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

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.

journal_name

Eur J Endocrinol

journal_title

European journal of endocrinology

authors

Trainer PJ,Newell-Price JDC,Ayuk J,Aylwin SJB,Rees A,Drake W,Chanson P,Brue T,Webb SM,Fajardo C,Aller J,McCormack AI,Torpy DJ,Tachas G,Atley L,Ryder D,Bidlingmaier M

doi

10.1530/EJE-18-0138

subject

Has Abstract

pub_date

2018-08-01 00:00:00

pages

97-108

issue

eissn

0804-4643

issn

1479-683X

pii

EJE-18-0138

journal_volume

179

pub_type

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