Hot Topics: Cushings Disease and Acromegaly

Mark E Molitch, M.D. Division of Endocrinology, Metabolism & Molecular Medicine Northwester University Feinberg School of Medicine Chicago, IL 60611

Disclosures
Research Support:
Corcept - mifepristone Novartis - Pasireotide, Octreotide Ipsen/Tercica Lanreotide Chiasma Oral Octreotide Endo - Octreotide implants

Consultant
Corcept Novartis Abbott Laboratories

Cushings Disease Treatment

Dopamine agonists Somatostatin analogs

CRH

Pituitary
ACTH

Adrenals
Ketoconazole Mitotane Metyrapone Etomidate

Cortisol

Mifepristone GR Tissues

Adrenal Steroid Inhibition - Ketoconazole

X Side chain cleavage 17-OH X
3-HSD 17-OH 17,20 lyase

X X

3-DH 17,20 lyase

3-DH

21-OH

21-OH

X 11-OH X aldo synthase

X 11-OH

Treatment of Cushings Disease with Ketoconazole

1600 1400 1200 Urinary Free 1000 Cortisol 800 (nmol/24h) 600 400 200 0 Sonino et al
Pre Post

Tabarin et al
Pre Post

Percent Normalized

94%

100%
Sonino et al, Clin Endocrinol1991;35:347 Tabarin et al, Clin Endocrinol1991;34:63

Ketoconazole for Cushings Syndrome

Dosing 200 to 1600 mg daily divided BID or TID Proton pump inhibitor use may impair absorption Side effects: Hepatic toxicity Gastrointestinal symptoms Rash Strong CYP3A4 inhibitor (substrates include amiodarone, carbamazepine, amitriptyline, SSRIs, benzodiazepines, calcium channel blockers, statins, colchicine) Hypogonadism in men Teratogenic

Monitoring Liver function tests Serum and urine cortisol Long-term may escape from control

Dopamine Receptor Expression and Function in Corticotroph Tumors

Dopamine D2 receptors found in 80% of corticotroph tumors Of those with D2 receptors, 100% had significant inhibition of ACTH secretion in vitro with cabergoline Of those with D2 receptors, in vivo 60% had significant reduction of cortisol levels and 40% had normalization of cortisol levels with 1-3 mg cabergoline per week So, 80% x 40% = 32% of all patients (since measurement of D2 receptors not routine) can expect control of hypercortisolism with cabergoline

Pivonello et al., JCEM 2004;89:2452

Effect of Cabergoline at doses of 1-3 mg/week on Urinary Free Cortisol Levels in Patients
1200

Urinary cortisol/24h

900

600

300

0 0 1 Months
Pivonello et al., JCEM 2004;89:2452

Mifepristone
Mifepristone was initially developed as a progesterone receptor antagonist and used widely as an abortifacient (RU486) Mifepristone is also a glucocorticoid receptor antagonist with greater affinity for the receptor than either cortisol or dexamethasone Since 1985, 51 Cushings Syndrome patients treated with Mifepristone had been reported prior to the large, multicenter SEISMIC trial

Mifepristone Mechanism of Action

nucleus nucleus

agonist GR mifepristone

Complex translocates to the nucleus

Mifepristone competes with an agonist for binding to the GR

Complex binds to GRE

GRE

Antagonist-bound GR prevents agonist-bound GR from binding to glucocorticoid response elements (GREs) Antagonist-bound GR/GRE complex does not cause transcription or any downstream effects

Mifepristone SEISMIC Study Design

Screen 42 days

stop Mifepristone

24 week openWeek TreatmentMIFE 300 Safety 24 label study of 6 week 1200 mg/day
D1 Wk6 Wk10 Wk16 Wk24

Screened: 84 Enrolled: 50

50 subjects with Cushings syndrome who failed multi-modality therapy

Completed: 34 Early Termination (ET): 16

Starting dose 300 mg po qd Escalation until Week 10

Mifepristone Main Eligibility Criteria

ACTH-dependent and independent Cushings syndrome Intolerant of or not responsive to other therapy DM2/IGT and/or hypertension At least 2 signs and symptoms of Cushings syndrome No concomitant treatment for Cushings syndrome Stable doses of mitotane allowed in adrenal cancer

Mifepristone Baseline Characteristics (n=50)

Cushings disease - 43 42 failed previous surgery 18 also had pituitary radiation
Average time from radiation 32 7 months

Ectopic ACTH - 4 Adrenal cancer - 3 Mean age - 45 12 yr Females - 35 (70%) 25 with diabetes (C-DM) 21 with hypertension without diabetes (C-HT)

Improvement in Glucose Tolerance on oGTT (C-DM) with Mifepristone

n=25

n=20

*
p=.01
14

Improvement in HbA1c in C-DM with Mifepristone

p<0.001 vs baseline

p<0.001 vs baseline

N=25

N=20

N=22

Decrease in Insulin Levels with Mifepristone (C-DM not on insulin and C-HT)

Subjectsnottakinginsulin(N=24) mean SD

# p= .01 vs baseline * p =.03 vs baseline

Decrease in Weight with Mifepristone

5.7 1.5%
p<0.001 vs Baseline

mean SE

Decrease in Waist Circumference with Mifepristone

Baseline (cm):

122.4

111.3

117.9
0 -2 -4 -6

132.5

111.4

120.4

Mean change from baseline (cm)

0 -2 -4 -6 -8 -10 -12

-8 -10

C-DM (N=19)

C-HT Overall (N=13) (N=32)

-12

C-DM (N=6)

C-HT (N=8)

Overall (N=14)

Females * P<0.001 vs baseline

Males

Decreases in Diastolic BP or BP Medications with Mifepristone in all Subjects with Hypertension at Baseline
n (%) (n=40) Subjects with either 5 mmHg reduction from baseline in DBP OR had a reduction in antihypertensive medications at Week 24/ET Responder Nonresponder 21 (52.5) 19 (47.5)

Quality of Life (SF-36) Improved with Mifepristone

p = .02

p = .01

N= 46 baseline, 40 W24/ET

mean SD

ACTH and Cortisol Dynamics (Cushings disease)

21

Adverse Effects Hypokalemia

Likely due to mineralocorticoid receptor activation in setting of rising cortisol with glucocorticoid receptor blockade Common but generally mild to moderate and associated with alkalosis and edema
3 cases of severe hypokalemia (defined as K 2.5) during treatment Responded well to potassium replacement and spironolactone

Adverse Effects Adrenal Insufficiency

Glucocorticoid withdrawal symptoms frequently seen Two subjects had adrenal insufficiency noted as AE
One treated with dexamethasone One event resolved without glucocorticoid

Five additional subjects had AEs potentially consistent with adrenal insufficiency and were treated with glucocorticoid
Mifepristone was held and restarted at lower dose without AI recurrence

Adverse Effects Endometrial Hyperplasia

Mifepristone has known anti-progestin activity Increases in endometrial thickness in half of the women 5 cases of vaginal bleeding
2 with prolonged bleeding after stopping mifepristone

3 women underwent D&C for non-resolved endometrial thickening after stopping mifepristone

Somatostatin Receptor Subtype mRNA in Corticotroph Adenomas (n=30)

sst/hprt 0.15

Pasireotide targets 4 of 5 sst

0.10

0.05

0.00

sst-1
LJ Hofland et al. Eur J Endocrinol 2005 Batista DL et al. JCEM 2006

sst-2

sst-3

sst-4

sst-5

de Bruin C et al. Rev Endocr Metab Disord 2009 Bruns C et al. Eur J Endocrinol 2002

Pasireotide Study Design

329 patients screened
Core study
Randomization (n = 162)

Extension

Primary efficacy (Normalization of UFC without dose up-titration before 6 months)

n = 82

Screening

Patients with UFCbid 2xULN and less than baseline at month 3 Pasireotide 600 g sc continued at their randomized dose, double blind, until month 6 600 g bid was and were considered nonresponders for the primary efficacy analysis
n = 80

900 g bid (unblinded)*

All other patients were unblinded Washout of other increased by 300 g bid1200 g bid until month 6, Pasireotide 900 g sc bid (unblinded)* meds
900 g bid

dose titration per the dose and investigator

Optional extension phase

Month 1

Day 1

Month 3

Month 6

Month 12

Screening

Double blind

Partially blind

Open label

*For patients who had a mean baseline UFC 2xULN with a 3-month UFC > 2xULN OR For patients who had a mean baseline UFC 1.52xULN with a 3-month UFC above their baseline UFC

Baseline demographics by randomized dose

Overall (n = 162) Mean age, years Female, n (%) Mean time since diagnosis, months Cushings disease status Persistent/recurrent, n (%) De novo, n (%) Previous surgery, n (%) Previous medication, n (%) Previous pituitary irradiation, n (%) 135 (83.3) 27 (16.7) 128 (79.0) 78 (48.1) 7 (4.3) 67 (81.7) 15 (18.3) 64 (78.0) 36 (43.9) 3 (3.7) 68 (85.0) 12 (15.0) 64 (80.0) 42 (52.5) 4 (5.0) 40.2 126 (77.8) 54.0 600 g bid (n = 82) 40.5 62 (75.6) 53.4 900 g bid (n = 80) 39.9 64 (80.0) 54.5

Change in UFC from baseline to month 6

in the 103 patients with baseline and month-6 UFC measurements

2500 1400 UFC (g/24h) 720 540 360 180 0

600 g bid 900 g bid

Baseline UFC Month 6 UFC Month 6 UFC ULN

ULN

Individual patients sorted by baseline UFC

Median percent UFC change from baseline was -47.9% in both groups
Reference

line is the upper limit normal UFC, which is 52.5 g/24h (145 nmol/24h)

Mean UFC over time

543 Mean UFC SE (g/24h) 471 400 326 254 181 109
ULN: 52.5 g/24h (145 nmol/24h)

600 g bid 900 g bid

Similar trends seen for: Serum & salivary cortisol Plasma ACTH

36
n=

0
153 144 132

3
131 123 116

6 Month
111

9
93

12
77

Within 12 months, patients with inadequate biochemical response can be identified with 90% accuracy

Primary Efficacy Results

6-month response: normal UFC without uptitration at 3 months

600g bid N=82

6-month response, n (%) 95% Confidence Interval 12-month response, n (%) 12 (14.6) (7.0, 22.3) 11 (13.4)

900g bid N=80

21 (26.3) (16.6, 35.9) 20 (25.0)

Overall N=162
33 (20.4) (14.2, 26.6) 31 (19.1)

Median percent UFC change from baseline was -47.9% for both groups
900g bid group met the preset statistical criterion for efficacy: the lower bound of the 95% CI for a dose group had to be >15%

UFC Response According to Baseline UFC Level

Higher rate of UFC normalization with lower baseline UFC
Baseline UFC shown as fold elevations above ULN >5x >2x to 5x >1.5 to 2x 1/22 4/39

(8%)
10/40 7/26

600 g bid (n = 82) 900 g bid (n = 80)

(26%)
7/14

1/12

(31%)

0 10 20 30 40 50 60 Patients achieving normal UFC at month 6 (%)

Significant Decrease in Blood Pressure and UFC

450 360 270

Systolic blood pressure (SBP)

135 133 131 129

Mean UFC SE (g/24h)

180 90 0 450 360 270 180 90 0 Mean UFC Mean DBP

B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

127 125 Mean UFC Mean SBP

B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12

Significant change from baseline to month 12 was observed for: SBP -6.1 mmHg

Mean BP SE (mmHg)

123 121 88 87 86 85 84 83 82 81 80

Diastolic blood pressure (DBP)

DBP -3.7 mmHg

Month

Decrease in Weight and UFC

Significant decrease in weight of 6.7 kg from baseline to month 12
Mean UFC (g/24h)
450 360 270 180 90 0 B 0.5 1 1.5 2 2.5 3 4 5 6 Month 7 8 9 10 11 12 Mean UFC Mean weight

Mean weight (kg)

84 82 80 78 76 74 72

Improvement in HRQoL* and UFC

Significant (11.1 points) improvement from baseline to month 12
Mean UFC (g/24h)
450 360 270 180 90 0
B 0.5 1 1.5 2

HRQoL score Mean UFC HRQoL score

54 52 50 48 46 44 42 40 Month
2.5 3 4 5 6 7 8 9 10 11 12

*Measured via CushingQoL (Webb et al. Eur J Endocrinol 2008;158:623)

Pasireotide: Side Effects

Safety of pasireotide was generally similar to other somatostatin analogues, except for hyperglycemia
Most frequently reported AEs were gastrointestinal

As expected with an effective treatment for Cushings disease, some patients (8%) experienced hypocortisolism
Responded to dose reduction and/or temporary corticosteroid substitution

72.8% of patients had at least one hyperglycemiarelated AE,

HbA1c increased in both dose groups

Changes in Glycemia
600 g bid (n=82) 900 g bid (n=80) 150 Mean fasting plasma glucose (mg/dL) 140 130 120 110 100 90 Baseline Day 15 Month 3 Month 6 Month 12

Changes in Glycemia
8 Mean HbA1c (%) 7 6 5
Baseline Month 2 Month 6 Month 12

600 g bid (n=82) 900 g bid (n=80)

Changes in Glycemia
Of 67 patients normoglycemic at baseline, 14 (21%) remained normal, 29 (43%) became prediabetic and 23 (34%) became diabetic during treatment 2 other studies conducted in healthy volunteers Pasireotide reduced incretin & insulin secretion, without affecting insulin sensitivity Treatment with incretin-based antihyperglycemic agents liraglutide and vildagliptin significantly reduced pasireotideinduced hyperglycemia

Combination Drug Therapy

Cushings disease n = 17, sequential medication addition Pasireotide (max 750mcg) Cabergoline (max 0.75mg) Ketoconazole (max 600 mg)

Feelders, et al NEJM (2010) 362:1846

Combination Drug Therapy

11 Patients with severe, refractory Cushings Disease treated with high-dose therapy combining mitotane (3.05.0 g/24 h), metyrapone (3.04.5 g/24 h), and ketoconazole (400 1200 mg/24 h) concomitantly. Kamenick P et al. JCEM 2011;96:2796

Cushings Summary & Conclusions

Ketoconazole remains the mainstay of medical treatment of Cushings syndrome Cabergoline may be tried in patients with Cushings disease Other current therapies, such as metyrapone, mitotane much less successful Mifepristone offers high success clinically and metabolically but may be difficult to use because of difficulty in titrating dose and adverse effects of adrenal insufficiency and menorrhagia Pasireotide may be helpful in small percentage of patients with Cushings disease but has a major adverse effect of hyperglycemia Combination therapy may have a role in difficult to manage cases
41

Medical Therapy for Acromegaly

Dopamine Agonists bromocriptine cabergoline Somatostatin Analogs octreotide lanreotide GH Receptor Antagonist pegvisomant

Medical Therapy for Acromegaly

Somatostatin Analogs octreotide lanreotide GH Receptor Antagonist pegvisomant

Effects of Adjunctive Therapy With Cabergoline Following Surgery and/or Irradiation on IGF-I Levels in Patients With Acromegaly
Series Colao (1997) Abs (1998) Cozzi (1998) Moyes (2008) TOTAL
Colao et al., JCEM. 1997;82:518. Abs et al., JCEM. 1998;83:374. Cozzi et al., Eur J Endocrinol. 1998;139:516. Moyes et al., Eur J Endocrinol 2008;159:541.

N 11 64 18 15 108

% with Normal IGF-I 0 39 27 33 32

Somatostatin Analogs
Human somatostatin
ala ala gly gly cys cys lys lys asn asn phe phe phe phe trp trp lys lys thr thr

Octreotide
D D phe phe

cys cys

phe phe
D D trp trp

Amino acids essential for receptor binding

cys cys ser ser thr thr phe phe

lys lys
Thr Thr ol ol

cys cys

thr thr

Lanreotide
D D bnal bnal

cys cys

tyr tyr
D D trp trp

inhibits multitude of hormones T 3 minutes binds all 5 receptor sub-types

Thr Thr ol ol

lys lys cys cys val val

Comparison of Octreotide LAR to Lanreotide Autogel

Summary of 5 Studies

(n=75) (n=75)

Murray RD, Melmed S. JCEM 2008;93:2957

Equivalent Efficacy of Octreotide LAR and Lanreotide Depot

32 patients switched from octreotide 20 or 30 mg monthly to 90 or 120 mg lanreotide Depot

Salvatori et al., Pituitary 2010;13:115

Comparison of Approved Somatostatin Analogs

Long- Lanreotide acting depot octreotide

Octreotide LAR Requires reconstitution 10, 20, 30 mg IM q 4 wks (~1.5 inch needle) Volume; 2-2.5 mL Healthcare professional administration

Lanreotide Depot Ready to use, prefilled syringe 60, 90, 120 mg Deep SC q 4 wks (~3/4 inch needle) Volume; 0.3-0.5 mL Self or partner administration possible

Product Information Somatuline Depot, 2007. Bevan JS, et al. Clin Endocrinol (Oxf). 2008;68(3):343-349. Product Information Sandostatin LAR Depot, 2006.

Tumor Changes After Octreotide Therapy Expressed as a Percentage of the Pretreatment Volume in 20 Macroadenomas
Percentage of Original Size

120% 100% 80% 60% 40% 20% 0%

Baseline 12 Weeks 24 Weeks 48 Weeks
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.

Does Pre-op Somatostatin Analog Treatment Improve Surgical Outcomes?

Negative Studies
Author Kristof Biermasz Plockinger Losa Abe Journal Acta Neuro JCEM Acta Neuro J Neurosurg EJE Year 1999 1999 2005 2006 2001 Author Barkan Stevenaert Colao *Carlsen *Mao

Positive Studies
Journal JCEM Acta Endo JCEM JCEM Eur J Endo Year 1988 1993 1997 2008 2010

*Randomized, controlled trials

Primary Therapy: Octreotide (SQ)

6 No Previous Treatment n=25 5 U/L) 4 3 2 1 0 Previous Treatment n=80

Mean IGF-I (x10

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Treatment Duration (years)

Newman CB, et al. J Clin Endocrinol Metab. 1998;83:3034-40.

Summary of Surgical Debulking on the Responsiveness to Somatostatin Analogs

Study Colao1 Jallad2 Petrossi3 Totals (control) Normal GH Pre-op 12/86 4/11 7/24 23/121 (19%) Normal GH Postop 49/86 5/11 13/24 67/121 (55%) Normal IGF1 Pre-op 9/86 0/11 8/19 17/121 (14%) Normal IGF1 Post-op 48/86 9/11 18/23 75/121 (62%)

1 2

Colao et al. JCEM. 2006;91:85-92. Jallad, et al. Clin Endo. 2007;67:310-315. 3 Petrossians, et al. Eur J Endo. 2005;152:61-66.

Benefits of Adding Cabergoline to Somatostatin Analogs

60 40

IGF-1 % change

20 0 -20 -40 -60 -80 -100

IGF-I percent change during SA + CAB compared to SA alone

4 5 6 7 8 8 8 8 8 9 12 16 17 20 21 23 24 50 60

Patients are ranked by PRL (g/l) level shown on the x-axis

Cozzi et al Clin Endocrinol 2004;61:209

Extension of Time Between 20 mg Octreotide LAR Doses in Patients With Acromegaly

8 7

Final Dose Frequency

No. of Patients

6 5 4 3 2 1 0

10

12

off

Weeks Between Injections

Turner et al Clin Endocrinol 2004;61:224

Pegvisomant
IGF-I at Baseline and after 12 months
2500

(N=90)
2000

Serum IGF-I (ng/mL) 1500

1000 500

97% normalisation of IGF-I

16-24
van der Lely et al Lancet 2001:358;1754

25-39 40-54 Age (years)

55+

Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for > 6 Months
4 3 no radiation radiation

change 2 in 1 volume (cm3) 0

-1 -2 6
van der Lely et al Lancet 2001:358;1754

12

18

24

30

36

Time (months)

Tumor Enlargement While Receiving Pegvisomant

9 patients had tumor enlargement while taking Pegvisomant
1 patient, no RT, had increase in tumor volume from 1.61 cc to 1.93 cc. 6 patients had progressive growth before initiating pegvisomant. 2 patients with stable tumors while on octreotide experienced enlargement after octreotide discontinuation but remained stable on long-term pegvisomant therapy.
Jimenez et al., Eur J Endocrinol. 2008;159:517

Weekly Pegvisomant Added to Somatostatin Analogs in Resistant Patients Normalizes IGF-I

125 105 Monthly somatostatin analog Weekly added pegvisomant 40 mg* n=31 Therapy (35149 wk)

IGF-I (nmol/L)

85 65 45 25

30

40

Age (yrs)

50

60

70

*9 pts required > 100 mg/wk & 4 pts required 160 mg/wk
Neggers SJ, et al. JCEM 2007;92:4598

German Pegvisomant Observational Study

20/371 with elevated (>3x Nl) transaminases
7 had gall stones

Drug withdrawn in 7 with normalization in 6

Restarted in 3 with no reappearance of elevated transaminases

Drug continued in 11 with spontaneous normalization of elevated transaminases in 10

Buchfelder et al., Eur J Endocrinol 2009;161:S3

PegvisomantinducedLiverInjuryRelatedtoUGT1A1*28 PolymorphismofGilbertsSyndrome
Gilbertssyndrome unconjugatedhyperbilirubinemiadue todecreasedhepaticglucuronidationactivity Uridinediphosphate5glucuronosyltransferase1A1 (UGT1A1)conjugatesbilirubin. TheUGT1A1*28polymorphismhas2extrabasesin promoterregion,resultingina70%reductionin transcriptionalactivity&thereforereduced glucuronidationactivity. Instudyof36acromegalicpatientstreatedwith pegvisomantinSpain 10pts(28%)developedLFTabnormalities 43%ofCarriersofUGT1A1*28hadabnormalLFTs 7%ofwildtypeUGT1A1hadabnormalLFTs Alsomorefrequentinmalesthanfemales
Bernabeuetal.,JCEM2010;95:2147

Investigational Drugs
Vapreotide Dopastatin Octreotide Implant Pasireotide Octreolin

Investigational Drugs

Octreotide Implant (84 mg) Suppression of GH and IGF-1

GH
20 18 16 14 12 10 8 6 4 2 0 500 400

IGF1

300

200

10

15

20

25

100

10

15

20

25

Weeks

Weeks
FromChieffoCetal,ENDO2011 EndoPharmaceuticals

Pasireotide (SOM230) Effects on GH and IGF-1

Petersenn S et al, JCEM 95:2781, 2010

Octreolin
Transient Permeability Enhancer (TPE)
Induces increased intestinal paracellular permeation

Chiasma

Octreolin Inhibits GH Secretion in Rats

Chiasma

Octreolin Pharmacokinetic Results in Normal Subjects

Chiasma

Summary: Acromegaly
Somatostatin analogs - remain the mainstay of medical therapy
Depot somatostatin implants Pasireotide Oral somatostatin

Cabergoline
Worth a try in mild cases Often helpful added to somatostatin analogs

Pegvisomant
Can switch from somatostatin analogs Can add to somatostatin analogs (epecially if large tumor residual) Watch out for transaminase abnormalities (especially if have Gilberts syndrome)

Thank You