Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
AC430, a Potent JAK2 Inhibitor, Provides Protection in Multiple Inflammatory and Autoimmune Disease Models.
Belli1, Barbara, Brigham2, Daniel, Dao2, Alan, Nepomuceno2, Ron, Setti2, Eduardo, Liu2, Gary, Hadd2, Michael
Rheumatoid arthritis is a multi-factorial disease, and a sub-population of patients who are refractory to current therapy continues to exist. Recent clinical trials have demonstrated the safety and efficacy of small molecule inhibitors of the JAK kinase pathway in alleviating RA symptoms.
We have developed a potent JAK2 inhibitor, AC430, which demonstrates in vitro and in vivo activities comparable or superior to the activities of current clinical stage JAK inhibitors. In in vitro binding assays, AC430 binds potently to JAK2 and TYK2 with sub-nanomolar Kd values. In a TF-1 cell-based GM-CSF/JAK2/STAT5 driven transcriptional reporter system, AC430 inhibited reporter activity with an IC50 of 63 nM. BaF3 cell lines were generated that harbor an individual JAK family member gene fused to the activating TEL dimerization moiety. In these TELJAK cell lines AC430 inhibited JAK1, JAK2, JAK3 and TYK2 mediated STAT5 phosphorylation with IC50 values of 5500, 68, 7500 and 1300 nM, respectively. Each of the four TELJAK cell lines is leukemogenic following IV inoculation into SCID mice. The efficacy of AC430, and the clinical stage compound INCB18424, were tested in each leukemia disease model. Both compounds, when dosed at 60 mg/kg BID, demonstrated significant efficacy in the TELJAK2 driven model, providing an increase in life span (ILS) of 250% and 140% for AC430 and INCB18424, respectively. Marginal to no activity was observed in the other TELJAK driven leukemic models with either compound.
AC430 was tested in a classic delayed type hypersensitivity reaction model. Balb/C mice sensitized and challenged with ovalbumin in the ear pinna develop inflammation quantifiable by caliper measurement and increase in ear weight. AC430 dosed at 100 mg/kg QD led to a 60% reduction in inflammation. In an established mouse CIA model, therapeutic dosing of AC430 at 60 mg/kg BID led to a reduction in disease severity comparable to dexamethasone. AC430 was tested in two models of rat CIA. In the first model, therapeutic dosing initiated on day 1 of arthritis at 60 mg/kg QD or BID led to a significant reduction in disease severity comparable to the effect induced by dexamethasone, but with less toxicity than seen with dexamethasone. In the second model, therapeutic dosing initiated on day 3 of arthritis at 60 mg/kg BID led to a reduction of disease severity comparable to dexamethasone. In both models, clinical score correlated with histological score. In the standard disease model, 60 mg/kg BID resulted in no inflammation, cartilage damage, or pannus formation. AC430 was also tested in a mouse model of Experimental Autoimmune Encephalitis using a prophylactic dosing regimen. All doses greater than 5 mg/kg completed prevented the onset of disease, both clinically and histologically.
These data support the further development of AC430 as a treatment option for autoimmune or inflammatory disease.
To cite this abstract, please use the following information:
Belli, Barbara, Brigham, Daniel, Dao, Alan, Nepomuceno, Ron, Setti, Eduardo, Liu, Gary, et al; AC430, a Potent JAK2 Inhibitor, Provides Protection in Multiple Inflammatory and Autoimmune Disease Models. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :269