A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly.
AuthorsTrainer, Peter J
Ryder, W David J
AffiliationDepartment of Endocrinology, The Christie NHS Foundation Trust, University of Manchester, Manchester Academic Health Science Centre, Manchester
MetadataShow full item record
AbstractAbstract OBJECTIVE: ATL1103 is a second-generation antisense oligomer targeting the human GH receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. DESIGN: 26 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, ALS, GH, 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, respectivey. 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 at week 21 remained lower 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 (ISR). This study provides proof-of-concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.
CitationA randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly. 2018, Eur J Endocrinol
JournalEuropean Journal of Endocrinology
- Diagnostic value of the acid-labile subunit in acromegaly: evaluation in comparison with insulin-like growth factor (IGF) I, and IGF-binding protein-1, -2, and -3.
- Authors: Arosio M, Garrone S, Bruzzi P, Faglia G, Minuto F, Barreca A
- Issue date: 2001 Mar
- Successful use of weekly pegvisomant administration in patients with acromegaly.
- Authors: Higham CE, Thomas JD, Bidlingmaier M, Drake WM, Trainer PJ
- Issue date: 2009 Jul
- Differential effects of octreotide treatment and transsphenoidal surgery on growth hormone-binding protein levels in patients with acromegaly.
- Authors: Hernandez I, Soderlund D, Espinosa-de-los-Monteros AL, Ochoa R, Zarate A, Mercado M
- Issue date: 1999 Apr
- Octreotide as primary therapy for acromegaly.
- Authors: Newman CB, Melmed S, George A, Torigian D, Duhaney M, Snyder P, Young W, Klibanski A, Molitch ME, Gagel R, Sheeler L, Cook D, Malarkey W, Jackson I, Vance ML, Barkan A, Frohman L, Kleinberg DL
- Issue date: 1998 Sep
- Control of IGF-I levels with titrated dosing of lanreotide Autogel over 48 weeks in patients with acromegaly.
- Authors: Chanson P, Borson-Chazot F, Kuhn JM, Blumberg J, Maisonobe P, Delemer B, Lanreotide Acromegaly Study Group.
- Issue date: 2008 Aug