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

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

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.
PMID: 29789410 DOI: 10.1530/EJE-18-0138
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.

Figures
Products