CCR1 Program

CCR1 is an important chemokine receptor target for a number of inflammatory diseases including rheumatoid arthritis (RA). CCX354, which targets CCR1, has successfully completed a Phase II proof-of-concept clinical trial for the treatment of rheumatoid arthritis. Targeting CCR1 represents a new approach for the treatment of RA. Synovial fluid from the joints of RA patients contains high levels of activated CCR1 chemokine ligands. Blocking CCR1 is intended to reduce inflammation and prevent subsequent joint destruction by suppressing the infiltration of inflammatory cells into the arthritic joint. The high potency and bioavailability of the molecule are expected to provide continuous receptor coverage throughout the dosing period which is thought to be critical for efficacy.

Preclinical studies indicate that CCX354 has a favorable safety and PK profile. In pre-clinical studies, CCX354 is well absorbed when given orally and the compound is well tolerated at dose levels much higher than those required to cause inhibition of CCR1 function. In in vitro and pre-clinical studies, because of its potency and selectivity, CCX354 did not appear to have the safety concerns that have hindered others from successfully developing compounds blocking this receptor. In addition, CCX354 does not significantly inhibit the activity of a class of liver protein which is necessary for metabolizing other common drugs that patients may be taking. We believe that this lack of interference suggests that the compound may be safely administered along with other medications used concurrently by RA patients.

Preclinical data suggest that CCX354 selectively inhibits CCR1-mediated migration of monocytes and does not inhibit migration of inflammatory cells mediated by other chemokine receptors, even when the compound is given at high doses. We believe that this high degree of target specificity is an important safety feature that may allow CCX354 to be effective while avoiding unwanted side effects associated with existing injectable biologics and other immunosuppressive agents currently used to treat RA.

We successfully completed two Phase I clinical trials in a total of 84 healthy subjects, followed by a Phase I/II clinical trial in 24 patients with stable RA and a Phase II proof-of-concept clinical trial in 160 patients with moderate-to-severe RA. Results from the Phase II proof-of-concept clinical trial demonstrated that CCX354 was safe and well tolerated by patients with RA in this trial, and demonstrated clinical and biological activity at a dose of 200mg of CCX354 once-daily. This successful Phase II proof-of-concept clinical trial triggered GSK's option rights under our collaboration agreement. GSK exercised its option to further develop and commercialize CCX354 in November of 2011 and has an exclusive right to initiate a Phase IIb clinical trial for CCX354 in RA.

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