NEW YORK (Reuters Health) Feb 19 - Pamapimod, a p38 MAP kinase inhibitor, was less effective than methotrexate for rheumatoid arthritis (RA) in an international study.
In the February issue of Arthritis & Rheumatism, the investigators report that even at the highest dose, pamapimod had lower response rates than methotrexate. The study was the first large randomized trial of a p38 MAP kinase inhibitor to report efficacy and safety results.
Based on these and earlier results, Dr. Stanley B. Cohen of Metroplex Clinical Research, Dallas told Reuters Health, "I think it is unlikely that inhibiting p38 MAP kinases will succeed, as all studies have shown limited efficacy and similar toxicity. Other upstream kinases may be more suitable for blockade."
A small molecule of the pyridopyrimidine class, pamapimod selectively inhibits the alpha-isoform of p38 MAP kinase. The alpha-isoform is an enzyme important to the intracellular signaling pathway for the production of the proinflammatory cytokines tumor necrosis factor-alpha or interleukin 1-beta.
The 204 adult patients (predominantly female) in the 12-week double-blind study received either methotrexate or 1 of 3 dosages of pamapimod (50, 150, or 300 mg). At baseline, all 4 groups were generally similar in symptoms, pain and disease activity.
Methotrexate was given orally once weekly, beginning with 7.5 mg and increasing to 15 mg or 20 mg. Pamapimod was taken once daily. Patients taking pamapimod received methotrexate placebo; those taking methotrexate received pamapimod placebos.
Eighty-one percent of the patients completed the study. More patients discontinued in the 300 mg pamapimod group (21%) than in the other 3 groups (6-8%).
As assessed by American College of Rheumatology criteria, patients in the 300 mg pamapimod group generally did better than those in the lower-dosage groups, but patients receiving methotrexate typically did better than those in even the 300 mg pamapimod group.
Adverse events were less frequent in the methotrexate group than in patients receiving pamapimod, with the 300 mg pamapimod group having the highest incidence of adverse events. Adverse events particularly associated with pamapimod were infections and dizziness.
Arthritis Rheum 2009;60:335-3