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

Peter Trainer; John Newell-Price; John Ayuk; Simon Aylwin; Aled Rees; Will Drake; Philippe Chanson; Thierry Brue; Susan Webb; Carmen Fajardo; Javier Aller; Ann McCormack; David Torpy; Lynne Atley; George Tachas

doi:10.1530/endoabs.38.P308

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

SFEBES2015 Poster Presentations Pituitary (48 abstracts)

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

Peter Trainer ¹ , John Newell-Price ² , John Ayuk ³ , Simon Aylwin ⁴ , Aled Rees ⁵ , Will Drake ⁶ , Philippe Chanson ⁷ , Thierry Brue ⁸ , Susan Webb ⁹ , Carmen Fajardo ¹⁰ , Javier Aller ¹¹ , Ann McCormack ¹² , David Torpy ¹³ , Lynne Atley ¹⁴ & George Tachas ¹⁵

Err

Author affiliations

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.