A phase II randomised, open-label, parallelgroup study of the safety, tolerability, pharmacokinetics and efficacy of two subcutaneous dosing regimens of ATL1103 in adult patients with acromegaly

ATL1103 is a second generation antisense oligomer directed at the GH receptor. It is a 20mer with a phosphorothioate backbone and with 2′-0-methoxyethyl modifications of the five nucleotides at either end intended to increase its plasma half-life and affinity for the target RNA, post-hybridization leading to RNaseH degradation of the GHr RNA strand. ATL1103 is relatively rapidly distributed from plasma (Cmax in 2-4 hrs) into peripheral tissues, with a tissue clearance half-life of over 2-4 weeks in primates. Data from mouse and monkey studies indicate it to be a potent inhibitor of liver GHR mRNA expression and an inhibitor IGF-I secretion. A phase 1 study conducted in 36 healthy volunteers at a maximum single dose of 400 mg or repeated dosing of 250 mg on six occasions over three weeks demonstrated it to be well-tolerated with a fall in serum IGF-I and GHBP being seen with repeated dosing. 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 every jurisdiction and the study is registered as EudraCT 201200314730. Patients gave written informed consent. The protocol entailed appropriate washout from any ongoing medical therapy after which IGF-I had to be at least >1.30 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 eight weeks. The primary objectives as per protocol were to evaluate the safety and to understand the single dose and multiple dose pharmacokinetic profiles of ATL1103 in patients with acromegaly. 35 patients were recruited in 13 centres in Australia, France, Spain and UK. 26 were randomised all of whom completed treatment. The results from the study will be presented at the congress.