1. Development of a Long-Acting Growth Hormone Antagonist for the Treatment of Acromegaly
ECE 2016

2. Acromegaly & Treatment
Acromegaly: Chronic debilitating condition
Excess Growth hormone from pituitary tumour
Results in high IGF-I
Increased morbidity and mortality
Primary treatment:
Pituitary surgery cures ~50%
Secondary medical treatment:
Somatostatin analogues effective in ~60%
Postcard courtesy of Wouter W. de Herder in Acromegaly and Gigantism in the 20th century
ECE 2016

3. Tertiary Medical therapy: Pegvisomant
GH Antagonist (GHA)
Effective in >90% of patients
Daily injections 10-30mg daily
Expensive
ECE 2016

4. Aim: Create a Second Generation GH antagonist
Target product profile of weekly subcutaneous injection at <30mg per injection
Design based on long-acting GH agonist: IV SC
ECE 2016

5. GHA Candidate Molecules
ECE 2016

6. Hypothesis
The W104A mutation reduces both intra and inter-molecular interactions producing a more active molecule
ECE 2016

7. In Vitro Bioactivity Assay
SAMPLE
IC50 (nM )
SEM
GHA1 44
4.7
GHA2
198 25
GHA3 17
1.3
ECE 2016

8. Terminal half-life (hrs)
PK in Rats after IV injection
SAMPLE
Terminal half-life (hrs)
GHA1 20
GHA2
GHA3
ECE 2016

9. PK in Rabbits After SC Injection
SAMPLE
Terminal half-life (hrs)
GHA1
23.6
GHA2
17.4
GHA3
40.5
ECE 2016

10. Rabbit Model for Analysis of IGF-1
Bielohuby, M., et al., Validation of serum IGF-I as a biomarker to monitor the bioactivity of exogenous growth hormone agonists and antagonists in rabbits. Dis Model Mech, (11): p
ECE 2016

11. Conclusions
Site 1 mutations decrease bioactivity of fusion GHA presumed to result from intra- and inter-molecular interactions
W104A mutation in GHA3 increases bioactivity presumed by reducing intra- and inter-molecular interactions
GHA3 shows half-life of 20 hrs in a rat after IV and 40 hours in rabbit after SC injection
Single injection GHA3 reduces IGF-1 levels in a rabbit model
GHA3 candidate molecule for second generation long-acting GH antagonist
ECE 2016

12. Acknowledgements MRC DPFS Grant, Euro 3M (3 years)
Grant# X/
ECE 2016