EP4 receptor antagonist for immunomodulation in RA
CR6086 is an oral, potent and selective small molecule antagonist of the prostaglandin E2 receptor, EP4 subtype (i.e. the EP4 receptor). The extensive nonclinical development demonstrated that CR6086 is a novel targeted immunomodulator.
Pharmacology studies have shown that prostaglandin E2, via the EP4 receptor, plays a key role in the altered immune response observed in autoimmune diseases such as rheumatoid arthritis (RA) and ankylosing spondylitis (AS). These findings point to the EP4 receptor as a rational target for novel disease-modifying antirheumatic drugs (DMARDs)/immunomodulators which, in addition, have direct anti-inflammatory properties distinct from the general effects of e.g. mere NSAIDs.
In gold-standard animal models of arthritis, CR6086 performs better than first-line DMARDs such as methotrexate and similarly to DMARDs for the advanced disease (e.g. immunosuppressants like JAK inhibitors, or biologicals like TNF inhibitors).
The three completed Phase I studies of this compound have shown a very good safety/tolerability profile and favourable pharmacokinetics, with relevant concentrations for target engagement.
CR6086 is initially being developed as a first-line therapy in DMARD-naïve, early RA patients, i.e. an innovative paradigm compared to the vast majority of new, biological or small molecule interventions in RA, obliged to target the late phase disease because of their safety problems. In a completed Phase II trial, CR6086 was administered for 12 weeks in combination with MTX in DMARD-naïve patients with early RA, and the proof of concept of clinical efficacy was obtained in patients with at least 6 months disease duration.
Efficacy and safety of CR6086 in DMARD-experienced RA patients is strongly supported by its nonclinical pharmacological profile, and may be tested as a second step. Finally, recent scientific evidence provides compelling support to the clinical testing of CR6086 in AS.