1. Annual meeting NZ Acromegaly Society, 2016
1. Patient comments about medical treatment of acromegaly 2. Incidence and prevalence of acromegaly 3. New therapies for management
I M Holdaway
Endocrinologist, Auckland Hospital and Greenlane Medical Centre
Annual meeting NZ Acromegaly Society, 2016

2. Patients from nine centres in Europe
57% on LAR octreotide, 43% on lanreotide
Of those on LAR, 60% were on 30mg/month or more, 25% on 20mg/month
On average treated for 6.6 years
21% were also on cabergoline, and 16% were also on pegvisomant

3. Persistence of symptoms of acromegaly during treatment with LAR Octreotide

4. The impact of persisting acromegalic symptoms on the individuals in the study

5. Injection –related symptoms from injected octreotide
Comparing LAR with lanreotide indicated longer lasting pain in some individuals with LAR, and more skin reactions, local lumps etc with lanreotide

6. Experience of stress with the injections

7. Patient confidence in the treatment and degree of satisfaction

8. Assessed claims for acromegaly in a large database of numerous health-care insurances (n = 123 million individuals)
Incidence (new cases per year) was defined as any new claim in persons enrolled for at least 6 months, estimated as number per million of the “at risk” population (number of enrolled persons).
Prevalence (number of total cases in the population) was defined as the number of patients with any acromegaly claim per year, estimated from total enrolled persons for the year

9. Incidence of acromegaly (new cases per year)
Increased with age, no gender difference, constant over time
Prevalence of acromegaly (how many cases exist in the population at a given time)
78/year

10. Comment by IH:
In a 1999 review by Rajasoorya & Holdaway, the estimated incidence of new cases in NZ and other countries was about 3-4 per million, and prevalence about 60 per million, so the present data suggests a higher incidence of new cases in the USA but similar prevalence of total cases
The way of calculating new cases in the USA may over-state the situation, since they counted any new claim with no record in the previous 6 months as a “new” case (but it could have been an existing case with no claims for a long preceding period)
The study doesn’t allow for acromegalic individuals who didn’t make medical claims
There was no independent assessment of whether there was true acromegaly present (from medical records etc)

11. A study on the incidence and prevalence of acromegaly in Iceland
The authors claim that there were 52 patients with acromegaly over in about 300,00 total population, giving a prevalence of about 173 per million, but reducing to 133 per million subtracting those who had died over the time interval, and coming down to 121 per million if “patients lost to follow-up” were also subtracted (presumed died). This still suggests a much higher prevalence than expected for this population; they note some familial clusters suggesting there may be a genetic predisposition increasing the prevalence data.

12. Issues with current LAR octreotide treatment for acromegaly
Only fully efficacious in around 55% patients
Issues with side effects and patient tolerability
Predictors of poor efficacy:
Low abundance of somatostatin type 2 receptors in adenoma
Large adenoma size
High pre-treatment growth hormone level
Sparse granularity of adenoma on EM
Young age
Adenoma hyper-intense during T2 imaging on MRI scan
Development of more agents for treatment might help with individualised selection of therapy

13. Agents in development for the treatment of acromegalySS GH
Liver
IGF-I

14. Agents in development for the treatment of acromegaly
Somatoprim
A new somatostatin analogue
Somatoprim injection SS GH
Liver
IGF-I

15. Invitro efficacy:
1. Somatoprim stimulates the 2-, 4- and 5-SS somatostatin receptor subtypes
2. Similar to Pasireotide, which reacts with the 1-, 2-, 3-, and 5-SS somatostatin receptor subtypes, but Pasireotide also significantly suppresses insulin secretion which Somatoprim doesn’t

16. Clinical studies of Somatoprim
Patient studies (unpublished)
Phase 1 study (sponsored by Aspireo Pharmaceuticals Ltd) in normal volunteers showed GH suppression similar to octreotide, but somatoprim had much less inhibitory effect on insulin and glucagon. Octreotide therapy led to sustained increase in plasma glucose, not seen with Somatoprim. It is unclear what aspect of receptor action leads to the protective effect on insulin & glucagon.
Phase 2 study (Clinical Trials.gov) in untreated acromegalics comparing 3 dose schedules of Somatoprim given by subcut infusion over 23 hrs (900, 2700 and 5300ug) with octreotide 300ug (funded by Aspireo Pharmaceuticals). No published results as yet.

17. Agents in development for the treatment of acromegaly
Orally absorbed octreotide
Octreotide given by mouth ss GH
Liver
IGF-I
Liver

18. JCEM 100; 1699, 2015

19. Pharmacodynamic analysis of plasma octreotide concentration following morning dose of octreotide capsule
40mg bd
40mg am, 20mg pm
20mg bd
T ½ = 3-4hrs

20. Efficacy of oral octreotide
64% IGF-I <1.3 ULN
33% IGF-I <1 (c/f 43% at baseline)
95% GH<2.5
78% <1 (c/f 66% at baseline)

21. Agents in development for the treatment of acromegaly
LAR octreotide in a liquid crystalline matrix (CAM2029)
Subcutaneous injection of octreotide SS GH
Liver
IGF-I

22. Background
Octreotide LAR is octreotide incorporated into microspheres. There is a peak of octreotide in the blood after injection (hrs) that then declines over 3 days, followed by second stage release. However, levels tend to plateau by 3-4 months
(7 days)

23. CAM2029
CAM2029 is octreotide suspended in a liquid crystalline matrix, which absorbs water after being injected subcutaneously. The octreotide then diffuses passively from the matrix as it gradually degrades.
Phase 1 study: CAM2029 compared with octreotide in normal volunteers: levels of CAM declined linearly until day 28, whereas octreotide showed an initial burst of serum concentration, then a fall, the rising levels again. IGF-I suppression by CAM was > LAR octreotide over weeks 1-2.
Phase 2 study in patients is ongoing (ClinicalTrials.gov, 2015)
Note: CAM2029 is a liquid preparation able to be given subcutaneously through a small-bore needle. Stable at room temperature

24. An agent already in use for the treatment of acromegaly
Pegvisomant (a GH-receptor blocker) SS GH
pegvisomant
Liver
IGF-I

25. Pegvisomant
Phase 3 studies suggested >90% remission rate in acromegaly
Surveillance studies in clinical practice suggest 60% efficacy
Liver abnormalities 5-28% in trials, <3% in the largest observational study
Side effects of injection pain and lipohypertrophy
The underlying pituitary tumour persists, although tumour growth rarely increases

26. Agents in development for the treatment of acromegaly
Inhibition of growth hormone receptor synthesis in the liver by “knockdown” of mRNA controlling its manufacture SS GH
Injection of antisense oligonucleotide
Liver
IGF-I

27. Growth hormone bound to liver cells
3mg
30mg
control
control
Growth hormone bound to liver cells
Blood levels of IGF-I with treatment
Reduction of GH binding and IGF-I generation in vitro with antisense oligonucleotide treatment, and reduction of growth in treated mice
Weight of treated mice
Tachas et al, 2006

28. Phase 1 and 2 studies of GH receptor knockdown with antisense oligonucleotide ATL1103
Phase 1: dose finding study in normal subjects showed “a clear trend for lower IGF-I levels and levels of GH binding protein (produced by cleavage of the GH receptor)” ( in “Clinical Trial results”)
Phase 2: 26 patients with active acromegaly were treated with 200mg ATL1103 once or twice weekly for 13 weeks. 26% reduction in IGF-I (calculated nadir 21 weeks), with reduction in finger ring tightness.
(Trainer et al, in US Endo Soc abstracts 2015)

29. Wave Rock
Hyden WA

31. Two previous instruments for recording sequential data in acromegaly:
Pituitary 2016; 19, 39
Two previous instruments for recording sequential data in acromegaly:
Patient Assessed Acromegaly Symptoms Questionnaire (PASQ)
Acromegaly Quality of Life Score (AcroQoL)
Neither cover the full spectrum of the disorder including patient, biochemical and adenoma-related information. Thus a more comprehensive system was developed:
S = signs and symptoms
A = associated comorbidities
G = GH level SAGIT score
I = IGF-I level
T = tumour profile

32. The questionnaire was developed by a panel of endocrinologists, then pretested in Brazil, France, Germany, Italy, Spain, and the UK.
2 Endocrinologists from each country completed the questionnaire on 2 occasions at least 3-months apart, and were then interviewed using a standard “pragmatism” score to assess usefulness.
After redevelopment, a pilot study was performed.
14 Endocrinologists assessed 3 patients (one treated and controlled, one treated but still active, and one untreated)

33. The detailed scoresheet of the SAGIT system

34. Physician opinion of the SAGIT system

35. IMH Comments:
The main issue is how useful this tool will be over time to record an acromegalic individual’s progress, and where issues such as treatment(s) will be incorporated. In addition there is no patient-recorded information, so to be truly comprehensive a quality of life questionnaire from the patient needs to be added. The query also arises as to whether SAGIT will be used to assess progress at the clinic or whether it will be suitable for research, or both.