Medical options in the treatment of acromegaly

I M Holdaway

June 29 2013

Medical treatments for acromegaly (non-surgical and non-radiotherapy)

• Older treatments- medroxyprogesterone- oestrogen (tablets or patches or look-alike preparations)

• Dopamine – like agents:- bromocryptine - cabergoline (special authority)

• Somatostatin analogues:- aqueous octreotide (subcut injection) (special authority)

- depot octreotide (sandostatin LAR) (special authority)

- Lanreotide (not marketed in NZ)

- Oral octreotide (under trial in USA)

- Pasireotide (not available in NZ)

• Pegvisomant (Named Patient Pharmaceutical Assessment)

Growth hormone

IGF-I (insulin-like growth factor-I)

Growth and metabolic effects

Pituitary gland

liver

Brain (hypothalamus)

A few direct effects of growth hormone e.g. on fat cells

Action of growth hormone and insulin-

like growth factor-I (IGF-I)

Older studies of the medical treatment of acromegaly

• Medroxyprogesterone (depot-provera & Megace)

• Oestrogen- oral oestrogen tablets

- oestrogen patches

- oestrogen – like agents, anti-oestrogens

JCEM 1970

(Note – later studies could not replicate these results)

Remission level of GH

Pituitary, 2012

45% cure level of IGF-I

Published series using oestrogen to treat acromegaly

Dopamine – like agents

• Bromocryptine• Cabergoline (longer duration of action, very low rate

of side-effects compared with bromocryptine)

Labelled dopamine binding to its receptor in the pituitary

Cabergoline treatment in acromegalics with elevated IGF-I

A meta-analysis of 10 studies

20% given as initial treatment, 70% had received previous surgical treatment

51% developed normal IGF-I 48% GH <2.5

Individuals with elevated serum IGF-I during treatment with LAR octreotide, then treated

with addition of cabergoline

52% achieved normal IGF-I levels

45% GH <2.5ug/l

But you have to take tablets correctly……..

Somatostatin look-alike agents

• Octreotide – a potent somatostatin-like agent- aqueous octreotide injection (short duration of action)

- depot octreotide injection (long duration of action)

- aqueous and depot lanreotide similar

• Pasireotide – a somatostatin-like agent with a broader range of action than octreotide

• Orally active octreotide

SR 1

SR 2SR 3 SR 4

SR 5

Signal to interior of pituitary cell to stop

making growth hormone

Main receptor for octreotide and lanreotide

Somatostatin action on growth hormone – producing pituitary cells

Cell wall

SR = somatostatin receptor

1 year

5 years

Pre-treatment

Effect of 1 and 5yrs LAR octreotide therapy on GH and IGF-I levels in acromegalic men

Safe level

Safe level

Colao 2009

Serum GH with LAR therapy(mean SD)

Auckland patients

Basal GH On LAR05

101520253035404550556065

seru

m G

H (

ug

/l)

P = 0.002

Serum IGF-I with LAR therapy(Z-score, expressed as mean SD)

Auckland patients

Basal IGF-I IGF-I on LAR0

1

2

3

4

5

6

7

Ser

um

IG

F-I

(Z

-sco

re)

P = <0.001

baselineLarge adenoma

smaller

Almost gone

6 months LAR octreotide

18 months LAR octreotide treatment

Shinkage of acromegaly adenoma with LAR

octreotide

Meta-analysis

53% of individuals with acromegaly show more than 20% shrinkage of

their adenoma with LAR octreotide (average

volume reduction 50%)

53%

Effect of LAR octreotide on adenoma size

Giustina et al, 2012

Mean ± SEM proportion of acromegalicpatients achieving safe hormone levels

with LAR octreotide

GHIG

F-I0.0

0.2

0.4

0.6

0.8

1.0

Pro

po

rtio

n w

ith

tar

get

lev

els

Meta-analysis by Freda et al, 2005, n= 612

Remission ratewith surgery

0

10

20

30

40

50

60

70

80

90

all tumours microadenomas

Per

cen

t re

mis

sio

n

17 surgical series 1987-2011

Remission of acromegaly with initial surgery or with LAR octreotide

SR 1

SR 2SR 3 SR 4 SR 5

Signal to pituitary cell to stop making growth

hormone

Pasireotide

A somatostatin-like agent with a broad range of action

Cell wall

SR = somatostatin receptor

Pasireotide

Pituitary tissue – microscopic view, stained for various somatostatin receptors

Type 1

Type 2

Type 3

Type 4

Type 5

Use of the somatostatin receptor analogue, Pasireotide in the treatment of acromegaly

Bronstein M US Endo Soc meeting 2012

Serum IGF-I and GH levels in an acromegalic subjectgiven a single injection of pasireotide

June

2011

July

201

1

Aug 201

1

Sept 2

011

Oct 2

011

Nov 20

11

Dec 2

011

0

200

400

600

0.0

0.2

0.4

0.6

0.8

IGF-I Growth hormone

PS

eru

m I

GF

-I (

ug

/l) S

erum

GH

(ug

/l)

Sent from my iPad

.

                                                                                                                                                                                                                                                                    

                                                                                                              

TPE absorption system for small peptides such as octreotide

Oral octreotide - the way of the future?

Tight junctions between cells (impermeable)

Tight junctions opened up by oily film (allows entry of larger molecules into circulation)

Blood flow

Intestinal contents

Cells lining the intestine

Barrier to absorbing large molecules from the intestine

Stimulated GH

Stimulated GH after oral octreotide

Effect of oral octreotide (Chiasma) on growth hormone secretion

stimulated by GHRH

Tuvia, 2012

Pegvisomant

A drug designed to block the growth hormone receptor and prevent the adverse effects of high growth hormone levels in acromegaly

Growth hormone

IGF-I (insulin-like growth factor-I)

Growth and metabolic effects

Pituitary gland

liver

Brain (hypothalamus)

A few direct effects of growth hormone e.g. on fat cells

Action of growth hormone and insulin-

like growth factor-I (IGF-I)

Growth hormone

↓ IGF-I (insulin-like growth factor-I)

↓ Growth and metabolic effects

Pegvisomant

Blockade of growth hormone action by

Pegvisomantpituitary

liver

Direct actions of GH e.g. on fat cells

Design of Pegvisomant

Serial IGF-I measurements during pegvisomant treatment in the German observational study

Schreiber et al, 2007

76% normalised

n = 229

What of the future?

• Effective oral octreotide

• By-passing surgery and using medical treatment as first option

• Treatment with a drug linked to either a chemotherapy agent such as tozolamide, or linked to a radioactive agent to kill the tumour cells

• A combined dopamine/octreotide agent

THE END!

Australian acromegaly awareness campaign

• While there was minimal mainstream print, radio and television consumer media coverage the more targeted media ran the story. Targeting magazines was effective.

• The medical media release hit all the targets and more with the smaller groups keen to run the story for their local newsletters.

• An increase in the Australian Pituitary Foundation website hits saw June (????), July (907 hits), August (982 hits), September (583 hits) (Note- medical media release issued mid July and consumer media release issued 1 August)

• A key learning is that mainstream media may not always be the best approach when it comes to disease awareness campaigns of this type.

• This a good example of widespread medical and patient/consumer coverage via non-mainstream mediums.

Pretreatment with SSAs prior to pituitary surgeryin acromegaly

contro

l

pretre

ated

contro

l

pretre

ated

0

10

20

30

40

50

60

70

80

90

POTA study (Norway)

Abe & Ludecke (Hamburg)

Per

cen

t cu

red

at

surg

ery

Abe et al, 2001

concept

57 90

30

32

Symptomatic response to octreotide LAR (n=10)

Symptom n before n afterHeadache 4 0

OSA - like 7 1

Arthralgia 5 2

Sweating 6 1

CTS 4 0

Hypertension 3 2

Diabetes 2 2

Cabergoline + LAR octreotide therapy

Individual patientsSandret et al, 2011

Effect of cabergoline on GH secretion in acromegaly

52% had normal IGF-I