Hot Topics: Cushing’s Disease and Acromegaly
Mark E Molitch, M.D.Division of Endocrinology, Metabolism & Molecular Medicine
Northwester University Feinberg School of MedicineChicago, IL 60611
Disclosures• Research Support:
Corcept - mifepristone Novartis - Pasireotide, OctreotideIpsen/Tercica – LanreotideChiasma – Oral OctreotideEndo - Octreotide implants
• ConsultantCorceptNovartisAbbott Laboratories
CRH
ACTH
Cortisol
Adrenals
PituitaryDopamine agonists
Somatostatin analogs
KetoconazoleMitotane
MetyraponeEtomidate
Mifepristone
GR
Cushing’s Disease Treatment
Tissues
Adrenal Steroid Inhibition - Ketoconazole
X
X
XX
X
Side chain cleavage
3β-HSD
17α-OH
17α-OH3β-DH
21-OH 21-OH
11β-OH 11β-OH
17,20 lyase
17,20 lyase3β-DH
aldo synthaseX
X
X
X
X
Treatment of Cushing’s Disease with Ketoconazole
0200400600800
1000120014001600
Urinary Free Cortisol
(nmol/24h)
Sonino et al Tabarin et alPre Post Pre Post
Percent Normalized 94% 100%
Sonino et al, Clin Endocrinol1991;35:347Tabarin et al, Clin Endocrinol1991;34:63
Ketoconazole for Cushing’s Syndrome
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
Dosing
200 to 1600 mg daily divided BID or TID
Proton pump inhibitor use may impair absorption
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
0
300
600
900
1200
0 1 2 3
Months
Uri
na
ry c
ort
iso
l/2
4h
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 Cushing’s Syndrome patients treated with Mifepristone had been reported prior to the large, multicenter SEISMIC trial
Mifepristone Mechanism of Action
Mifepristone competes with an agonist for binding to the GR
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
agonist
GR
Complextranslocates
to the nucleus
nucleus
Complex bindsto GRE
nucleus
MifepristoneSEISMIC Study Design
• 24 week open label study of MIFE 300 –1200 mg/day
• 50 subjects with Cushing’s syndrome who failed multi-modality therapy
Starting dose 300 mg po qd Escalation until Week 10
Screen 42 days
D1 Wk6 Wk10 Wk16
24 Week Treatment Safety 6 week
Wk24
stopMifepristone
Screened: 84Enrolled: 50
Completed: 34Early Termination (ET): 16
Mifepristone Main Eligibility Criteria• ACTH-dependent and independent
Cushing’s syndrome• Intolerant of or not responsive to other therapy• DM2/IGT and/or hypertension• At least 2 signs and symptoms of Cushing’s
syndrome• No concomitant treatment for Cushing’s
syndromeStable doses of mitotane allowed in adrenal cancer
Mifepristone Baseline Characteristics (n=50)
• Cushing’s disease - 4342 failed previous surgery18 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
14
p=.01
*
n=25
n=20
Improvement in HbA1c in C-DM with Mifepristone
p<0.001vs baseline
N=25 N=22N=20
p<0.001 vs baseline
Decrease in Insulin Levels with Mifepristone(C-DM not on insulin and C-HT)
# p= .01 vs baseline* p =.03 vs baseline
## **
Subjects not taking insulin (N=24)
mean ± SD
Decrease in Weight with Mifepristone
↓ 5.7 ± 1.5%p<0.001
vs Baseline
mean ± SE
-12
-10
-8
-6
-4
-2
0
Decrease in Waist Circumference with MifepristoneM
ean
chan
ge fr
om b
asel
ine
(cm
)
C-DM(N=19)
C-HT(N=13)
Overall(N=32)
Females
-12
-10
-8
-6
-4
-2
0
C-DM(N=6)
C-HT(N=8)
Overall(N=14)
Males* P<0.001 vs baseline
122.4 111.3 117.9 132.5 111.4 120.4Baseline (cm):
**
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 21 (52.5)Nonresponder 19 (47.5)
Quality of Life (SF-36) Improved with Mifepristone
N= 46 baseline, 40 W24/ET
p = .01p = .02
mean ± SD
ACTH and Cortisol Dynamics (Cushing’s disease)
21
Adverse EffectsHypokalemia
• 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 treatmentResponded well to potassium replacement and spironolactone
Adverse EffectsAdrenal Insufficiency
• Glucocorticoid withdrawal symptoms frequently seen
• Two subjects had adrenal insufficiency noted as AE
One treated with dexamethasoneOne 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 EffectsEndometrial Hyperplasia
• Mifepristone has known anti-progestin activity
• Increases in endometrial thickness in half of the women
• 5 cases of vaginal bleeding2 with prolonged bleeding after stopping mifepristone
• 3 women underwent D&C for non-resolved endometrial thickening after stopping mifepristone
sst-1 sst-2 sst-3 sst-4 sst-50.00
0.05
0.10
0.15
sst/hprt
Pasireotidetargets 4 of 5 sst
de Bruin C et al. Rev Endocr Metab Disord 2009Bruns C et al. Eur J Endocrinol 2002
Somatostatin Receptor Subtype mRNA in Corticotroph Adenomas (n=30)
LJ Hofland et al. Eur J Endocrinol 2005Batista DL et al. JCEM 2006
Pasireotide Study Design329 patients screened
Core study
900 μg bid(unblinded)*
1200 μg bid(unblinded)*
Month 12
Open label
Extension
Day 1
Screening
Month –1
Screening
Washoutof other meds
Partially blind
Month 6
Primary efficacy(Normalization of UFC without dose up-titration before 6 months)
600 μg bid
900 μg bid
*For patients who had a mean baseline UFC ≥ 2xULN with a 3-month UFC > 2xULN ORFor patients who had a mean baseline UFC 1.5–2xULN with a 3-month UFC above their baseline UFC
Randomization(n = 162)
Pasireotide 900 μg sc bid
Pasireotide 600 μg sc bid
Month 3
Double blind
n = 80
n = 82
↓↑ dose titrationper investigator
Optional extension phase
Patients with UFC ≤ 2xULN and less than baseline at month 3 continued at their randomized dose, double blind, until month 6
All other patients were unblinded and the dose wasincreased by 300 μg bid until month 6, and were considered
nonresponders for the primary efficacy analysis
Baseline demographics by randomized dose
Overall
(n = 162)
600 µg bid
(n = 82)
900 µg bid
(n = 80)
Mean age, years 40.2 40.5 39.9
Female, n (%) 126 (77.8) 62 (75.6) 64 (80.0)
Mean time since diagnosis, months 54.0 53.4 54.5
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)
2500
Change in UFC from baseline to month 6in the 103 patients with baseline and month-6 UFC measurements
Individual patients sorted by baseline UFC
UFC
(μg/
24h)
0
180
360
540
720
1400
600 µg bid900 µg bid
ULN†
Baseline UFCMonth 6 UFCMonth 6 UFC ≤ ULN*
†Reference line is the upper limit normal UFC, which is 52.5 μg/24h (145 nmol/24h)
Median percent UFC change from baseline was -47.9% in both groups
Mean UFC over time
Month
Mea
n U
FC ±
SE (μ
g/24
h)
0 3 6 9 12
543
471
400
326
254
181
109
36
900 µg bid600 µg bid
ULN: 52.5 µg/24h (145 nmol/24h)
n = 153 144 132 131 123 116 111 93 77
Similar trends seen for:• Serum & salivary cortisol• Plasma ACTH
Within 1–2 months, patients with inadequate biochemical responsecan be identified with 90% accuracy
900µg bid group met the preset statistical criterion for efficacy:the lower bound of the 95% CI for a dose group had to be >15%
600µg bid
N=82
900µg bid
N=80OverallN=162
6-month response, n (%) 12 (14.6) 21 (26.3) 33 (20.4)
95% Confidence Interval (7.0, 22.3) (16.6, 35.9) (14.2, 26.6)
12-month response, n (%) 11 (13.4) 20 (25.0) 31 (19.1)
Primary Efficacy Results6-month response: normal UFC without uptitration at 3 months
Median percent UFC change from baseline was -47.9% for both groups
UFC Response According to Baseline UFC Level
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 (%)
Higher rate of UFC normalization with lower baseline UFC
0 10 20 30 40 50 60
>1.5 to ≤2x
>2x to ≤5x
>5x 1/224/39
10/407/26
7/141/12 (31%)
(26%)
(8%)
450
360
270
180
90
0
450
360
270
180
90
0
135
133
131
129
127
125
123
121B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12
Mea
n U
FC ±
SE (μ
g/24
h) Mean B
P ±SE (m
mH
g)
Month
Systolic blood pressure (SBP)
888786858483828180
B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12
Mean SBPMean UFC
Diastolic blood pressure (DBP)
Significant Decrease in Blood Pressure and UFC
Significant change from baseline to month 12 was observed for:
SBP -6.1 mmHg
DBP -3.7 mmHg
Mean DBPMean UFC
84
82
80
78
76
74
72
450
360
270
180
90
0B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12
Month
Mean UFC (μg/24h) Mean weight (kg)Mean UFCMean weight
Decrease in Weight and UFCSignificant decrease in weight of 6.7 kg
from baseline to month 12
Month
Improvement in HRQoL* and UFC
B 0.5 1 1.5 2 2.5 3 4 5 6 7 8 9 10 11 12
Mean UFC (μg/24h) HRQoL score450
360
270
180
90
0
54
52
50
48
46
44
42
40
Mean UFCHRQoL score
Significant (11.1 points) improvement from baseline to month 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 Cushing’s disease, some patients (8%) experienced hypocortisolism– Responded to dose reduction and/or temporary
corticosteroid substitution• 72.8% of patients had at least one hyperglycemia-
related AE, – HbA1c increased in both dose groups
Changes in Glycemia
Mean fastingplasma glucose(mg/dL)
600 µg bid (n=82)900 µg bid (n=80)
90
100
110
120
130
140150
Baseline Day 15 Month 3 Month 6 Month 12
Changes in Glycemia
Mean HbA1c
(%)600 µg bid (n=82)900 µg bid (n=80)
5
6
7
8
Baseline Month 2 Month 6 Month 12
Changes in Glycemia• Of 67 patients normoglycemic at baseline, 14
(21%) remained normal, 29 (43%) became pre-diabetic 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 pasireotide-induced hyperglycemia
Combination Drug Therapy
Feelders, et al NEJM (2010) 362:1846
Cushing’s disease n = 17, sequential medication addition
Pasireotide(max 750mcg)
Cabergoline(max 0.75mg)
Ketoconazole(max 600 mg)
Combination Drug Therapy
11 Patients with severe, refractory Cushing’s Diseasetreated with high-dose therapy combining mitotane (3.0–5.0 g/24 h), metyrapone (3.0–4.5 g/24 h), and ketoconazole (400–1200 mg/24 h) concomitantly. Kamenický P et al. JCEM 2011;96:2796
Cushing’s Summary & Conclusions• Ketoconazole remains the mainstay of medical
treatment of Cushing’s syndrome• Cabergoline may be tried in patients with
Cushing’s 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 Cushing’s 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• cabergolineSomatostatin Analogs• octreotide• lanreotideGH Receptor Antagonist• pegvisomant
Medical Therapy for Acromegaly
Somatostatin Analogs• octreotide• lanreotideGH Receptor Antagonist• pegvisomant
Effects of Adjunctive Therapy With Cabergoline Following Surgery and/or Irradiation on IGF-I Levels in Patients With
Acromegaly
Series N % with Normal IGF-I
Colao (1997) 11 0Abs (1998) 64 39
Cozzi (1998) 18 27Moyes (2008) 15 33
TOTAL 108 32
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.
alaala
thrthr
trptrp
glygly cyscys lyslys asnasn phephe phephe
lyslys
phephethrthrcyscys serser
Human somatostatin
Amino acids essential
for receptor binding
Somatostatin Analogs
• inhibits multitude of hormones
• T ½ 3 minutes
•binds all 5 receptor sub-typesvalval
DtrpD
trp
Dbnal
Dbnal cyscys tyrtyr
lyslys
cyscysThrolThrol
Lanreotide
thrthr
DtrpD
trp
Dphe
Dphe cyscys phephe
lyslys
cyscysThrolThrol
Octreotide
Comparison of Octreotide LAR to Lanreotide AutogelSummary 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
Octreotide LAR Lanreotide DepotRequires
reconstitutionReady to use,
prefilled syringe
10, 20, 30 mg 60, 90, 120 mg
IM q 4 wks (~1.5 inch needle)
Deep SC q 4 wks (~3/4 inch needle)
Volume; 2-2.5 mL Volume; 0.3-0.5 mL
Healthcare professional
administration
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.
Long-acting
octreotide
Lanreotide depot
Tumor Changes After Octreotide Therapy Expressed as a Percentage of the Pre-
treatment Volume in 20 Macroadenomas
0%
20%
40%
60%
80%
100%
120%
Baseline 12 Weeks 24 Weeks 48 Weeks
Bevan J. et al., J Clin Endocrinol Metab. 2002; 87:4554-4563.
Perc
enta
ge o
f Orig
inal
Siz
e
Author Journal Year
Kristof Acta Neuro 1999
Biermasz JCEM 1999
Plockinger Acta Neuro 2005
Losa J Neurosurg 2006
Abe EJE 2001
Author Journal Year
Barkan JCEM 1988
Stevenaert Acta Endo 1993
Colao JCEM 1997
*Carlsen JCEM 2008
*Mao Eur J Endo 2010
*Randomized, controlled trials
Negative Studies Positive Studies
Does Pre-op Somatostatin Analog Treatment Improve Surgical Outcomes?
Primary Therapy: Octreotide (SQ)
•Mea
n IG
F-I (
x103
U/L
)No Previous Treatment n=25
Previous Treatment n=80
6
4
2
00 0.5 1.0 1.5 2.0
Treatment Duration (years)
2.5 3.0 3.5
5
3
1
Newman CB, et al. J Clin Endocrinol Metab. 1998;83:3034-40.
Summary of Surgical Debulking on the Responsiveness to Somatostatin Analogs
StudyNormal GH
Pre-op
Normal GH Post-
op
Normal IGF1
Pre-op
Normal IGF1 Post-op
Colao1 12/86 49/86 9/86 48/86
Jallad2 4/11 5/11 0/11 9/11
Petrossi3 7/24 13/24 8/19 18/23
Totals (control)
23/121 (19%)
67/121 (55%)
17/121 (14%)
75/121 (62%)
1Colao et al. JCEM. 2006;91:85-92.2Jallad, et al. Clin Endo. 2007;67:310-315.3Petrossians, et al. Eur J Endo. 2005;152:61-66.
Benefits of Adding Cabergoline to Somatostatin Analogs
Cozzi et al Clin Endocrinol 2004;61:209
Patients are ranked by PRL (µg/l)
level shown on the x-axis
IGF-I percentchange
during SA +CAB compared
to SA alone
60
40
20
0
-20
-40
-60
-80
-100
4 5 6 7 8 8 8 8 8 9 12 16 17 20 21 23 24 50 60
IGF-
1 %
cha
nge
Extension of Time Between 20 mg Octreotide LAR Doses in Patients With
Acromegaly
Turner et al Clin Endocrinol 2004;61:224
Weeks Between Injections
Final Dose Frequency8
7
6
5
4
3
2
1
04 6 8 10 12 off
No.
of P
atie
nts
Serum IGF-I(ng/mL)
500
1000
1500
2000
2500
Age (years)55+16-24 25-39 40-54
PegvisomantIGF-I at Baseline and after 12 months
(N=90)
van der Lely et al Lancet 2001:358;1754
97% normalisation of IGF-I
-2
-1
0
1
2
3
4
6 12 18 24 30 36
Time (months)
change in
volume (cm3)
no radiationradiation
Tumor Volume Changes in 92 Patients Receiving Daily Pegvisomant for > 6 Months
van der Lely et al Lancet 2001:358;1754
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
Neggers SJ, et al. JCEM 2007;92:4598
25
45
65
85
105
125
IGF-
I (nm
ol/L
)
30 40 50 60 70Age (yrs)
Monthly somatostatin analogWeekly added pegvisomant 40 mg*
Weekly Pegvisomant Added to Somatostatin Analogs in Resistant Patients Normalizes IGF-I
*9 pts required > 100 mg/wk & 4 pts required 160 mg/wk
n=31 Therapy (35–149 wk)
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
Pegvisomant‐induced Liver Injury Related to UGT1A1*28 Polymorphism of Gilbert’s Syndrome
• Gilbert’s syndrome – unconjugated hyperbilirubinemia due to decreased hepatic glucuronidation activity
• Uridine diphosphate‐5’glucuronosyltransferase 1A1 (UGT1A1) conjugates bilirubin.– The UGT1A1*28 polymorphism has 2 extra bases in
promoter region, resulting in a 70% reduction in transcriptional activity & therefore reduced glucuronidation activity.
• In study of 36 acromegalic patients treated with pegvisomant in Spain– 10 pts (28%) developed LFT abnormalities– 43% of Carriers of UGT1A1*28 had abnormal LFT’s– 7% of wild type UGT1A1 had abnormal LFT’s– Also more frequent in males than females
Bernabeu et al., JCEM 2010;95:2147
Investigational Drugs
VapreotideDopastatinOctreotide ImplantPasireotideOctreolin
Investigational Drugs
GH
Weeks0 5 10 15 20 25
02468101214161820
IGF‐1
Weeks0 5 10 15 20 25
100
200
300
400
500
From Chieffo C et al, ENDO 2011
Octreotide Implant (84 mg) Suppression of GH and IGF-1
Endo Pharmaceuticals
Petersenn S et al, JCEM 95:2781, 2010
Pasireotide (SOM230) – Effects on GH and IGF-1
Transient Permeability Enhancer (TPE)Induces increased intestinal paracellular permeation
Octreolin
Chiasma
Chiasma
Octreolin Inhibits GH Secretion in Rats
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 Gilbert’s syndrome)
Thank You
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