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.

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

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

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

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

Disclosure

Consultant: Ipsen, Novartis Pharmaceuticals, Pfizer, Inc.

Comorbidities in Acromegaly Hypertension, cardiomyopathy,

valvular disease

Glucose intolerance/

diabetes mellitus

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

Mortality in Acromegaly Biochemical Determinants

Holdaway IM, et al. Eur J Endocrinol. 2008;159:89-95.

Rajasoorya C, et al. Clin Endocrinol (Oxf). 1994;41:95-102.

Mortality in Acromegaly Clinical Determinants

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.

De Marinis L, et al. Pituitary. 2008;11:13-20.

Pts Groups

Poorly controlledControlledCured

Left

vent

ricul

ar m

ass

inde

x

300

200

100

0

SURGERY NEUROSURGERY +

SOMATOSTATIN ANALOGS

Pts Groups

Poorly controlledControlledCured

Inte

rven

tricu

lar s

eptu

m th

ickn

ess

(cm

)

1,8

1,6

1,4

1,2

1,0

,8

,6

,4

SURGERY NEUROSURGERY +

SOMATOSTATIN ANALOGS

Cardiovascular Disease in Acromegaly

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.

Paper

Type of therapy

N° of patients with improved

SAS/Total

Mean AHI before therapy

Mean AHI after therapy

Grunstein et al., 1994 SRLs NA 39 19 Ip et al., 2001 SRLs NA 29 13 Herrmann et al., 2004 SRLs 9/14 NA NA Berg et al., 2009 PEG 9/12 23 18 Pekkarinen et al., 1987

S 1/3 20,6 18,3 Sze et al., 2007 S 6/6 41 11,3 Davì et al., 2008 S, SRLs, RT 5/6 31,2 21,3 Rosenow et al., 1996 S, SRLs, RT,

DA 24/32 NA NA

Davì MV, et al. Exp Rev Endocrinol Metab. 2012;7:55-62.

Sleep Apnea in Acromegaly/2

Dreval AV, et al. Endocr Connect. 2014;3:93-98.

Diabetes in Acromegaly

Skeletal Fragility in Acromegaly

Clinical evidence!

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

0

20

40

60

80

100

120

0102030405060708090

Controls Controlled/Curedfor 36 months

Active for 1-12months

Active for 13-24months

Active for 25-36months

Med

ian

of to

tal d

urat

ion

of a

ctiv

e ac

rom

egal

y (m

onth

s)

Inci

denc

e of

VF

(%)

OUTCOME OF ACROMEGALY DURING 3-YEAR FOLLOW-UP

a

a,b,c 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.

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.

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

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

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.

IGF-

I (ng

/mL)

2200

1800

1400

1000

600

22 26

Heel Pad Thickness (mm) 30 34

r = 0.73 P<0.00001

38

r = 0.74 P<0.00001

Fasting Blood Glucose (mg/dL)

2200

1800

1400

1000

600

100 140 180 360

Adapted from: Clemmons DR, et al. N Engl J Med. 1979;301:1138-1142.

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

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

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

IGF-I Age Adjusted Reference Ranges

Bidlingmaier M, et al. J Clin Endocrinol Metab. 2014;99:1712.

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

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.

Background matrix

Recovery value, %

hGH, μg/ml Immulite Cobas e411 hGH-

sensitive ELISA

DiaSorin IDS

PBS 5.05 <1 0.60 <1 <1 <1

hGH-depleted serum

5.18 38 38 32 28 31

Charcoal-stripped serum

5.09 28 28 23 21 23

SRM 971 male

5.03 25 22 17 16 20

Sheep serum 5.12 28 24 20 15 18

Reconstitution 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.

Comparison of LC-MS and Immunoassay Techniques with Respect to hGH Quantification

Sample A B C

[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/L 42.2 (1.8) 21.2 (1.6) 24.7 (1.4) Decrease in [hGH] upon addition of 10 μg/L GHBP, %

9.7 10.6 14.8

[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.

Surgical Cure Rates for Acromegaly According to Tumor Size and Criteria Used

% Cured

Series Micros Macros

Abosch (n=254) 75 71

Swearingen (n=149) 91 48

Freda (n=99) 88 53

Beauregard (n=103) 82 47

Shimon (n=98) 84 64

Krieger (n=181) 80 31

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.

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.

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

IGF-I at Diagnosis Predicts OA Severity

Biermasz NR, et al. J Clin Endocrinol Metab. 2005;90:2731-2739.

Physician vs Computer Model

Sensitivity Specificity Positive predictive value

Accuracy

Physicians Average 46 96 85 26 Worst 33 100 100 16 Best 83 96 95 90 Computer 71 100 100 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.

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)

MRI and Histology

Case 2

• 44-year-old woman presented for evaluation of new onset diabetes

• BMI 26 kg/mm2 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

MRI: Microadenoma

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

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

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.

Therapeutic Approaches to Acromegaly Management

Shlomo Melmed, MD Cedars-Sinai Medical Center Los Angeles, CA

Disclosure

• Consultant: Chiasma, Genentech • Principal Investigator: Ipsen, Pfizer,

Novartis

Governor Pio Pico 1847

Acromegaly: Approach to Management

Hours Days Weeks Years Months

Unchanged

Improved, with disease persistence

Recurrence

Spontaneous resolution

Long-term normalization

GH BP DM SA OA QOL …..etc

Treatment Outcomes

Melmed 2014

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.

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-

SCO

RE

0.1 0.11 1.0 3.3 10 33 100 GH (µg/L) If IGF-1 nl ... probably controlled!

If GH elevated … likely sign of early relapse!

Uncontrolled

Partial

Controlled

n=229

IGF-

1 (µ

g/L)

Acromegaly Treatment Outcomes

Adapted from: Alexopoulou O, et al. J Clin Endocrinol Metab. 2008;93:1324-1330.

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

Pro

babi

lity

of re

mis

sion

(%) 80

60

40

20

0

Nadir GH (µg/L) 0 2 4 6

Time (hr)

Nonremission

12

10

8

6

4

2

0 2 6 12 18 48 72 24

GH

(µg/

liter

)

Remission

GH as a Postoperative Remission Biomarker

Adapted from: Kim EH, et al. Neurosurgery. 2012;70:1106-1113.

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.

1 2-3 4-7 8+

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 5-9 10-24 25+

`

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

30 33

86

52 66

20

40

60

80

100

Micro Macro Overall

% Post-op GH<2.5 ng/mL

8 Surgeons SINGLE Surgeon

Lissett CA, et al. Clin Endocrinol (Oxf). 1998;49:653-657.

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 complications 25 • Diabetes insipidus 10 • Electrolyte abnormalities 9 • Neurologic deficit 5 • CSF rhinorrhea 1.5 • Mortality 1 • More complications:

– Low-volume surgeon – Comorbidity

Melmed 2014

% o

f Pat

ient

s (N

=47)

Normal IGF-I

0

20

40

60

80

2 years Post RT

Hypopituitarism

5 years Post RT 10 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.

MORTALITY RT SMR (O/E) 95% CI P 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

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

• Mean tumor volume reduction 62% • 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.

• 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

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

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.

Diabetes Biomarkers Baseline 6 Mos 24 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

Pro

porti

on o

f pat

ient

s (%

)

Years on Rx 1 2 3 4 5

n

435 426 339 257 160

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.

105

125

IGF-

I (nm

ol/L

)

Age (yrs)

25

45

65

85

30 40 50 60 70

= monthly SRL = +pegvisomant

Morbidity Improved IGF-I Controlled ~80% Pituitary function Uncompromised Tumor size Shrinkage ~50% Adverse effects Similar to adjuvant Rx

Avoiding other less safe Rx Patient choice

Combined SRL and Pegvisomant

Adapted from: Neggers SJ, et al. J Clin Endocrinol Metab. 2007;92:4598-4601.

Pasireotide µg (bid)

Octreotide 100 µg tid (n=58)

200 (n=21) 400 (n=17) 600(n=20)

P = 0.019

70

60

50

40

30

20

10

0

Pat

ient

s (%

)

GH ≤2.5 µg/L + normal IGF-I GH ≤2.5 µg/L Normal IGF-I

Adverse events (%)

Gastro-intestinal 25 BS 6 HbA1c 5 Diabetes 5

Weckbecker Endocrinol 2003

SSTR1 SSTR2 SSTR3 SSTR4 SSTR5

Ratio OCT/SOM

30 0.4 5 - 35

Adapted from: Van der Hoek J, et al. J Clin Endocrinol Metab. 2004;89:638-645.

GH inhibition %

-75

-100

-50

-25

0

-75

-100

-50

-25

0

octreotide100µg

SOM230250µg

*

n=8

n=3

Pasireotide* Control of Acromegaly

Adapted from: Petersenn S, et al. J Clin Endocrinol Metab. 2010;95:2781-2789. *Not FDA approved

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

0 . 0

0 . 5

0

1 . 5

2 . 0

2 . 5

3 . 0

3 . 5

4 . 0

- 1 . 0 - 0 . 5 0 . 0 0 . 5 1 . 0 1 . 5 2 . 0 2 . 5

83% inhibition of basal GH

Pre dose Basal Secretion

Ser

um G

H µ

g/m

L

Octreolin

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

Octreolin GHRH-Arg

0

10

20

30

40

50

60

70

- 1 . 0 0 . 0 1 . 0 2 . 0 3 . 0 4 . 0 5 . 0 Hours of Study

Pre dose Basal Secretion GHRH-Stimulated

Ser

um G

H n

g/m

L 79% inhibition of GHRH-induced GH OOA

Control

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.

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 controlled Partial response No response

Well controlled No response No response Well controlled

Adapted from: Giustina A, et al. Nat Rev Endocrinol. 2014;10:243-248.