Download - ECE2016 pituitary update

New developments in the medical treatment of
Cushing’s syndrome
European Congress of Endocrinology 2016
Richard Feelders
Erasmus MC, Rotterdam, The Netherlands
Cushing’s syndrome
• ACTH-dependent:
• pituitary adenoma
• ectopic ACTH production
• ACTH-independent:
• adrenal adenoma
• bilateral adrenal hyperplasia
• adrenal carcinoma
Cushing’s syndrome: morbidity
Neuropsychiatric
disturbances
• Depression
Endocrine changes
• Psychosis
Metabolic syndrome
• Hypothyroidism
• Impaired memory
• Central obesity
• Insomnia
• Hypertension
• Hypogonadism
• Adrenal androgens 
• Diabetes Mellitus
• Dyslipidemia
Body composition
Hypercoagulability
• Altered fat distribution
• Venous thrombosis
• Muscle and skin atrophy
• Pulmonary embolism
• Osteoporosis
Cushing’s disease: phenotype
Dog and Owner Look Alikes
Mortality in Cushing’s disease
First author, year
SMR cure
SMR persistent CD
• Lindholm, 2001
0.31
5.1
• Hammer, 2004
1.18
2.8
• Dekkers, 2007
1.8
4.38
• Clayton, 2011
3.3
16
• Hassan-Smith, 2012
2.47
4.12
• Ntali, 2013
10.8
9.9
Treatment of Cushing’s disease
Before
After
Courtesy Dr. H.S. Kooistra,
UMCU, The Netherlands
Treatment options after (first) surgical failure
• Second transsphenoidal surgery
• Radiotherapy
• Bilateral adrenalectomy
• Medical therapy
Indications for medical therapy
• Surgical failure
• Bridging therapy after radiotherapy
• Severe complications of hypercortisolism
• Pretreatment before pituitary surgery
• Primary medical therapy
Feelders  Hofland JCEM 2013
Drug targets in Cushing’s disease
Bone
Anterior pituitary
ACTH
sst2
Smooth muscle
Adrenal
cortisol
GR
Liver
D2R
17-20 lyase
Adipose tissue
sst5
Somatostatin analogs
Dopamine agonists
Ketoconazole
Etomidate
Metyrapone
Mitotane
(LCI699)
Glucocorticoid
receptor antagonists
Mifepristone
Feelders  Hofland JCEM 2013
Adrenal blocking drugs
• Ketoconazole
• Metyrapone
• Mitotane
• New developments:
• Fluconazole
• LCI699 (Osilodrostat)
• COR-003 (Levoketoconazole)
Feelders  Hofland JCEM 2013
Effects of ketoconazole and fluconazole in vitro
Normal adrenal cortex; 96h.
150
100
Cortisol (% control)
Cortisol (% control)
150
*
50
**
0
100
**
50
**
**
**
0
C
5
1
0.5
0.1
[Ketoconazole] ( M)
0.05
C
1000
500
100
50
10
[Fluconazole] ( M)
van der Pas et al. J Endocrinol 2012
Pilot study with LCI699 (Osilodrostat)
LCI699 dose escalation
Washout
Mean UFC ± SE (fold ULN)
7
At day 70:
6

All 12 patients had normalized
UFC or ≥50% reduction

11/12 had normal UFC

UFC normalized in all
12 patients at least once
5
4
3
2
1
0
1
14
28
42
Time (days)
56
70
84
Bertagna et al. JCEM 2014
Effects of LCI699, metyrapone, and ketoconazole on
cortisol production in HAC-15 cells
Basal
ACTH stimulated
A
B
150
Ratio cortisol/DNA
(% ACTH stimulation)
Ratio cortisol/DNA
(% control)
150
100
50
0
100
LCI699
Metyrapone
Ketoconazole
50
0
C
0.01
0.1
1
A
Concentration ( M)
0.01
0.1
1
Concentration ( M)
IC values
50
p-value vs LCI699
LCI699
0.038 µM (0.031-0,048)
-
Metyrapone
0.084 µM (0.0602-0.117)
Ketoconazole
0.670 µM (0.473-0.950)
IC values
50
p-value vs LCI699
LCI699
0.057 µM (0.046-0.070)
-
p < 0.0001
Metyrapone
0.087 µM (0.067-1.07)
p = 0.0148
p < 0.0001
Ketoconazole
0.946 µM (0.671-1.333)
p < 0.0001
Creemers at al. ESE 2016
Effects of LCI699, metyrapone, and ketoconazole on
cortisol production in primary adrenal cultures
LCI699
Metyrapone
150
Cortisol (nmol/L)
% control
Cortisol (nmol/L)
% control
100
50
B
150
Cortisol (nmol/L)
% control
A
150
100
50
0
0
C
0.01
0.1
1
50
value
p-value vs LCI699
C
100
50
0
C
0.01
0.1
1
[Metyrapone] ( M)
[LCI699] (M)
Mean IC
Ketoconazole
C
0.01
0.1
1
[Ketoconazole] ( M)
LCI699
Metyrapone
Ketoconazole
0.066 µM (0.046-0.096)
0.128 µM (0.0405-0.406)
0.171 µM (0.082-0.36)
-
p = 0.1197
p = 0.0414
Creemers at al. ESE 2016
Effects of LCI699, metyrapone, and ketoconazole on
cortisol production in primary adrenal cultures
LCI699
Metyrapone
A
150
150
Ketoconazole
B
150
C
100
Cortisol (nmol/L)
% control
Cortisol (nmol/L)
% control
Cortisol (nmol/L)
% control
Poster GP26
100
LCI699 is a Potent Inhibitor of Cortisol
Production in Vitro
50
50
Creemers S et al.
0
0
C
0.01
0.1
1
100
50
0
C
0.01
0.1
1
[Metyrapone] ( M)
[LCI699] (M)
C
0.01
0.1
1
[Ketoconazole] ( M)
Guided poster tour, Tuesday 31/5 12.45 - 13.45 h
Mean IC
50
value
p-value vs LCI699
LCI699
Metyrapone
Ketoconazole
0.066 µM (0.046-0.096)
0.128 µM (0.0405-0.406)
0.171 µM (0.082-0.36)
-
p = 0.1197
p = 0.0414
Creemers at al. ESE 2016
Phase III study (LINC 3) is ongoing to evaluate the efficacy
and safety of osilodrostat in a larger population
Courtesy Novartis
LINC 4 will evaluate the efficacy of osilodrostat versus
placebo
Courtesy Novartis
Levoketoconazole, the 2S, 4R enantiomer of ketoconazole, may
provide better safety and efficacy than racemic ketoconazole
Ketoconazole (racemic mixture)
Compared to racemic ketoconazole:
•
stronger inhibition of Cyp11B1
•
less induction of cholestasis via
inhibition of hepatic Cyp7A
•
less hepatic exposure
Levoketoconazole
COR-003 (Levoketoconazole) Phase III trial
 Single-arm, open-label study
 90 patients with endogenous Cushing’s syndrome
◼ ~ 90 sites globally
◼ 60 activated
sites
Primary endpoint: UFC level measured
DOSE TITRATION:
2 to 21 weeks
MAINTENANCE:
6 months
Titrate in 150 mg increments up to max
600 mg 2x daily until UFC
normalization is achieved
EXTENDED EVALUATION:
6 months
Maintain UFC normalization with
fixed therapeutic dose
Primary endpoint
Responder rate (normalized 24-hour urinary free cortisol (UFC) at 6
months maintenance without dose increase)
Key secondary
endpoints
Clinical signs and symptoms, HbA1c and glucose, blood pressure, lipid
profile, CRP, weight, quality of life measures
https://www.clinicaltrials.gov; NCT01838551
Courtesy Strongbridge Biopharma
Drug targets in Cushing’s disease
Bone
Anterior pituitary
ACTH
sst2
Smooth muscle
Adrenal
cortisol
GR
Liver
D2R
17-20 lyase
Adipose tissue
sst5
Somatostatin analogs
Dopamine agonists
Ketoconazole
Etomidate
Metyrapone
Mitotane
(LCI699)
Glucocorticoid
receptor antagonists
Mifepristone
Feelders  Hofland JCEM 2013
Somatostatin and dopamine receptors
Pituitary
Somatostatin receptor
(sst2,sst5)
G
Dopamine receptor
(D2)
G
Inhibition of ACTH production
Feelders  Hofland JCEM 2013
Pasireotide: universal somatostatin analogue
Pasireotide
sst/hprt
0.15
0.10
0.05
0.00
sst 1
sst 2
sst 3
sst 4
sst 5
Feelders et al. Nat Rev Drug Discov 2012
Phase III trial with pasireotide sc (n=162)
Average UFC  50 %
Normal UFC in 15 % and 26 %
Colao et al. NEJM 2012
Phase III trial with pasireotide LAR (n=150)
Primary efficacy endpoint
UFC ≤ ULN
30 mg/28 days
Washout
of other
medicines
RANDOMIZATION
Pasireotide LAR
10 mg/28 days
10 mg/28 days
↓Dose for safety
(30 to 10 mg or 10 to
5 mg)
40 mg/28 days
Pasireotide LAR
30 mg/28 days
Month -1
Day 1
Screening
↑↓ dose titration
30 mg/28 days
Month 4
Double blind
Month 7
Month 9
Month 12
Partial blind
Lacroix et al. ENDO 2016. Poster # SAT546
Individual UFC values from baseline to month 7
Pasireotide LAR 30 mg (n=76)
1700
1700
1600
1600
1500
1500
1400
1400
1300
1300
1200
1200
mUFC(nmol/d)
mUFC(nmol/d)
Pasireotide LAR 10 mg (n=74)
1100
1000
900
800
700
1100
1000
900
800
700
600
600
500
500
400
400
300
300
200
200
100
100
0
0
Baseline value
Month 7 value
Baseline value
Month 7 value
Lacroix et al. ENDO 2016. Poster # SAT546
Primary efficacy analysis
Primary efficacy endpoint was met in both pasireotide LAR groups
n=31/74
n=31/76
41.9%
(95% CI: 30.5, 53.9)
40.8%
(95% CI: 29.7, 52.7)
Response (mUFC ≤ ULN at month 7)
Lacroix et al. ENDO 2016. Poster # SAT546
Efficacy in relation to baseline UFC
Screening mUFC
In both arms, the response rate was higher in the lower mUFC strata
n=18/49
n=18/51
n=13/25
n=13/25
Lacroix et al. ENDO 2016. Poster # SAT546
Dopamine receptor subtype 2 expression in
corticotroph adenomas (n=30)
DA/hprt
1.5
1.0
0.5
n.d.
0.0
D2
D4
D2L
D2S
de Bruin et al., JCEM 2009
Effects of cabergoline on UFC in Cushing’s disease
Short-term response:
75 %
Long-term response:
35 %
Pivonello et al. JCEM 2004
Sst2, sst5 and D2 receptor expression in
corticotroph adenomas
Non-invasive
2
sst or D / hprt
Micro
Macro
Invasive
Micro
Macro
2.0
sst2
1.5
sst5
1.0
D2
0.5
0.3
0.2
0.1
0.0
de Bruin et al., JCEM 2009
Enhanced functional activity of D2DR-sst5 heterodimers
SST-14
Quinpirole
SST+Quin
Forskolin-stimulated cAMP
levels (% of maximum)
100
80
sst5
D2DR
60
sst5/D2DR
40
-10
-9
-8
-7
-6
Agonist [log M]
Rocheville et al. Science 2000
UFC levels in pasireotide mono- and combination
therapy
pasireotide
pasireotide + cabergoline
pasireotide + cabergoline
+ ketoconazole
UFC (nmol/24h)
750
n=5 (29 %)
n=4 (24 %)
n=8 (47 %)
500
250
0
0
20
40
60
80
Time (days)
Feelders et al. NEJM 2010
Study B2411 (CAPACITY): A Phase II trial to assess
efficacy and safety of pasireotide alone or in
combination with cabergoline in Cushing’s disease
Pasireotide-untreated patients at screening
Pasireotide 900 µg bid
+ cabergoline 0.5 mg qd
Pasireotide 900 µg bid
Pasireotide 900 µg bid
+ cabergoline 1 mg qd
Pasireotide 600 µg bid
Time
(weeks)0
8
9
17 18
26 27
35
Patients treated with maximal tolerated doses pasireotide monotherapy
Pasireotide 300–900 µg bid
+ cabergoline 0.5 mg qd
Time
(weeks)0
8
9
Pasireotide 300–900 µg bid
+ cabergoline 1 mg qd
17 18
26 27
35
Feelders R et al. Endocrine Abstracts 2014;35:abst P885
Is cortisol-mediated sst2 down-regulation reversible ?
•
Evaluation of sst2 and sst5 expression in adenomas of:
•
21 patients with elevated cortisol production preoperatively
•
11 patients with normalized cortisol production preoperatively
•
Mean duration of normocortisolism: 10.3 weeks
•
Compared with GH-producing pituitary adenomas (n=10).
van der Pas et al. JCEM 2013
Sst2 and sst5 mRNA expression
Corticotroph adenomas
Relative expression
(normalized to HPRT)
2.0
1.5
Elevated UFC
n=21
2.0
1.5
Normalized UFC
n=10
Somatotroph
2.0
adenomas
1.5
1.0
1.0
1.0
0.5
0.5
0.5
0.0
0.0
0.0
sst2
sst5
sst2
sst5
n=10
sst2
sst5
van der Pas et al. JCEM 2013
Sst2 and sst5 protein expression
Immunoreactivity score (IRS)
sst5
Elevated UFC
12
12
10
Normalized UFC
n=5
10
8
8
6
6
4
4
2
2
0
0
sst2
sst5
n=7
sst2
sst2
sst5
van der Pas et al. JCEM 2013
Patient with occult ectopic ACTH production
Treatment with Mifepristone
Baseline
Post-treatment
de Bruin et al. JCEM 2012
Patient with occult ectopic ACTH production
Baseline
Post-treatment
De Bruin et al. JCEM 2012
CT and octreoscan before and after treatment
de Bruin et al. JCEM 2012
Immunohistochemistry for the sst2 and D2 receptor in
patient’s bronchial carcinoid tissue
Negative control
Sst2 staining
D2 staining
de Bruin et al. JCEM 2012
Patient with a corticotroph macroadenoma
Female, 27 years
• ACTH-producing macroadenoma
• Initial SMS-scan negative
• SMS-scan positive after 4 months
treatment with ketoconazole
Altered expression of factors involved in:
• POMC expression:
• Testicular orphan receptor 
• Glucocorticoid-mediated negative feedback:
• Brg1 ↓, HDAC2 ↓
• 11--HSD2 , HSP90 
• Cell cycle:
• Cyclin-dependent kinases 
• Cell growth:
• EGFR 
Sbiera et al. Trends Endocrinol Metab 2015
New insights in molecular pathophysiology
Lacroix, Feelders, Stratakis & Nieman, Lancet 2015
USP mutants inhibit EGFR downregulation
Reincke et al., Nature Gen 2015
New targets for medical treatment: EGFR
•
Gefitinib inhibits ACTH secretion
and cell proliferation and induces
apoptosis in primary cell cultures
derived from human ACTHsecreting tumors
•
Mutations in the USP8 gene are
associated with an impaired
downregulation of EGFR
•
A phase II study will evaluate the
effect of gefitinib in patients with
USP8-mutated Cushing’s disease
Gefitinib,
a tyrosine kinase inhibitor,
blocks EGFR activity
EGFR
Courtesy Dr. R. Pivonello and Novartis
Fukuoka et al. Mol Endocrinol 2011;25:92–103, Reincke et
al. Nat Gen 2015;47:31–38
New targets for medical treatment: CDK (cyclin E)
PTTG
Cyclin E
CDK2
Roscovitine
Rb-E2F
E2F1
G1 – S
POMC gene
Proliferation
Tpit
Hyperplasia/tumor
•
Roscovitine is a selective
CDK inhibitor that
induces corticotroph
tumor cell cycle arrest in
murine and zebrafish
models via suppression of
CDK2/cyclin E activity
•
In human corticotroph
tumors, it inhibits POMC
transcription and ACTH
expression by targeting
the cyclin E/E2F1 pathway
ACTH overexpression
Cushing’s
disease
Courtesy Dr. R. Pivonello and Novartis
Liu NA et al. Proc Natl Acad Sci U S A 2011;108:8414–8419,
Liu NA et al. J Clin Endocrinol Metab 2015:100:2557–2564
HSP90 in corticotroph adenomas
Riebold et al. Nature Med 2015
Effects of HSP90 inhibition on corticotroph tumors
Silibinin:
•
enhanced dex-mediated ACTH
suppression
•
decreased tumor growth
•
improved Cushingoid phenotype
Riebold et al. Nature Med 2015
Drug targets in Cushing’s disease
Bone
Anterior pituitary
ACTH
sst2
Smooth muscle
Adrenal
cortisol
GR
Liver
D2R
17-20 lyase
Adipose tissue
sst5
Somatostatin analogs
Dopamine agonists
Ketoconazole
Etomidate
Metyrapone
Mitotane
(LCI699)
Glucocorticoid
receptor antagonists
Mifepristone
Feelders  Hofland JCEM 2013
CORT125134
Cort125134:
•
selective glucocorticoid receptor
antagonist
•
does not bind to progesterone
receptor
Courtesy Corcept
Phase 2 study: safety and efficacy of CORT125134
Study Period
Treatment
Follow-up
Weeks 1–12
Weeks 13 –16
Screening
Days – 42 to –1
Group 1 (n = 15)
Group 1
patients
4 Weeks
100 mg
Day 1:
Baseline
4 Weeks
4 Weeks
150 mg
200 mg
Dose
Escalation
PK Data
Dose
Escalation
Patients
complete
follow-up
assessments
Group 2
patients
4 Weeks
4 Weeks
4 Weeks
250 mg
300 mg
350 mg
Day 1:
Baseline
Dose
Escalation
Dose
Escalation
PK Data
The assigned dose is administered orally once daily in the morning, with no food for 4 hours before and 1 hour after dosing.
Courtesy Corcept
Tailor-made medical therapy for Cushing’s syndrome
Patient
characteristics
Drug efficacy,
adverse events
Choice of
medical
treatment
Severity of
hypercortisolism
Availability and
costs
Conclusions
• Adjuvant medical treatment after unsuccesful surgery should be
tailor-made and aim to completely normalize cortisol production
• Combination therapy is frequently needed to induce biochemical
remission
• Combined targeting of somatostatin and dopamine receptors is a
promising approach of tumor-directed therapy
• Cortisol-mediated sst2 down-regulation in corticotroph adenomas
may be reversible
Conclusions
• New adrenal blocking drugs in phase III trials:
• LCI699 (Osilodrostat)
• COR-003
• Phase III trial with Pasireotide LAR shows promising results
• New targets for pituitary-directed therapy:
• EGFR
• CDK
• HSP90
• Future studies should explore the optimal order and combination
of medical treatment modalities
Thank you !