In a 12 week, Phase 2b, dose ranging study of baricitinib, a JAK1/JAK2 inhibitor, in com bination with nonbiologic DMARDs, increases in SCr of 0. 09 to 0. 11 mg/dl following two doses of baricitinib for placebo were observed. In a 12 week monotherapy study of the investigational JAK3 selective inhibitor, VX 509, increases in SCr across the dose range were re ported versus ?0. 01 mg/dl for placebo. The JAK signaling pathway is utilized by receptors for interleukins, interferons, and hormones such as growth hormone and erythropoietin to mediate intracellular signaling. Inhibition of JAK1 and/or JAK3 by tofacitinib blocks signaling through the common gamma chain containing receptors for several cy tokines, including IL 2, ?4, ?7, ?9, ?15, and ?21, as well as through receptors for cytokines such as IL 6, IFN gamma, and type 1 IFN.

However, the mechanism for increases in SCr with JAK inhibitors is not understood. JAK 1, 2, and 3 have been identified in kidney cells and tissue, but their role is not defined. The available data do not suggest a deleterious role for JAK inhibition in renal injury models. JAK inhibitor AG 490 was beneficial in several renal injury models, and JAK inhibitor NC1153 was not nephrotoxic in direct contrast to cyclosporine A in the low salt rat model. Tofacitinib was not nephrotoxic in standard nonclinical toxicity studies. No effects on SCr or urea nitrogen were observed, and no adverse histologic findings were detected in studies of up to six months in rats, and nine months in monkeys.

Systemic expo sures, based on area under the plasma concentration versus time curve for unbound tofacitinib, were up to 188 times in rats and six times in monkeys compared to that in patients with RA at a dose of 5 mg BID. Given that small dose dependent increases in mean CK were observed with tofacitinib treatment in the Phase 3 clinical program, we examined the relationship of CRP, as a marker of in flammation, with both SCr and CK. Serum CK has been shown to be lower in patients with RA versus healthy vol unteers and to correlate with the level of inflammation. Generally, mean CK tended to plateau after six months of tofacitinib treatment, stayed within the normal reference range and was not associated Entinostat with clinical myopathy or changes in markers of muscle catabolism. Exploratory analyses revealed an association between high baseline CRP levels and low baseline SCr in this RA population. Furthermore, the higher the CRP, the greater the increases seen in SCr upon treatment with tofacitinib. similar results were observed following adalimumab treatment, but of a lesser magni tude. A similar relationship was observed between CK and CRP and patients with greater CK increases also displayed greater SCr changes.