Session Information
Session Type: Abstract Submissions (ACR)
Background/Purpose
Janus kinase (JAK) is a family of four tyrosine kinases that play a critical role in cytokine signaling and downstream lymphocyte activation and function. Inhibition of JAK enzymes as therapeutic targets in rheumatoid arthritis (RA) has been validated by multi-JAK inhibitors that modify disease in clinical studies. However, there is also evidence from these trials that JAK inhibition with Tofacitinib increases the risk of infections as well as highlighting other potential toxicity concerns. These side effects are thought to be attributable to JAK2 inhibition, suggesting that better therapeutic ratios might be achieved with selective JAK inhibitors that spare JAK2 activity. Here we report the in vitro and in vivopreclinical characterization of a highly selective JAK1 inhibitor (Compound B) as compared to the effects of a multi-JAK inhibitor (Compound A).
Methods
Biochemical assays were used to determine JAK family kinase potencies. Cellular assays included: 1) IL-6 induced pSTAT3 driven gene expression in ME-180 cells and 2) erythropoietin induced pSTAT5 driven gene expression in TF1 cells. Collagen-induced arthritis (CIA) in female Lewis rats was performed with a subcutaneous injection of bovine collagen on Days 1 and 8. Inflammation was monitored by measuring paw thickness; µCT imaging and histopathological evaluation were also performed in the ankle joint at the end of the study. Inhibition of baseline hematological parameters was assessed separately in naïve female Lewis rats following compound administration.
Results
Compounds A and B are reversible ATP competitive inhibitors of JAK1 and JAK2. Compound A has comparable activity in both enzymatic and cellular assays, whereas Compound B displays ~10X selectivity for JAK1 to JAK2 in the same assays. Therapeutic administration of both compounds dose-dependently inhibited the inflammation resulting from CIA in rats in vivo. Compound exposure levels corresponding to 50% inhibition were approximately 70µM*hr and 12µM*hr for Compounds A and B, respectively. Inhibition of hematological parameters (reticulocytes, hemoglobin and hematocrit levels) in naïve rats was observed with compound administration at exposures comparable to that required for efficacy in the rat CIA model for the non-selective JAK inhibitor, Compound A. In contrast, for the JAK1 selective Compound B, changes in these parameters were not observed until >10X exposures of that required for efficacy in the rat CIA model were achieved. Furthermore, Compound B inhibited bone mineral density loss by µCT and attenuated inflammation, pannus formation, and cartilage damage by histopathology.
Conclusion
We identified a JAK1 selective compound using enzymatic and cellular assays where selectivity translated to in vivo selectivity in rats. These data demonstrate that a similar degree of preclinical efficacy is achievable with a JAK1 selective inhibitor as compared to a multi-JAK inhibitor. Importantly, the JAK1 selective inhibitor provided ~10X therapeutic window to adverse events. The optimal JAK selectivity profile to achieve maximal clinical efficacy with minimal side effects in patients remains to be determined.
Disclosure:
L. Y. Moy,
Merck Pharmaceuticals,
3;
C. S. Chiu,
Merck Pharmaceuticals,
3;
R. Faltus,
Merck Pharmaceuticals,
3;
M. Zielstorff,
Merck Pharmaceuticals,
3;
K. Chakravarthy,
Merck Pharmaceuticals,
3;
S. Deshmukh,
Merck Pharmaceuticals,
3;
I. Kariv,
Merck Pharmaceuticals,
3;
J. Klappenbach,
Merck Pharmaceuticals,
3;
J. Brubaker,
Merck Pharmaceuticals,
3;
D. Liu,
Merck Pharmaceuticals,
3;
T. Siu,
Merck Pharmaceuticals,
3;
J. Young,
Merck Pharmaceuticals,
3;
H. Yu,
Merck Pharmaceuticals,
3;
F. Elwood,
Merck Pharmaceuticals,
3;
M. Cicmil,
Merck Pharmaceuticals,
3.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/efficacy-of-a-novel-orally-bioavailable-jak1-selective-compound-in-a-preclinical-rat-collagen-induced-arthritis-model/