1925 - Safety and Efficacy After 24 Week (WK) Dosing of the Oral JAK Inhibitor CP-690,550 (CP) in Combination with Methotrexate (MTX) in Patients (PTS) with Active Rheumatoid Arthritis (RA)

Tuesday, October 20, 2009: 3:15 PM
Auditorium (Pennsylvania Convention Center)
J. Kremer1, S. Cohen2, B. Wilkinson3, D. Gruben3, G.V. Wallenstein3, K.S. Kanik3 and S.H. Zwillich3, 1Albany Medical College, Albany, NY, 2Metroplex Clinical Research Centre, Dallas, TX, 3Pfizer Inc, New London, CT
Presentation Number: 1925

Purpose:  To compare the efficacy, safety, and tolerability of 6 doses of CP compared with placebo (PBO) for treatment of active RA in pts with an inadequate response to stable background MTX alone.

Methods: This was a 24-wk, double-blind, placebo-controlled Phase 2B study.  Pts with active RA (≥6 tender/swollen joints, CRP >7 mg/L or ESR > ULN) were randomized to: CP 1, 3, 5, 10, 15 mg BID, 20 mg QD, or PBO.  Pts receiving CP 1 mg BID, 3 mg BID, 20 mg QD, or PBO not achieving ≥20% decrease from baseline in tender and swollen joint counts at Wk 12 (non-responders) were reassigned to CP 5 mg BID for the rest of the study (13-21 per arm).  Pts remained on stable background MTX of 7.5 to 25 mg/wk. Data are from Wk 24 final analyses.

Results: 507 pts were randomized.

18 (26%), 21 (30%), 13 (19%) and 13 (16%) of PBO, 1 mg BID, 3 mg BID and 20 mg QD dose groups, respectively, were advanced to 5 mg BID at Wk 12 (non–responders in efficacy analysis).  Previous interim results reported pts receiving 3 mg BID and higher had statistically significant efficacy compared with placebo by ACR 20/50/70 and DAS28 at Wk 12.  Efficacy was seen at doses of 5 mg BID and higher at Wk 24 (Fig 1).

Overall, 188 (37.1%) pts had a total of 896 treatment emergent adverse events (TEAEs), and 21 (4.1%) had serious AEs (SAEs).  The most common TEAEs across all CP arms (n=438) were: UTI 27 (6.2%), headache 26 (5.9%), diarrhea 25 (5.7%), nasopharyngitis 24 (5.5%), and nausea 21 (4.8%) and were more common at higher doses. The most common TEAEs across the PBO arm (n=69) were: UTI 3 (4.3%), nasopharyngitis 3 (4.3%), and pharyngitis 3 (4.3%).

5 (1.0%) pts had serious infections: 3 pneumonia (CP 3 mg BID, 5 mg BID and 20 mg QD), 1 UTI (CP 3 mg BID), and 1 respiratory tract infection (CP 10 mg BID).  There were no opportunistic infections, malignancies, or lymphomas.  One pt with treatment related pneumonia (CP 3mg BID) died due to complications of respiratory and cardiac failure. 

6 pts had confirmed >50% increase in serum creatinine levels from baseline (5 pts in CP groups and 1 pt in PBO [reassigned to CP 5 mg BID at Wk 12]), none discontinued. 13 pts on CP and 1 pt on PBO had confirmed severe anemia (OMERACT criteria, none discontinued), and no pts had confirmed severe neutropenia (OMERACT criteria, none discontinued). There was a dose response in increases in LDL with the highest doses having the highest increase; the proportion of CP pts with a LDL <130 mg/dl at baseline that increased to >130 mg/dl at any time during the study ranged from 32% to 42% for the highest doses. 5 pts had elevations in ALT>3xULN (4 pts CP 15 mg BID and 1 pt each CP 10 mg BID, CP 20 mg QD, and PBO).

Conclusion: In pts with active RA despite MTX, CP dosed at 5 mg, 10 mg, and 15 mg BID showed sustained efficacy and a manageable safety profile through 24 wks.

Keywords: DMARDs, Janus kinase (JAK) and rheumatoid arthritis (RA)

Disclosure: J. Kremer, Abbott, Amgen, BMS, Centocor, Genentech, Pfizer, UCB, 2, BMS, Centocor, Pfizer, UCB, 5 ; S. Cohen, Pfizer Inc, Amgen, Wyeth, Proctor and Gamble, Genentech, Biogen-Idec/Roche, 2, Genentech/Roche/Amgen/ Biogen-Idec, 5 ; B. Wilkinson, Pfizer Inc, 3 ; D. Gruben, Pfizer Inc, 3 ; G. V. Wallenstein, Pfizer Inc, 3 ; K. S. Kanik, Pfizer Inc., 3 ; S. H. Zwillich, Pfizer Inc, 3 .