Effect of SOM230 a stable somatostatin analogue with a universal binding profile on GH, IGF-1 and glucose levels in rats

Abstract

Somatostatin is expressed in many tissues throughout the body including the CNS, the gastrointestinal (GI) tract and the pancreas. Somatostatin exerts effects on target cells via activation of 5 SRIF receptors (sst1 to sst5) and inhibits effectively growth hormone and insulin-like growth factor-I (IGF-I) release. Natural somatostatins (SRIF 14 or 28) bind with high affinity to all sst receptors, however their use is limited by the rapid proteolytic degradation in plasma (t½ ≤3min). The octapeptide Sandostatin (SMS 201–995) is successfully used in 2/3 of acromegaly patients and patients with gastroenteropancreatic (GEP) tumors, although desensitization of the inhibitory response occurs in GEP tumor patients after prolonged treatment. SOM230 is a new SRIF analog which binds with nanomolar affinity to sst1–3 and sst5. In short term (1h) rat experiments SOM230 and SMS 201–995 inhibit GH release with similar potency; however, the inhibitory effect of SOM230 on GH release was 4-fold more potent at 6h post injection than SMS 201–995, indicating its increased metabolic stability. In fact, PK studies in rats demonstrated a plasma half-life of SOM230 of 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 analogue 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. This enhanced effect of SOM230 on IGF-1 plasma levels was confirmed in an 8-week study where both analogs were infused at the high dose of 50µg/kg/h in rats. The marked suppression of plasma IGF-1 levels corresponded with potent inhibition of body weight gain of rats. In acute studies in Rhesus monkey, SOM230 and SMS 201–995 treatment resulted in GH inhibition at 1h with ID50 values of 0.5 and 0.4µg/kg respectively, but plasma IGF-1 levels were only lowered by SOM230 at this early time point (-53% at 24h post injection). In Cynomolgus monkeys a 2-week infusion of SOM230, but to a much lesser extent SMS 201–995, lowered plasma GH levels significantly (from 16.3 to 1.8 ng/ml). At 10µg/kg s.c. SOM230 caused a marked increase in glucose concentration 1h after dosing, whereas after 6h the glucose levels were back at control values. Lower doses and SMS 201–995 at all doses did not increase plasma glucose concentrations at any time point. In long-term studies 10µg/kg/h s.c. SOM230 had no effect on basal glucose levels after more than 14 days of dosing. The transient increase in plasma glucose concentration in rats is not observed in dogs, mice and monkeys and is in line with a strong inhibition of insulin secretion in rats. In conclusion, SOM230 has a unique structure, binds almost universally to human sst's and inhibits potently the GH/IGF-1 axis in various species. SOM230 is currently being evaluated in healthy volunteers and acromegalic patients.