Endocrine Abstracts (2015) 38 P308 | DOI: 10.1530/endoabs.38.P308

Antisense oligomer therapy directed at the GH receptor is associated with reduction in circulating GHBP levels

Peter Trainer1, John Newell-Price2, John Ayuk3, Simon Aylwin4, Aled Rees5, Will Drake6, Philippe Chanson7, Thierry Brue8, Susan Webb9, Carmen Fajardo10, Javier Aller11, Ann McCormack12, David Torpy13, Lynne Atley14 & George Tachas15

1The Christie NHS Foundation Trust, Manchester, UK; 2University of Sheffield, Sheffield, UK; 3University Hospital Birmingham, Birmingham, UK; 4King’s College Hospital, London, UK; 5Cardiff University, Cardiff, UK; 6St Bartholomew’s Hospital, London, UK; 7University Paris-Sud, Paris, France; 8Hopital de la Conception, Marseille, France; 9Hospital de Sant Pau, Barcelona, Spain; 10Hospital Universitario La Ribera, Valencia, Spain; 11Hospital Universitario Puerta de Hierro, Madrid, Spain; 12St. Vincent Hospital, Sydney, Australia; 13Royal Adelaide Hospital, Adelaide, Australia; 14Antisense Therapeutics, Melbourne, Australia; 15Ludwig-Maximilians University, Munich, Germany.

ATL1103 is a second generation antisense 20mer intended to inhibit expression of the GH receptor (GHR) gene. Phosphorothioate and 2′-O-methoxyethyl modifications to nucleotides increase its plasma half-life and affinity for the target RNA to allow post-hybridization RNaseH degradation. We previously reported a phase 2, randomised, open-label, parallel group study of ATL1103 in 26 patients with acromegaly which demonstrated a fall in serum IGF-I of 26% with 200 mg twice weekly (577±198 vs 411±174 ng/ml, P<0.0001) and rise in GH. Once weekly dosing did not result in a significant fall in IGF-I. Here we present the changes in GHBP during this study.

In humans, circulating GHBP is the result of proteolytic cleavage of the extracellular domain of the cell-surface GHR with plasma levels being influenced by GH secretory status, body composition and age. Approximately 50% of circulating GH is bound to GHBP and it is a potential regulator of GH action. It has been suggested that GHBP levels reflect GHR number. GHBP was measured by a modification of a ligand immunofunctional assay.

At baseline, median GHBP were higher in the once weekly cohort than those randomised to twice weekly (1179 (range 386–7637) vs 525 (<69–6434) pmol/l) and the difference persisted throughout the dosing period. ATL1103 resulted in significant decrease in median GHBP in the once and twice weekly cohorts at week 14 of −453.0 (range −2219 to −237 (P=0.0046)) and −309.3 (−2392 to 443, P=0.0186) pmol/l, respectively.

In conclusion, these data indicate that plasma GHBP levels fall with ATL1103 which is further evidence of the efficacy of ATL1103 and its ability to inhibit GHR gene expression but suggest that dosing can be further optimised. Data from future clinical trials will help to evaluate the relationship between ATL1103 dose, GH levels, GHBP levels and the change in IGF1 with treatment.