Update on of interest and non-approved medications Cushings disease - - PDF document

Update on Cushing’s disease

Beverly MK Biller, MD

Professor of Medicine Harvard Medical School Neuroendocrine Clinical Center Massachusetts General Hospital Boston, MA

PI of research grants from Cortendo & Novartis to MGH Occasional consulting for Cortendo, HRA Pharma, Ipsen, Novartis Slides will indicate investigational medications

(includes those available for other indications but not approved for Cushing’s)

Disclosure of potential relevant conflicts

• f interest and non-approved medications

The Endocrine Society Clinical Guidelines

First-line treatment for Cushing’s Syndrome Operation by an experienced surgeon is recommended as the initial treatment So, other therapies should be used mainly for persistent or recurrent Cushing’s disease

Nieman JCEM 2015

Cushing’s disease (CD) Case

36 year old pregnant woman with:

• Facial rounding
• Hypertension
• Fungal infections

Cushing’s syndrome later diagnosed with high UFC levels; ACTH not low Pituitary MRI: ? small right lesion IPSS: Centralized

Clear clinical and biochemical features of CS; testing pointed to pituitary

PATIENT PHOTO

Cushing’s disease (CD)

• 36 year old with CD pituitary surgery by expert surgeon

very low cortisol levels post-op

• In remission good clinical improvement, euthyroid, eugonadal,

normal growth hormone axis

• HPA axis recovered in ~1 year off glucocorticoids

Before surgery ~8 years after surgery Moved away

PATIENT PHOTO PATIENT PHOTO

Case 2

• 27 yo F with CD diagnosed after pregnancy
• MRI showed 1cm macroadenoma
• Pituitary surgery 2011 levels normal (not low)
• Good clinical improvement over the next year

PATIENT PHOTOS Cushing’s disease (CD) Cases

What are their chances of recurrence?

We used to say 5-10% of CD cases recur, but

Swearingen Ann Int Med 1999

We were wrong – it is higher!

y ,

We

PATIENT PHOTOS

Valassi 2010 (n=620) Alwani 2010 (n=79) Jagannathan 2009 (n=261) Fomekong 2009 (n=40) Atkinson 2008 (n=42) Jehle 2008 (n=193) Prevedello 2008 (n=167) Xing 2008 (n=266) Carrasco 2008 (n=68) Romanholi 2008 (n=57) Patil 2008 (n=215) Rollin 2007 (n=108) Pouratian 2007 (n=111) Acebes 2007 (n=44) Shah 2006 (n=65) Hoffmann 2006 (n=100) Esposito 2006 (n=40) Atkinson 2005 (n=63) Hammer 2004 (n=289) Rollin 2004 (n=41) Pereira 2003 (n=78) Chen 2003 (n=174) Flitsch 2003 (n=147) Shimon 2002 (n=82) Rees 2002 (n=54) Barbetta 2001 (n=68) Chee 2001 (n=61) Imaki 2001 (n=49) 10 20 30 40 50 60 70 80 90 100

Patients (%)

Remission Recurrence

Recurrence rates were as high as 27%!

Studies in the last 5 years have shown even higher rates

Most are from expert centers

Recurrent Cushing’s after transsphenoidal surgery

(28 studies with varied definitions of biochemical control, follow up, number of subjects)

Case

• Fall 2013 recurrent symptoms

− emotional lability/moodiness − weight gain − but did not look Cushingoid

• Serum cortisols done locally were “normal”
• LNSCs & UFCs 1-2 fold upper limit of normal
• Head MRIs unchanged over 2 years

PATIENT PHOTO

• 2012 new diabetes (DM), weight

gain, ↑ blood pressure

• Asked local endo if CD back; told

no: metformin helped DM, lost weight, serum cortisol “normal”

Case

1990s ~2013

• Came to Boston for evaluation
• 8/8 UFCs were normal; looked well
• but 66% of late night salivary

cortisols (LNSCs) were high

PATIENT PHOTOS

Case

Head MRI

(first in many years) Mass on right side of pituitary gland ~1.5 x 1.3 x 0.7 cm ? right cavernous sinus invasion Normal gland pushed left

• These patients had typical recurrences

− mild clinical & biochemical abnormalities − one had unchanged MRI, abnormal UFCs − one had normal UFCs, abnormal MRI

• Recurrence may be many years after surgery

− 31 series with N>40: relapse between 6m-12y − This patient recurred at 21 years! Longest we’ve seen: 27y

• Sequence of hormone changes in recurrent CD

− ↑midnight cortisol (serum or saliva) usually precedes ↑UFC − mean time to elevation: - 38 months (m) for midnight cortisol

• 45 m for 1mg overnight DST
• 51 m for UFC
• Thus, all post-surgery patients must be followed

– can’t rely on UFC alone for diagnosis (use LNSC, ONDST) – LNSC appears to be most sensitive test

Cases

(Khalil EJE 2011, Tritos Nature Rev Endocrinol 2011, Carroll ENDO 2014 , Danet-Lamasou Clin Endo 2014)

PATIENT PHOTOS

Lindholm 0.31 (0.14-0.69)

• 0.126

7.93 1 Hammer Dekkers Clayton Overall (I-squared = 82.2%; p = 0.001) 1.18 (0.56-2.48) 1.80 (0.75-4.32) 3.30 (1.37-7.93) 1.20 (0.45-3.18)

Mortality among CD patients in remission

Clayton R N et al. JCEM 2011;96:632-642.

Hammer 5.06 (2.27-11.26)

• 0.026

38.4

Clayton R N et al. JCEM 2011;96:632-642.

1 Lindholm Dekkers Clayton

Overall

(I-squared = 67.2%, p = 0.027) 2.80 (1.33-5.87) 4.38 (1.82-10.52) 16.0 (6.66-38.44)

5.50 (2.69-11.26)

Mortality among CD patients with recurrence

Cushing’s syndrome and etiology established biochemically Treat co-morbidities ACTH-dependent Cushing’s syndrome ACTH-independent Cushing’s syndrome Presumed EAS Imaging: No tumor Presumed CD Based on IPSS or >6 mm mass Presumed EAS Imaging: Tumour Remission Tumor resection Resection not possible Monitor for recurrence Failed surgery, no surgery,

• r recurrence

Adrenal imaging Unilateral or bilateral adrenalectomy Treat metastatic disease if applicable Remission Repeat localization studies if applicable Control hypercortisolism If Cushing’s disease, consider: Repeat transsphenoidal surgery Pituitary-directed medical treatment Radiotherapy and steroidogenesis inhibitors For all etiologies, consider: Steroidogenesis inhibitors GC receptor antagonist Bilateral adrenalectomy

Nieman JCEM 2015

dent Cushing’s synd e ACTH-independent Cushing’s s Presu ed o m umor r Failed surgery, no surgery,

• r recurrence

aging rena R

• l hypercortisolism

er: urgery

Endocrine Society Clinical Guidelines – Treatment of Cushing’s synrome

CRH ACTH Cortisol Adrenal glands Pituitary gland Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* What are the treatment options for recurrent Cushing‘s disease?

GR

Mifepristone GRs on target tissues

Tissues (* not FDA approved for Cushing’s)

RADIATION

G n GR Rs on

ADRENALECTOMY

Ad l l d

MEDICATIONS

Pituitary gland

R PITUITARY SURGERY

Repeat transsphenoidal surgery

• Pros

− Well tolerated − Immediate effect (if successful) − Chance for tumor removal and remission

• Cons

− Glucocorticoids needed until axis recovers − Higher risk of pituitary hormone deficiencies − Risk of recurrent Cushing’s − Lower chance of success than 1st surgery (<75%) Remission rates after repeat transsphenoidal surgery for persistent or recurrent CD

20 40 60 80 100 Nakane 1987 (N=8) Friedman 1989 (N=31) Ram 1994 (N=17) Knappe 1996 (N=24) Shimon 2002 (N=13) Locatelli 2005 (N=12) Benveniste 2005 (N=30) Hofmann 2006 (N=16) Hofmann 2008 (N=35) Aghi 2008 (N=13) Patil 2008 (N=36) Wagenmakers 2009 (N=8) Remission Rate (%)

Varied definitions of biochemical control, follow up, Ns

(McLaughlin Can J Neurol Sci 2011)

1st surgery remission rates 70-90% 2nd surgery remission rates lower, but it works for some patients

19

Radiation

CONVENTIONAL Six weeks of daily tx

• Pros

− Well tolerated − Single treatment (if radiosurgery) − Provides tumor control in most patients − Biochemical control in some patients

• Cons

− Delayed effectiveness (6 months to many years) − Medical treatment needed in the interim − Long term risks:

› Pituitary hormone deficiencies/need for replacement › Risk to surrounding neurovascular structures › Risk of secondary neoplasia › Recurrence (rare)

(Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014) 20

Radiation

CONVENTIONAL Six weeks of daily tx

• Conventional

Fractionated

• Radiosurgery (RS)

− Single high dose to target − Lower dose to other tissue − 3 types

› Linear accelerator (LINAC) › Gamma knife › Proton beam

LINAC gamma knife proton beam

No direct comparisons available

• RS may be faster
• For CD, similar cortisol control

21

Radiation

10 20 30 40 50 60 70 80 90 100 Littley 1990 Murayama 1992 Levy 1991 Tsang 1996 Estrada 1997 Witt 1998 Laws 1999 Sheehan 2000 Kobayashi 2002 Devin 2004 Colin 2005 Jagannathan 2007 Minniti 2007 Petit 2008 Wilson 2014 Patients (%)

Tumor control (83-100%) Biochemical control (28-86%)

(Starke Curr Opin Endocrinol Diab Obes 2010, Tritos Nature Rev Endocrinol 2011, Wilson J Clin Neurosci 2014)

15 studies with at least 20 pts

Varied RT methods, definitions of tumor & biochemical control, follow up, Ns

CRH ACTH Cortisol Adrenal glands Pituitary gland Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699* Potential targets for medical treatment of Cushing‘s disease

GR

Mifepristone GRs on target tissues

Tissues (* not FDA approved for Cushing’s)

Rationale: affinity for receptors on corticotroph adenomas

• cabergoline for dopamine (D2) receptor
• pasireotide for somatostatin (sst5) receptor

↓ ACTH secretion

Cabergoline in Cushing’s disease

• 20 Cushing’s disease pts, mean UFC > 2-fold above nl
• 2-year study: 1-7mg/wk cabergoline (median 3.5mg/wk)
• 2 dropouts for “asthenia, hypotension”; adrenal insufficiency?
• Cardiac echos: tricuspid regurg progressed in 1, no change in others
• Similar findings in two other studies; suggests this is an option for CD

Non- responders Early response, Later “escape” Long-term responders

normal range

months

(Pivonello JCEM 2009, Godbout EJE 2010, Vilar Pituitary 2010) (not FDA approved for Cushing’s disease)

“Responder” means normal UFC

2500

Pasireotide - baseline & month 6 UFCs

Individual patients sorted by baseline UFC Color denotes starting dose

UFC (μg/24h) 180 360 540 720 1400 600 μg s.c. bid 900 μg s.c. bid

normal

Baseline UFC Month 6 UFC Month 6 UFC ULN

*

<52.5 μg/24h

Normal UFC, n (%) 12 (14.6) 21 (26.3) 33 (20.4)

Colao NEJM 2012

N=103

Colao NEJM 2012

600 μg sc bid 900 μg sc bid All patients

Clinical changes on pasireotide up to 12m

Colao NEJM 2012

FDA approved for CD pts not controlled with/able to have surgery

Subcutaneous pasireotide side effects

• Adrenal insufficiency symptoms in 13 (8%)

– Responded to dose reduction and/or temporary corticosteroids

• Most frequent side effects were gastrointestinal
• Similar to other SMS analogues, except for hyperglycemia
• 73% of patients had at least one hyperglycemia event

– No diabetic ketoacidosis or hyperosmolar coma – Attainment of UFC control did not prevent hyperglycemia

Colao NEJM 2012

Mechanism based on study in healthy volunteers: Pasireotide reduces incretin & insulin secretion, without affecting insulin sensitivity

Changes in glycemia on subcutaneous pasireotide

Mean fasting plasma glucose (mg/dL)

600 μg bid (n=82) 900 μg bid (n=80)

Mean HbA1c (%)

600 μg bid (n=82) 900 μg bid (n=80)

90 100 110 120 130 140 150 Baseline Day 15 Month 3 Month 6 Month 12 5 6 7 8 Baseline Month 2 Month 6 Month 12

Of the 67 patients who were normoglycemic at baseline, 14 (21%) remained normal, 29 (43%) became pre-diabetic and 23 (34%) became diabetic during treatment

Henry JCEM 2013 Colao NEJM 2012

Pasireotide LAR* (once monthly)

Lacroix ENDO 2016

*(not FDA approved for Cushing’s)

20 40 60 ≥1.5 to <2.0 x ULN ≥2.0 to ≤5.0 x ULN Pasireotide LAR 10 mg Pasireotide LAR 30 mg Screening mUFC Percentage of responders (mUFC ≤ULN at month 7) n=18/49 n=18/51 n=13/25 n=13/25 36.7% 35.3% 52.0% 52.0%

• 150 patients randomized to 10mg/month or 30mg/month
• Proportion of “Responders” (normal UFC) at month 7 by

pasireotide LAR dose according to baseline UFC group

Side effects similar to bid subcut use

CRH ACTH Cortisol

Adrenal glands Pituitary gland

Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*

Tissues

GR

Mifepristone

GRs on target tissues

(* not FDA approved for Cushing’s)

Several used for over 50 years Reduce cortisol by inhibiting adrenal steroidogenesis

ACTH ↑ in pituitary Cushing’s (? of escape) What are the treatment options for recurrent Cushing‘s disease?

Ketoconazole

• Approved for treatment of fungal infections
• Inhibits several enzyme steps in cortisol production
• 4 past studies w/ >15 CD pts: cortisol control 49-99%

What‘s new?

• Large multicenter, retrospective French study

− 200 patients on monotherapy at 14 centers over 17y − Mean final dose 780mg/d (range 200-1200mg) − Control (2 consecutive normal UFCs) in 49% − Clinical improvements in DM, HTN, hypokalemia − ~20% discontinued for intolerance

most common: gastrointestinal, adrenal insuff, pruritis

− Liver enzyme elevations in 18% (>5XULN, 2.5%)

• Conclusion: effective with acceptable side effects

(Castinetti EJE 2008 & JCEM 2014, Sonino Clin Endo 1991, Valassi Clin Endo 2012) (not FDA approved for Cushing’s)

Metyrapone

• Inhibits last enzyme step in cortisol synthesis
• Cortisol control reportedly ~75%

− 3 studies from 1970s to early 1990s (15-53 patients)

What‘s new?

• Large multicenter, retrospective UK study (ENDO 2014 oral)

− 160 patients on metyr monotherapy at 13 centers over 16y − Control based on cortisol day curve or UFC or am cortisol − 74% controlled overall in Cushing‘s syndrome

(about 2/3rds who took metyrapone over 5m had CD)

X

Cortisol

11OHlase

11deoxycortisol

(Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985, Verhelst Clin Endo 1991, Daniel JCEM 2015) (not FDA approved for Cushing’s) (Jeffcoate BMJ 1977, Thorén Acta Endocrinol (Copenhagen)1985, Verhelst Clin Endo 1991, Daniel ENDO 2014)

Change in 9am cortisol during treatment for each individual patient

300 600 900 1200 1500 1800

151 patients

Reduction Increase Normal: 600nmol/L=21.7 mcg/dl Slide kindly provided by John Newell-Price, presented at OR-02-3 by Eleni Daniel

(not FDA approved for CD)

− Dose in CD patients with eucortisolemia was ~1.4 g/d − 25% had side effects (most common: GI, hypoadrenalism)

Conclusion: effective with satisfactory safety profile

• n metyrapone

Daniel JCEM 2015

33

Potent inhibitor of 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) Blocks last steps in cortisol and aldosterone production Hormones distal to the block fall and proximal hormones rise

• Oral, longer half-life than metyrapone (allows twice-daily dosing)
• Higher potency (in vitro IC50 for CYP11B1 of 2.5 nM vs. 7.5 nM)

IC50, half maximal inhibitory concentration

Pregnenolone 11-deoxycortisol Cortisol Cholesterol ACTH Aldosterone CYP11B2 Corticosterone 18-OH corticosterone LCI699 CYP11B1

Abnormal feedback loop in Cushing’s disease

Progesterone Dehydroepiandrosterone Androstenedione Testosterone 11-deoxycorticosterone Estradiol Estrone

X X

11-deoxycortisol ACTH Testosterone 11-deoxycorticosterone

Investigational medication LCI699 (osilodrostat)* Mechanism of action

(* not FDA approved)

34

Mean UFC SE (fold ULN)

1 2 3 4 5 6 7 1 14 28 42 56 70 84 Day

LCI699 dose escalation Washout

Open-label, proof-of-concept study with LCI699* was positive in 12 adults with Cushing’s disease

• Oral medication, given twice daily
• Dose escalated every 2 weeks until UFC normalized
• Maintained until day 70, followed by 2-week washout

Bertagna JCEM 2014

At day 70:

• 11/12 had normal UFC
• Most common side

effects: fatigue, nausea

(* not FDA approved)

35

Longer-term extension Change in UFC after 22 weeks of LCI699*

UFC (nmol/24h) 7000 9000 11000 2000 1800 1600 1400 1200 1000 800 600 400 200 Patients

Baseline Week 22 Follow-up cohort Expansion cohort

Overall response (n=19):

• Controlled, n=15 (78.9%)
• Uncontrolled, n=2 and

discontinued, n=2 (21.1%)

normal range

11–138 nmol/24h

(* not FDA approved)

(Fleseriu & Pivonello Pituitary 2016)

CRH ACTH Cortisol

Adrenal glands Pituitary gland

Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*

GR

Mifepristone

GRs on target tissues

(* not FDA approved for Cushing’s) Tissues

Blocks action of cortisol at glucocorticoid receptor (GR)

Doesn’t lower cortisol; ACTH and cortisol ↑ in pituitary Cushing’s What are the treatment options for recurrent Cushing‘s disease?

Oral glucocorticoid (GR) antagonist - greater affinity than cortisol or dexamethasone for the receptor Also has antiprogestin activity Phase 3 clinical trial in 50 patients reported in 2012 FDA approval for Cushing’s syndrome with hyperglycemia

Mifepristone in Cushing’s Syndrome

Blocks receptor (does not ↓cortisol) so response was assessed clinically

− Patients had diabetes/impaired glucose tolerance or HTN − Primary endpoints related to improvements in these disorders (25% reduction in AUCgluc on OGTT, 5mmHb reduction in DBP)

(Fleseriu JCEM 2012)

Decrease in HbA1c in diabetes cohort

4 5 6 7 8 9 10 Baseline Week 16 Week 24/ET HbA1c (%) p<0.001 vs baseline N=25 N=22 N=20 mean SD p<0.001 vs baseline Glucoses on OGTT and insulin levels also decreased significantly Diabetes drugs were reduced in 7/15 patients

(Fleseriu JCEM 2012)

(mean SE)

Decrease in weight

• 9%
• 8%
• 7%
• 6%
• 5%
• 4%
• 3%
• 2%
• 1%

0% 1% 2% D7 D14 D28 W6 W8 W10 W12 W16 W20 W24 % Change from baseline Baseline 99.5 ± 4.4 kg n=46

↓ 5.7 1.5%

p<0.001 vs Baseline

/ET

(Fleseriu JCEM 2012, Katznelson Clin Endo 2013)

“Global Clinical Assessment”

• f many features, including

appearance in photographs, rated by 3 independent reviewers improved in 88% of patients (p<0.001)

• Adrenal insufficency (AI)

− Classified as AI or typical symptoms & treatment with glucocorticoid (dex) in 7 − High measured cortisols despite AI may be misleading

• Most common: nausea, fatigue, headache
• Hypokalemia

− Common, associated with alkalosis, edema; treated with K & spironolactone − Likely due to mineralocorticoid receptor activation from rising cortisol

• Endometrial Effects (progesterone receptor blockade)

− Increased endometrial thickness in half of women − 5 cases of vaginal bleeding − 3 women had D&C for unresolved endometrial thickening after discontinuation

• Thyroid – elevated TSH
• Lipids – decreased HDL

Drug-drug interactions require careful attention

Mifepristone side effects

(Fleseriu JCEM ‘12, Endocrine Practice ’13)

CRH ACTH Cortisol Adrenal glands Pituitary gland Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*

Many choices - how to decide which treatment to use?

GR

Mifepristone GRs on target tissues

(* investigational for Cushing’s) Tissues

CRH ACTH Cortisol Adrenal glands Pituitary gland Cabergoline* Pasireotide Ketoconazole* Metyrapone* Mitotane* Etomidate* LCI699*

R GR GR

Mifepristone GRs on target tissues

(* investigational for Cushing’s) Tissue es Severity/urgency, treatment goals (cortisol/tumor) Other medications (beware drug–drug interactions)* Medical history and patient factors Method of delivery (oral versus injection) Side-effect profile Cost and availability

How do we decide which medication to use?

Consider many factors Tailor choice to each patient’s individual situation

Especially with mifepristone and ketoconazole* (*not FDA approved for Cushing’s)

• 29 yo F Cushing’s disease recurrence
• Treatments discussed; considering the options
• Phone call to fellow… patient was excited to report….
• Pregnant! What are the treatment options now?
• Choices are limited
• Metyrapone* started

(* not FDA approved for this use) (Lindsay JCEM 2005)

Case outcomes

• targeted UFCs in normal pregnant range, 1.5-2 fold above ULN
• due to concern about precursors proximal to 11ßOHlase blockade,

careful monitoring of potassium & blood pressure (weekly OB visits)

She delivered a healthy boy

PATIENT PHOTO

Case Outcome

Before second surgery 2013 After second surgery June 2014 Most recent visit Dec 2015

She decided to undergo second transsphenoidal surgery by an expert pituitary surgeon; “I’d be happy with another 20-year remission by spending just 1 day in the hospital” in remission Diabetes and hypertension resolved (medications stopped) Pituitary hormone replacements adjusted, feeling well

PATIENT PHOTOS

Conclusions – Cushing’s

• All patients in remission from CD should

have lifelong monitoring for recurrence

• Late night salivary cortisol levels are more

sensitive than other tests

• Treatment is important to lower mortality risk
• Emerging therapies include:

– More sophisticated transsphenoidal techniques – Stereotactic radiosurgery refinements – New medications and new versions of older medications – There are other medications in earlier development

Thank you

Questions?