Medical options in the treatment of acromegaly I M Holdaway June

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 2 SR 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 Colao 2009

P = 0.002

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

Meta-analysis by Freda et al, 2005, n= surgical series Remission of acromegaly with initial surgery or with LAR octreotide

SR 1 SR 2 SR 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

Sent from my iPad TPE™ Syste m Applications. 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 Pegvisomant pituitary 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, % 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 surgery in acromegaly Abe et al, 2001 concept

Symptomatic response to octreotide LAR (n=10) Symptom n before n after Headache40 OSA - like71 Arthralgia52 Sweating61 CTS40 Hypertension32 Diabetes22

Cabergoline + LAR octreotide therapy Individual patients Sandret et al, 2011 Effect of cabergoline on GH secretion in acromegaly 52% had normal IGF-I