ECE2015 Guided Posters Pituitary–Acromegaly (10 abstracts)
A phase 2 study of antisense oligonucleotide therapy directed at the GH receptor demonstrates lowering of serum IGF1 in patients with acromegaly.
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 , George Tachas 14 , Lynne Atley 14 & Martin Bidlingmaier 15
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 oligomer directed at the GH receptor. It is a 20mer with a phosphorothioate backbone and 2′-O-methoxyethyl modifications of the five nucleotides at either end intended to increase its plasma half-life and affinity for the target RNA to allow post-hybridization RNaseH degradation. We report a phase 2 randomised, open-label, parallel group study of subcutaneously administered ATL1103 in patients with active acromegaly. Appropriate ethical approval was obtained in each centre and the study is registered as EudraCT 01200314730. Patients gave written informed consent. The protocol entailed appropriate washout from ongoing medical therapy after which IGF1 had to be at least >1.3 times age-related ULN. Patients were randomised to receive either ATL1103 200 mg once or twice weekly for 13 weeks. After completion of drug administration, patients were monitored for a further 8 weeks. The primary objectives were to evaluate the safety and pharmacokinetics. 34 patients were recruited in 13 centres and 26 (mean age 50.4 years; 11 male) were randomised, and all completed treatment. ATL1103 was well tolerated with mild to moderate injection site reactions being the most common drug-related AE. Four SAEs were reported (three in a single patient) but none were felt to be study drug related. Two patients withdrew at completion of dosing. There was a significant fall in serum IGF1 of 26% by week 14 with 200 mg twice weekly (577±198 vs 411±174 ng/ml (mean±S.D.), P<0.0001) although the nadir had not been reached. Once weekly dosing did not result in a significant fall in IGF1. The fall in IGF1 with twice weekly dosing was associated with a mean reduction ring size circumference of 1.150 mm (P=0.014) and an increase in GH (P=0.001). This study provides proof-of-concept that ATL1103 is able to significantly lower IGF1 in patients with acromegaly.
Volume 37
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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