegaly Adapted from: Mazziotti G, et al. J Clin Endocrinol Metab. 2009;94:1500-1508.

22. Outcome of Comorbidities in Acromegaly Comorbidities Generally improved with medical treatment Variable or uncertain response to medical treatment Left ventricular hypertrophy Left ventricular dysfunction Hypertension Obstructive sleep apnea Arthropathy Diabetes/glucose intolerance No reversal of skeletal changes Melmed S, et al. Pituitary. 2013;16:294-302.

23. Summary Severe comorbidities make acromegaly a life- threatening disease heavily impairing quality of life of affected patients Early diagnosis and effective and sometimes aggressive treatment is mandatory to avoid the onset, stop the progression, or reverse comorbidities All patients with acromegaly, including those in biochemical remission, should undergo structured follow-up in order to monitor evolution of comorbidities

24. CHALLENGES IN DIAGNOSING AND FOLLOWING ACROMEGALY David R. Clemmons, MD Sarah Graham Kenan Professor of Medicine Director, Diabetes Center of Excellence University of North Carolina-Chapel Hill Chapel Hill, NC

25. Diagnosis of Acromegaly Single measurement of growth hormone (GH) is not an accurate indicator of elevation since secretion is pulsatile – Random GH sampling results in both false-positive and false-negative results – Patients can have active disease even though GH levels fall within normal range – Diagnosis can be confirmed by demonstrating failure to suppress GH <1 ng/mL after glucose administration Measurement of insulin-like growth factor (IGF)-I levels is a reliable marker for the diagnosis of acromegaly – Representative of average daily GH secretion – Levels remain stable throughout the day; not affected by meals Freda PU. Endocrinologist. 2000;10:237-244. Melmed S, et al. J Clin Endocrinol Metab. 1998;83:2646-2652.

26. IGF-I (ng/mL) 2200 1800 1400 1000 600 2226 Heel Pad Thickness (mm) 3034 r = 0.73 P<0.00001 38 r = 0.74 P<0.00001 Fasting Blood Glucose (mg/dL) 2200 1800 1400 1000 600 100140 180360 Adapted from: Clemmons DR, et al. N Engl J Med. 1979;301:1138-1142. Correlation Between IGF- Correlation Between IGF-I and Clinical Indices fasting GH: r = 0.12 fasting GH: r = 0.08 nadir GH: r = 0.34 nadir GH: r = 0.36

27. Why Measure GH? Provides a direct measure of tumor output Necessary to exclude the diagnosis in 2.5% of normal population who have an elevated IGF-I Correlates with degree of improvement after surgery Predicts long term mortality outcome

28. Summary of Criteria for Selecting IGF-I Assays 1. Adequate age-adjusted normative data 2. Interassay variability is stated 3. Method is adequate to eliminate binding protein interference 4. Assay results show proven GH dependence 5. Reference values are available that allow comparison of results to other commercial assays

29. IGF-I Age Adjusted Reference Ranges Bidlingmaier M, et al. J Clin Endocrinol Metab. 2014;99:1712.

30. Summary of Criteria for Selecting IGF-I Assays 1. Adequate age-adjusted normative data 2. Interassay variability is stated 3. Method is adequate to eliminate binding protein interference 4. Assay results show proven GH dependence 5. Reference values are available that allow comparison of results to other commercial assays

31. Sample Mean concentration, ng/mL Central calibrator, CV, % a Local calibrator, CV, % b 1 85 4.0 16.4 2 90 5.6 19.3 3 210 6.1 10.6 4 356 6.9 5.5 5 179 3.5 11.8 Mean CV, % c 5.2 12.8 Interlaboratory Agreement of Insulin-like Growth Factor 1 Concentrations Measured by Mass Spectrometry Comparison of a central calibrator vs a local calibrator. ↵ a One laboratory generated a single calibration curve and distributed it. ↵ ↵ b Each laboratory generated its own calibration curve using rat plasma and reference material. ↵ ↵ c Average CV was calculated from the CV of all 4 samples. ↵ Cox HD, et al. Clin Chem. 2014;60:541-548.

32. Background matrix Recovery value, % hGH, μg/mlImmuliteCobas e411 hGH- sensitive ELISA DiaSorinIDS PBS 5.05 <1 0.60 <1 hGH- depleted serum 5.18 38 32 28 31 Charcoal- stripped serum 5.09 28 23 21 23 SRM 971 male 5.03 25 22 17 16 20 Sheep serum 5.12 28 24 20 15 18 Reconstitutio n in PBS- BSA PBS-BSA 4.94 145 135 103 89 106 hGH- depleted serum 5.01 107 98 88 81 89 Charcoal- stripped serum 5.03 103 94 81 82 88 SRM 971 male 4.91 106 90 83 80 92 Sheep serum 4.97 122 100 90 77 90 Results from a HGH Recovery Study Boulo S et al. Clin Chem. 2013;59:1074-1082.

33. Comparison of LC-MS and Immunoassay Techniques with Respect to hGH Quantification Sample ABC [hGH] by LC-MS, μg/L Peptide T12 7.250 (0.023)5.205 (0.010)4.365 (0.019) Peptide T6 6.348 (0.005)4.458 (0.017)3.675 (0.012) [GHBP], μg/L42.2 (1.8)21.2 (1.6)24.7 (1.4) Decrease in [hGH] upon addition of 10 μg/L GHBP, % 9.710.614.8 [hGH] by immunoassay, μg/L Siemens 9.78 (0.31)7.14 (0.44)4.21 (0.18) Roche 9.29 (0.21)7.26 (0.12)4.10 (0.11) Mediagnost 7.91 (0.17)5.62 (0.06)3.14 (0.07) DiaSorin 6.90 (0.87)5.60 (0.30)2.87 (0.15) IDS 7.99 (0.76)6.18 (0.25)3.25 (0.13) Boulo S et al. Clin Chem. 2013;59:1074-1082.

34. Surgical Cure Rates for Acromegaly According to Tumor Size and Criteria Used % Cured SeriesMicrosMacros Abosch (n=254)7571 Swearingen (n=149)9148 Freda (n=99)8853 Beauregard (n=103)8247 Shimon (n=98)8464 Krieger (n=181)8031 Abosch A, et al. J Clin Endocrinol Metab. 1998;83:3411-3418. Beauregard C, et al. Clin Endocrinol. 2003;58:86-91. Swearingen B, et al. J Clin Endocrinol Metab.1998;83:3419-3426. Freda PU, et al. J Neurosurg. 1998;89:353-358. Shimon I, et al. Neurosurgery. 2001;48:1239-1243.Krieger MD, et al. J Neurosurg. 2003;98:719-724.

35. Correlation Between Tumor Size and Remission Rate After Surgery Microadenoma Macroadenoma Giant adenoma N 142 (27%) 378 (70.7%) 12 (2.2%) Diameter (mm) 2-9 10-37 41-60 Avg. Diameter (mm) 7.6±1.75 16.7 ± 5.6 50.9±9.5 GH level (µg/l) 1-142 4-357 10-398 Average GH 16.4±15.2 42.6±38.4 102.4±64.3 level (µg/l) Remission rate N= 107 (75.3%) 186 (48.6%) 1(8.3%) Nomikos P et al. Eur J Endocrinol. 2005;152:379-387.

36. Odds Ratio for Presence of Left Ventricular Hypertrophy, Diastolic and Systolic Dysfunction in Patients with Estimated Duration of Acromegaly ≥10 Years Compared with Those with Estimated Disease Duration <10 Years Colao A et al. Eur J Endocrinol 2011;165:713-721. © 2011 European Society of Endocrinology

37. IGF-I at Diagnosis Predicts OA Severity Biermasz NR, et al. J Clin Endocrinol Metab. 2005;90:2731-2739.

38. Physician vs Computer Model SensitivitySpecificity Positive predictive value Accuracy Physicians Average 46 96 85 26 Worst 33 100 16 Best 83 96 95 90 Computer 71 100 86 Ten physicians, internists, or family practitioners, examined 49 8 × 10 color photographs and decided which represented patients with acromegaly or normal subjects. The same photographs were analyzed by the computer model. The computer was more accurate (86%) than all but one of the physicians (90%). Miller RE, et al. Clin Endo. 2011;75:226-231.

39. Case 1 46-year-old man referred for evaluation of enlarged thyroid Noted to have osteoarthritis Recalled hand and foot enlargement, sweaty palms, and change in facial features Sleep apnea, hypertension, and impaired fasting glucose GH 1.6 ng/ml IGF-I 609 ng/mL (87-267)

40. MRI and Histology

41. Case 2 44-year-old woman presented for evaluation of new onset diabetes BMI 26 kg/mm 2 and no family history of diabetes Reported changing ring size twice and shoe size once, modest increase in sweating IGF-I 804 ng/mL (110-368) GH suppression nadir 2.2 ng/mL

42. MRI: Microadenoma

43. Case 3 36-year-old man presented with clicking jaw symptoms of TMJ History revealed joint pain and weight gain Occupation: Barber, had to enlarge his scissors because fingers didn’t fit IGF-I 1600 ng/mL GH 13.9 ng/mL

44. Consensus Guidelines: Initial Evaluation Screening: There are no consensus guidelines for screening Diagnostic testing: Consensus recommendation is to measure IGF-I and growth hormone after glucose Initial evaluation should include: MRI, visuals field (if large tumor), prolactin, testosterone/LH (males), FSH estrogen (females) Comorbidity evaluation: Fasting glucose; calcium assessment of arthritis; sleep study, if symptomatic ECG, followed by echocardiogram, if LVH is present; colonoscopy; dexa scan and radiographs of spine and hip films, if history of fracture or if hypogonadism is present; genetic analysis, if family is positive for pituitary tumors

45. Summary Confirmation of the diagnosis of acromegaly is straightforward the major problem is early detection. IGF-I measurements provide an index of disease severity and are useful for diagnosis and monitoring the response to treatment. GH suppression testing is useful for confirming that an elevated IGF-I is due to a GH secreting tumor. Assays for both IGF-I an GH have improved and further steps to improve the comparability of results among different reference labs are being undertaken. Abnormal enlargement of the hands and feet are the most common presenting symptoms of acromegaly and merit investigation. Early diagnosis predicts a much higher rate of surgical cure. Consensus guidelines recommend both GH and IGF-I measurements at diagnosis and proactive use of these tests to determine the need for further therapy.

46. Therapeutic Approaches to Acromegaly Management Shlomo Melmed, MD Cedars-Sinai Medical Center Los Angeles, CA

47. Disclosure Consultant: Chiasma, Genentech Principal Investigator: Ipsen, Pfizer, Novartis

48. Governor Pio Pico 1847 Acromegaly: Approach to Management

49. HoursDaysWeeksYearsMonths Unchanged Improved, with disease persistence Recurrence Spontaneous resolution Long-term normalization GH BP DM SA OA QOL …..etc Treatment Outcomes Melmed 2014

50. Acromegaly Treatment Goals: Eliminate morbidity Reduce mortality to expected rates Strategy: Safe treatments Remove tumor or control growth Normalize GH secretion and action Preserve pituitary function Assessment: Age­-adjusted IGF­I Nadir GH <1 mg/L after OGTT Giustina A, et al. J Clin Endocrinol Metab. 2010;95:3141-3148.

51. High IGF-1 24% Controlled 30% High GH 11% Active Disease 35% 8.0 6.0 4.0 2.0 0.0 -2.0 -4.0 IGF-1 Z-SCORE 0.10.111.03.31033100 GH (  g/L) IGF-1 nl If IGF-1 nl... probably controlled! GH elevated If GH elevated … likely sign of early relapse! Uncontrolled Partial Controlled n=229 IGF-1 (  g/L) Acromegaly Treatment Outcomes Adapted from: Alexopoulou O, et al. J Clin Endocrinol Metab. 2008;93:1324-1330.

52. Caveats: IGF-1 normalization might be delayed after surgery Medication effects might be delayed and progressive 24-hour postop GH <1 µg/L has 98% predictive value 100 Probability of remission (%) 80 60 40 20 0 Nadir GH (  g/L) 0246 Time (hr) Nonremission 12 10 8 6 4 2 0 261218487224 GH (  g/liter) Remission GH as a Postoperative Remission Biomarker Adapted from: Kim EH, et al. Neurosurgery. 2012;70:1106-1113.

53. GH-secreting Adenoma: Remission Predictors Densely granulated Sparsely granulated Predictors for postsurgical disease persistence Macroadenoma Parasellar extension Young age High GH/IGF1 …………Choice of surgeon Osamura RY, et al. Histochem Cell Biol. 2008;130:495-507. Fougner SL, et al. Clin Endocrinol (Oxf). 2012;76:96-102. Kiseljak-Vassiliades K, et al. Endocrine. 2012;42:18-28. Arita H, et al. J Clin Endocrinol Metab. 2012;97:2741-2747. Larkin s, et al. Eur J Endocrinol. 2013;168:491-499. Melmed S, et al. Endocr Rev. 1983;4:271-290.

54. 1 2-34-78+ 0.5 1.5 2.0 Mortality (%) 534 surgeons 305 95 36 1.0 2.5 0.5 1.0 1.5 Mortality (%) 1-4 5-910-2425+ ` 408 hospitals 140 68 20 Hospital and Surgeon Volume Determine Outcome Adapted from: Barker FG 2nd, et al. J Clin Endocrinol Metab. 2003;88:4709- 4719. Admissions/yr 54 3033 86 52 66 20 40 60 80 100 MicroMacroOverall % Post-op GH<2.5 ng/mL 8 SurgeonsSINGLE Surgeon Lissett CA, et al. Clin Endocrinol (Oxf). 1998;49:653-657. Surgical skill as biomarker ! !

55. Surgery Advantages – Rapid GH decrease – One-time cost – Potential cure – Debulking may enhance adjuvant therapy Disadvantages – Tumor persistence – Hypopituitarism – Not all appropriate candidates Risks% Temporary vs permanent Overall complications25 Diabetes insipidus10 Electrolyte abnormalities9 Neurologic deficit5 CSF rhinorrhea1.5 Mortality1 More complications: – Low-volume surgeon – Comorbidity Melmed 2014

56. % of Patients (N=47) Normal IGF-I 0 20 40 60 80 2 years Post RT Hypopituitarism 5 years Post RT10 years Post RT Glucose-suppressed GH (<1 mcg/L) Radiotherapy Adapted from: Minniti G, et al. J Clin Endocrinol Metab. 2005;90:800-804. Adapted from: Sherlock M, et al. J Clin Endocrinol Metab. 2009;94:4216-4223. MORTALITYRTSMR (O/E)95% CIP All Cancer CV Cerebrovascular No Yes No Yes No Yes No Yes 1.4 2.1 1.1 2.4 1.7 2.2 1.7 4.1 1.7, 2.6 0.8, 2.2 1.6, 3.1 0.8, 3.3 2.3, 6.6 0.006 0.442 0.247 0.034

57. Radiotherapy Advantages – Permanent – No long-term therapy – No drug-related adverse events – One-time cost – Patient compliance Disadvantages – Ineffective and slow onset – IGF-I not normalized – Hypopituitarism – CVA – Cost of interim medical therapy – Visual problems – Secondary brain malignancies – CNS damage

58. Mean tumor volume reduction62% Reduction to empty sella Cavernous sinus resolution Tumor disappeared 11 patients % Tumor shrinkage: Progressive Before hormone normalization 45 Without GH control 35 None, with GH control 3 Tumor Shrinkage in 55 Patients Receiving Primary Octreotide Therapy Cozzi R, et al. J Clin Endocrinol Metab. 2006;91:1397-1403.

59. Poor likelihood of surgical cure Frailty Patient declines surgery Unacceptable anesthetic risk Advantages Avoid noncurative surgery and radiation with attendant side effects Medications can be personalized Primary Medical Treatment

60. SRL Therapy Advantages Rapid GH and/or IGF-I control and symptom relief No hypopituitarism Tumor mass control Adverse effects Gallbladder – Gallstones or sludge Gastrointestinal – Diarrhea – Nausea – Abdominal discomfort Glucose – Hypo/hyperglycemia Cardiac – Sinus bradycardia Other – Injection site pain – Headache – Alopecia Disadvantages – Cure not permanent – Long-term treatment – Cost – Patient compliance required Doppman The Endocrinologist 1998

61. GH Receptor Antagonist Goals – Normalize IGF-I – Control symptoms Efficacy Biomarker (nl IGF-I) – >60% at 20-40 mg/day Disadvantages – Elevated liver enzymes – Lipodystrophy – Very rare increase in tumor volume; uncertain if due to drug or natural history van der Lely AJ, et al. Lancet. 2001;358:1754-1759. Trainer PJ, et al. N Engl J Med. 2000;342:1171-1177. Melmed S. J Clin Invest. 2009;119:3189-3202.

62. Diabetes BiomarkersBaseline6 Mos24 Mos Glucose Fasting (mg/dL) 141 ± 61 N=58 126 ± 56 N=51 102* ± 24 N=28 HbA1c (%) 7.0 ± 1.4 N=71 6.5* ± 1.2 N=65 6.5 ± 1.3 N=41 *P<0.05. 100 80 60 40 20 0 Proportion of patients (%) Years on Rx 12345 n 435426339257160 63% Mean dose ( 18 mg/day) IGF-I normalized ACROSTUDY: Pegvisomant Biomarkers Adapted from: Van der Lely AJ, et al. J Clin Endocrinol Metab. 2012;97:1589-1597.

63. 105 125 IGF-I (nmol/L) Age (yrs) 25 45 65 85 3040506070 = monthly SRL = +pegvisomant MorbidityImproved IGF-IControlled ~80% Pituitary functionUncompromised Tumor sizeShrinkage ~50% Adverse effectsSimilar to adjuvant Rx Avoiding other less safe RxPatient choice Combined SRL and Pegvisomant Adapted from: Neggers SJ, et al. J Clin Endocrinol Metab. 2007;92:4598-4601.

64. Pasireotide  g (bid) Octreotide 100  g tid (n=58) 200  (n=21) 400  (n=17) 600(n=20) P = 0.019 70 60 50 40 30 20 10 0 Patients (%) GH  2.5  g/L + normal IGF-I GH  2.5  g/L Normal IGF-I Adverse events (%) Gastro-intestinal 25  BS   HbA 1c  Diabetes  Weckbecker Endocrinol 2003 SSTR1SSTR2SSTR3SSTR4SSTR5 Ratio OCT/SOM 300.45-35 Adapted from: Van der Hoek J, et al. J Clin Endocrinol Metab. 2004;89:638-645. GH inhibition % Pasireotide* Control of Acromegaly Adapted from: Petersenn S, et al. J Clin Endocrinol Metab. 2010;95:2781-2789. *Not FDA approved

65. Comparing Treatment with Pasireotide* LAR and Octreotide LAR Overall, the number of patients with GH <2.5 µg/L and normal IGF-1 was significantly greater with pasireotide LAR compared to octreotide LAR (p=.007) Safety profile of pasireotide similar to octreotide, except for hyperglycemia- related AEs (57% vs 22%) Colao A, et al. J Clin Endocrinol Metab. 2014;99:791-799. *Not FDA approved

66. 0.0 0.5 0 1.5 2.0 2.5 3.0 3.5 4.0 -1.0-0.50.00.51.01.52.02.5 83% inhibition of basal GH Pre dose Basal Secretion Serum GH µ g/mL Octreolin Control Effect of Octreolin* on Basal GH in 18 Healthy Subjects Adapted from: Tuvia S, et al. J Clin Endocrinol Metab. 2012;97:2362-2369. *Not FDA approved

67. Effect of Oral Octreotide on GH Surge in 18 Healthy Subjects Adapted from: Tuvia S, et al. J Clin Endocrinol Metab. 2012;97:2362-2369.

68. Medical Management of Acromegaly SRL + pegv Pegv + cabergoline SRL + dopamine agonist Increase pegv dose and/or add cabergoline Somatostatin Receptor Ligand Consider reducing SRL dose or increasing dose interval Increase SRL dose or decrease dose interval SRL + pegv Switch to pegv Monitor IGF-I Consider reducing pegv dose and/or increasing dose interval Well controlledPartial responseNo response Well controlledNo response Well controlled Adapted from: Giustina A, et al. Nat Rev Endocrinol. 2014;10:243-248.

69. Challenges for Improved Treatment Efficacy Delivery modes Targeted Rx Safety Surgical technology Cost