A quarter of active rheumatoid arthritis (RA) patients receiving either 10mg (24.6%) or 15mg (28.1%) twice daily of the investigational oral JAK-3 (janus-associated kinase) inhibitor CP-690,550 (CP) achieved ACR70* after 12 weeks, according to the results of a new study presented June 11 at EULAR 2009, the Annual Congress of the European League Against Rheumatism in Copenhagen, Denmark. The primary outcome for the study was ACR20*, with 75.4% of patients achieving this measure at 12 weeks for both 10mg and 15mg doses.
The study also showed that, comparatively, the ACR70* responses for adalimumab (ADA, a monoclonal antibody and anti-TNF) and placebo, were 3.8% and 5.1% respectively at the same follow up point.
At the 12 week interim analysis, three doses (5mg, 10mg and 15mg twice daily) of CP demonstrated statistical superiority to placebo in nearly all clinical outcomes measured, including: ACR20, HAQ-DI** and DAS28***, in patients who had had a previously inadequate response to a DMARD (disease-modifying anti-rheumatic drug). Of patients receiving 15mg twice daily CP, 75.4% achieved ACR20 and 40.4% reached DAS28 remission; compared with 47.2% of ADA and 28.8% of placebo patients for ACR20; and 4.4% of ADA and 6.7% of placebo patients for DAS28 remission respectively.
Dr Roy Fleischmann, Clinical Professor of Medicine, University of Texas, Dallas, USA who led the study, said: "The development of oral small-molecule JAK inhibitors, such as CP which targets the JAK-1/3 enzyme pathway, represents a new approach in the treatment of RA. These drugs offer the potential for more precise targeting than existing oral DMARD treatments, in addition to a more convenient oral administration than biologic treatments. The results of this study would suggest that the compound appears worthy for future phase III investigation."
In the 6-month double-blind phase IIb dose-ranging study, 384 patients were randomised to various trial doses of oral CP: 1mg, 3mg, 5mg, 10mg and 15mg twice daily; or to ADA 40mg subcutaneous injection every other week for 12 weeks followed by CP 5mg twice daily or placebo.
The most frequently-reported CP treatment-emergent all-cause AEs were urinary tract infections (4.4%), diarrhoea (4.0%), bronchitis (3.7%), and headache (3.7%). Most frequently-reported ADA treatment-emergent all-cause AEs were bronchitis and pruritus (5.7% each), and blood creatinine increase, dizziness, headache, influenza, nausea, rash, and swelling (3.8% each).
The inclusion criteria for the study were as follows: patients with active RA (6 tender joints and 6 swollen joints (66/68 joint count)), and CRP (c-reactive protein) >7 mg/dL or ESR (erythrocyte sedimentation rate) > ULN). 87% of the 384 patients who were randomised to receive a study drug were female, with mean baseline value ranges as follows: age 52.4 - 55.1 years; disease duration 7.7 - 11.0 years; HAQ DI 1.4 - 1.6; DAS28-3 (CRP) 5.4 - 5.6; and 70 - 83% RF positive. The data presented at EULAR are taken from a week 12 interim analysis of the 6-month study and include efficacy and safety assessments taken at weeks: 2, 4, 6, 8, 10, and 12. The HAQ-DI response was classified as a 0.22 unit improvement from baseline, and DAS28 remission was set at DAS28-3 (CRP) achieving < 2.6.
Oral JAK inhibitors are also currently being investigated for a variety of other therapeutic uses, including: other autoimmune diseases (such as multiple sclerosis and psoriasis), prevention of organ rejection following transplant and certain cancers.
* ACR (American College of Rheumatology) criteria measures improvement in tender or swollen joint counts and improvement in three of the following five parameters: acute phase reactant (such as sedimentation rate), patient assessment, physician assessment, pain scale and disability/functional questionnaire. ACR20 refers to a 20% improvement in tender/swollen joint counts, as well as three of the five other criteria. ACR50 refers to a 50% improvement, and ACR70 refers to a 70% improvement.
** HAQ (Health Assessment Questionnaire) is a disability index used by physicians to measure an individual's physical functioning. It assesses ability to undertake everyday activities such as dressing, eating and walking, and whether assistance from another person or disability aids is required. A higher score indicates greater disability.
*** DAS28 (Disease Activity Score) is an index used by physicians to measure how active an individual's RA is. It assesses number of tender and swollen joints (out of a total of 28), the erythrocyte sedimentation rate (ESR, a blood marker of inflammation), and the patient's 'global assessment of global health'. A higher score indicates more active disease.
Materials provided by European League Against Rheumatism. Note: Content may be edited for style and length.
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