Somatotaxins are synthetic ligands that bind to the ‘CTLP site’ on sstr2. They are the first drugs to target the CTLP pathway and therefore mimic the anti-inflammatory effects of natural CTLPs implicated in the physiological resolution of inflammation. As a result, they have impressive efficacy in a range of preclinical models of chronic inflammatory diseases [see examples of published studies in the Publications section].
Somatotaxins are characterized in vitro by the ability to inhibit leukocyte chemotaxis at sub-nanomolar concentrations. This activity is entirely dependent on sstr2, since several classical sstr2-specific antagonists block the effect completely. It is useful surrogate for CTLP activity but unlikely to be responsible for all (or perhaps even the majority) of the anti-inflammatory effects seen in vivo. Since the activity of somatotaxins depends on cell surface sstr2, their effects are focusing on cells involved in the inflammatory response (that have up-regulated sstr2), while avoiding undesirable immunosuppressive effects on cells of the adaptive immune system (that generally lack sstr2).
Early somatotaxins, like CTLPs, partially compete for somatostatin binding resulting in antagonist effects on endocrine signalling – elevating GH and IGF-1. However, FXT has discovered somatotaxins that bind to the CTLP site but do not affect somatostatin binding to sstr2, allowing the anti-inflammatory activity to be exploited without side-effects.
FX125L is the lead somatotaxin and the best of these “clean” somatotaxins, exhibiting “pharma grade” pharmaceutical properties, including ADME suitable for once-daily oral dosing. FX125L has completed the single and multiple dose Phase I clinical trials in the USA and is ready for “gold standard” three month Phase II studies in major inflammatory conditions, planned to start during 1H 2011.
The clinical indications targeted with FX125L include respiratory disorders such as asthma and COPD, supported by numerous studies in animal models that consistently suggested that in the clinic FX125L may have similar efficacy but better safety than corticosteroids and superior efficacy than montelukast. Other somatotaxins have also been identified as back up molecules to FX125L and as candidates for development as topical anti-inflammatory agents.