Celgene opens Phase 2 study of CC-220 in SLE

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• CC-220 is a small molecule developed by Celgene that has previously been reported to bind cereblon.  This intracellular protein forms part of the E3 ubiquitin ligase, a multi-protein complex responsible for protein degradation. Thalidomide also binds cereblon and this is believed to produce its well known teratogenic activity by inhibiting the ubiquitination process and in turn reducing FGF levels

• When incubated with SLE monocytes, CC-220 reduces IRF-4, BLIMP-1, XBP-1 levels, and blocks immunoglobulin production suggesting it may share the immunomodulatory activity of thalidomide and related IMiDs

• Following two earlier Phase 1 studies Celgene has now opened a does ranging study in SLE patients

• The study will randomize 140pts with skin involvement to placebo or 4 dosing regimens

• The study will be in two parts, the first will evaluate safety and PK activity in 40pts

• The second part of the study will be initiated once safety has been demonstrated and will aim to demonstrate improvement in skin manifestations

• Celgene also plans to open studies in sarcoidosis and systemic sclerosis

Comments:   The risk of teratogenicity and venous thrombosis with thalidomide and its analogues is well recognized, however It has previously been suggested that the therapeutic and teratogenic effects of these agents can be dissociated.  It is unclear whether the molecular mode of action of CC-220 allows this dissociation, in turn supporting the immunomodulatory effects of the IMiDs without the AEs.  We presume that since Celgene is developing CC-220, it has identified a mechanism suggestive of an increase in therapeutic index