Newswise — A novel new therapy in development known as a JAK inhibitor may be an effective treatment for people with rheumatoid arthritis who haven’t been successfully treated with methotrexate, according to research presented this week at the American College of Rheumatology Annual Scientific Meeting in Philadelphia, Pa.
Rheumatoid arthritis is a chronic disease that causes pain, stiffness, swelling, and limitation in the motion and function of multiple joints. Though joints are the principal body parts affected by RA, inflammation can develop in other organs as well. An estimated 1.3 million Americans have RA, and the disease typically affects women twice as often as men.
Immune cells receiving external activation signals utilize a variety of enzymatic reactions in order to transmit these signals to the nucleus, where the cell’s genetic signals and protein-producing apparatus are located. One of the enzymes involved in this process is designated janus kinase, or JAK as it is commonly called, and inhibitors of JAK may reduce the activity of immune-mediated diseases such as rheumatoid arthritis.
Researchers recently compared the effectiveness, safety and tolerability of six different doses of an oral JAK inhibitor with placebo in people with RA who did not respond adequately to methotrexate alone.
To study the difference in outcomes over a 24-week time period, researchers placed 507 people in one of seven dosing groups: one, three, five, 10 or 15 milligrams of JAK inhibitor two times a day; 20 milligrams once a day; or on placebo. All patients remained on methotrexate throughout the study. Anyone who didn’t have a 20 percent decrease in tender and swollen joints at 12 weeks was placed on five milligrams of JAK inhibitor twice a day for the rest of the study.
Clinical response was seen for all six doses of the JAK inhibitor, but was most notable for the five, 10, and 15 milligram twice daily and the 20 milligram once daily doses. Sixty-five patients (all from the placebo, one and three milligram twice daily, and the 20 milligram once daily groups) did not have a 20 percent decrease in tender and swollen joints and were placed on the five milligrams twice a day at 12 weeks.
Overall, 37 percent of patients on the JAK inhibitor experienced side effects such as headache, diarrhea, inflammation of the nasal passages, and nausea. Approximately four percent of patients had serious side effects such as respiratory tract infections, urinary tract infections, or pneumonia (in 3 cases). No one experienced opportunistic infections or cancer. One patient who was being treated for pneumonia died due to complications of respiratory and heart failure.
Six patients had a 50 percent increase in serum creatinine levels (five of whom were on the JAK inhibitor), which may be an indication of impaired kidney function. Thirteen patients on the JAK inhibitor and one on placebo suffered from anemia; no one had an abnormally low white blood cell count.
“JAK inhibition is clearly a promising treatment for patients with RA,” explains Joel M. Kremer, MD; Pfaff family professor of medicine, Albany Medical College; director of research, The Center for Rheumatology, Albany N.Y., and lead investigator in the study. “JAK is unique in that it has the efficacy of the biologic agents and is an oral drug. Like all new agents in development, we will need to determine the longer term safety and efficacy of the JAK inhibitor. The dose of the JAK inhibitor which might eventually be used in the clinic has not yet been determined with finality.”
Patients should talk to their rheumatologists to determine their best course of treatment.
The ACR is an organization of and for physicians, health professionals, and scientists that advances rheumatology through programs of education, research, advocacy and practice support that foster excellence in the care of people with or at risk for arthritis and rheumatic and musculoskeletal diseases. For more information on the ACR’s annual meeting, see www.rheumatology.org/annual.
Editor’s Notes: Dr. Kremer will present this research during the ACR Annual Scientific Meeting at the Pennsylvania Convention Center at 3:15 PM on Tuesday, October 20 in the Auditorium. Dr. Kremer will be available for media questions and briefing at 1:30 PM on Sunday, October 18 in the on-site press conference room, 109 A.
Presentation Number: 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)
J. Kremer, MD , Albany Medical College, Albany, NY S. Cohen , Metroplex Clinical Research Centre, Dallas, TX B. Wilkinson, PhD , Pfizer Inc, New London, CT D. Gruben , Pfizer Inc, New London, CT G.V. Wallenstein , Pfizer Inc, New London, CT K.S. Kanik, MD , Pfizer Inc, New London, CT S.H. Zwillich, MD , Pfizer Inc, New London, CT J. Frain , Complete Medical Communications, Macclesfield, United Kingdom
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.
(View press release and full abstract with table at www.rheumatology.org).
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.
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.
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