A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly PMID: 29789410

ADC Targets in Oncology

2026-04-10

A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly

Eur J Endocrinol. 2018 Aug;179(2):97-108. doi: 10.1530/EJE-18-0138.

Peter J Trainer ¹ , John D C Newell-Price ² ³ , John Ayuk ⁴ , Simon J B Aylwin ⁵ , Aled Rees ⁶ , William Drake ⁷ , Philippe Chanson ⁸ ⁹ , Thierry Brue ¹⁰ ¹¹ , Susan M Webb ¹² , Carmen Fajardo ¹³ , Javier Aller ¹⁴ , Ann I McCormack ¹⁵ , David J Torpy ¹⁶ , George Tachas ¹⁷ , Lynne Atley ¹⁷ , David Ryder ¹⁸ , Martin Bidlingmaier ¹⁹

Affiliations

1. Department of Endocrinology, The Christie NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
2. Department of Oncology and Metabolism, The Medical School, University of Sheffield, Sheffield, UK.
3. Royal Hallamshire Hospital, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK.
4. Medicine Endocrinology, Queen Elizabeth Hospital Birmingham, Edgbaston, UK.
5. King's College Hospital, London, UK.
6. Neuroscience and Mental Health Research Institute, School of Medicine, Cardiff University, Hadyn Ellis Building, Cardiff, UK.
7. Department of Endocrinology, St Bartholomew's Hospital, London, UK.
8. Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Hôpital de Bicêtre, Service d'Endocrinologie et des Maladies de la Reproduction, Le Kremlin-Bicêtre, France.
9. Inserm 1185, Fac Med Paris Sud, Univ Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
10. Aix-Marseille Université, CNRS, CRN2M UMR 7286, Marseille, France.
11. APHM, Hôpital Conception, Service d'Endocrinologie, Diabète et Maladies Métaboliques, Centre de Référence des Maladies Rares d'Origine Hypophysaire, Marseille, France.
12. Department of Endocrinology, CIBERER Group 747, IIB-S Pau, Hospital de la Santa Creu i Sant Pau, Universitat Autonoma de Barcelona, Barcelona, Spain.
13. Servicio de Endocrinología, Hospital Universitario de La Ribera, Alzira, Valencia, Spain.
14. Endocrinology Department, Hospital Universitario Puerta de Hierro Majadahonda, Majadahonda, Spain.
15. Garvan Institute of Medical Research and St Vincent's Hospital, Darlinghurst Sydney, New South Wales, Australia.
16. Royal Adelaide Hospital, North Terrace, Adelaide, Australia.
17. Antisense Therapeutics Limited, Toorak, Victoria, Australia.
18. Manchester Academic Health Science Centre (MAHSC) Clinical Trials Unit, The Christie NHS Foundation Trust, University of Manchester, Manchester, UK.
19. Endocrine Laboratory, Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany.

Abstract

Objective: ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly.

Design: Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period.

Methods: The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events.

Results and conclusions: Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.