Acromegaly is a chronic disorder resulting from excessive secretion of growth hormone, with a resulting increase in the production of the hormone known as insulinlike growth factor 1 (IGF-1). ATL1103 is a second-generation antisense drug designed to silence growth hormone receptor expression, thereby reducing levels of IGF-1 in the blood. It is currently under investigation as a potential treatment for diseases associated with excessive growth hormone action, such as acromegaly [Störmann S, Schopohl J. Expert Opin Emerg Drugs. 2014].

Peter J. Trainer, MD, The Christie National Health Service Foundation Trust, Manchester, United Kingdom, reported primary efficacy results from the phase 2 clinical trial of ATL1103 in patients with acromegaly [2012-003147-30]. The ATL1103 phase 2 trial was a randomized, open-label, multicenter, parallel group study of the safety, tolerability, pharmacokinetics, and efficacy of 2 subcutaneous dosing regimens of ATL1103 in 26 adult patients in the United Kingdom, France, Spain, and Australia. Patients were required to have active acromegaly, defined as an IGF-1 level > 130% of the upper limits of normal. In addition, patients had to undergo a washout from long-acting somatostatin agonists (4 months) and dopamine agonists (6-8 weeks). Patients were excluded if they had a tumor within 3 mm of the optic chiasm or had undergone pituitary surgery within 3 months or radiotherapy within 1 year.

Over a period of 13 weeks, patients were randomized to 2 groups. One group (n = 13) received the injection of 200 mg 3 times in the first week and 200 mg once weekly thereafter; the second group (n = 13) received 200 mg 3 times in the first week and 200 mg twice weekly thereafter. The primary end point was the percent change in IGF-1 at week 14. Pharmacokinetics and safety were also measured. At baseline, patients in the 200 mg once weekly group were younger (mean age, 48 ± 14 vs 53 ± 17) and had greater weight (97 ± 20 vs 85 ± 25) than those in the 200 mg twice weekly group. However, both groups had a similar number of male patients (5 vs 6), patients who had prior radiotherapy (5 vs 6), and those who had prior surgery (13 vs 12).

Only patients who received ATL1103 200 mg twice weekly showed a statistically significant reduction in IGF-1 levels at week 14 compared with baseline. Specifically, in the 200 mg twice weekly group, mean IGF-1 levels reduced by 26% from about 600 ng/mL at baseline to nearly 400 ng/mL at week 14 (P < .0001), whereas in the 200 mg once weekly group, mean IGF-1 levels were about 500 ng/mL at baseline, with a nonsignificant reduction at week 14. IGF-1 levels normalized in 1 patient in both groups at week 14. Mathematical modeling of the dose curve for the higher dose of ATL1103 suggests that the maximum reduction of IGF-1 would be seen at 17 or 21 weeks if the patients had been treated for that long.

There were no significant changes in 2 secondary outcomes among patients on either dose, including signs and symptoms and the global Acromegaly Quality of Life score. Patient ring size was reduced significantly in the higher dose group (P = .01).

The 2 most frequent treatment-emergent events included injection site reactions and headache. One patient in each group withdrew from the study and there were 4 serious adverse events, none of which were thought to be drug related. No patient reported flulike symptoms, which are a recognized side effect in drugs of this class.

Prof Trainer concluded that for many patients with acromegaly, a larger dose of ATL1103 taken over a longer period of time will likely be well tolerated and able to produce improved disease control.