The new somatostatin analog SOM230 in the treatment of acromegaly

Abstract

Most GH-secreting pituitary adenomas predominantly express sst2 and sst5, while sst1 and sst3 are moderately and sst4 almost not expressed. The clinically available SS-analogs octreotide and lanreotide display a high, low and moderate affinity to sst2, sst1+3 and sst5 respectively. Saveanu et al. reported that due to the heterogeneous expression of sst2 and sst5 subtypes in GH-secreting adenomas, a bispecific analog, such as BIM-23244 that can activate both receptors, and may achieve a better control of GH hypersecretion of acromegalic tumors. Bruns et al synthesized SOM230, a new cyclic hexapeptide somatostatin (SRIF) analog which binds with nanomolar affinity to sst1, 2, 3 and 5 receptors. In short term (1h) rat experiments, SOM230 and SMS 201–995 inhibit GH release with similar potency, but the effect of SOM230 was longer lasting, due to its increased metabolic stability. The plasma half-life of SOM230 in rats is 23h, as compared to 2h for SMS 201–995. The improved metabolic stability of SOM230 was confirmed in monkeys and humans. Continuous treatment of rats with SOM230 at 10µg/kg/h, decreased IGF-1 plasma levels on day 2 by 90% while under SMS 201–995 treatment plasma IGF-1 levels decreased only by 49%. After a 2-week infusion of somatostatin analogues in rats the suppression of GH and IGF-1 levels by SOM230 was still pronounced, while the response to SMS 201–995 was largely lost. Similar results were obtained in dogs and monkeys. Normalization of GH values was obtained recently in a first clinical study in acromegalic patients acutely treated with SOM230. Most importantly, SOM230 reduced plasma GH level in a patient unresponsive to octreotide and this patient showed a high expression of sst5. Similarly, sst5 receptors were found to be heavily expressed in ACTH secreting pituitary cells from Cushing's patients (Hofland et al.,) and SOM230 is shown strongly inhibiting ACTH release in vitro, in contrast to octreotide. In conclusion, SOM230 might be more efficacious than octreotide in established indications and has the potential for the treatment of additional endocrine indications, such as Cushing's disease, as well as non-endocrine indications, due to its multiligand binding properties. Studies evaluating effects of SOM230 in patients with Cushing's disease and somatostatin refractory carcinoid syndrome are ongoing.