pamapimod and Arthritis--Rheumatoid

To determine the efficacy and safety of pamapimod in adult patients with active rheumatoid arthritis (RA) who had an inadequate clinical response to methotrexate (MTX).. Patients receiving stable doses of MTX were randomised to one of six dose groups and received 12 weeks of double-blind pamapimod (up to 300 mg once daily) or matching placebo. The primary efficacy measure was the proportion of patients with > or =20% improvement in RA based on the American College of Rheumatology criteria (ACR20) at 12 weeks. Secondary measures were ACR50, Disease Activity Score (DAS)/European League Against Rheumatism (EULAR) responses and the individual ACR core set of parameters. Safety measures included adverse events (AEs), laboratory testing and immunology assessments.. On a background of MTX, the percentage of patients with an ACR20 response at week 12 in the pamapimod groups (31% to 43%) was not significantly different from placebo (34%). Secondary efficacy end points showed a similar pattern. AEs were typically mild and included infections, gastrointestinal disturbances, dizziness and rashes; AEs resulting in discontinuation of study drug were primarily attributed to infections.. In patients with active RA receiving stable doses of MTX, pamapimod showed non-significant improvement in efficacy outcomes compared to placebo.

Topics: Adolescent; Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Biomarkers; C-Reactive Protein; Double-Blind Method; Drug Therapy, Combination; Humans; Methotrexate; Middle Aged; p38 Mitogen-Activated Protein Kinases; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Severity of Illness Index; Treatment Outcome; Young Adult

This study evaluated the potential pharmacokinetic interaction of pamapimod, a p38 mitogen-activated protein kinase inhibitor, and methotrexate (MTX) when administered concomitantly in patients with rheumatoid arthritis (RA); the study also evaluated the pharmacodynamic effects of pamapimod. Twenty-two RA patients on a stable regimen of MTX (10-25 mg/wk; administered on days 1 and 8) were randomized to receive 300 mg of pamapimod (n = 17) or placebo (n = 5) once daily (qd) for 10 days (days 5-14). Blood and urine samples were collected pre- and postdose on days 1 (MTX alone), 7 (pamapimod alone), and 8 (MTX and pamapimod coadministered). No clinically significant changes were observed in plasma exposures and renal clearance of pamapimod, MTX, or their metabolites, whether administered separately or concomitantly. The combination of pamapimod (300 mg qd) for 10 days and weekly MTX was generally well tolerated. Parameters of RA disease--namely, tender joint count, swollen joint count, erythrocyte sedimentation rate, and C-reactive protein--generally decreased between days 5 and 14. The results of this study suggest that dose adjustments for either drug are not necessary when concomitantly administered and that pamapimod can decrease pharmacodynamic markers of disease activity.

Topics: Adult; Aged; Antirheumatic Agents; Arthritis, Rheumatoid; Drug Interactions; Drug Therapy, Combination; Female; Humans; Male; Methotrexate; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pyridones; Pyrimidines; Treatment Outcome

To determine the efficacy and safety of pamapimod (a selective inhibitor of the alpha-isoform of p38 MAP kinase) as monotherapy in comparison with methotrexate (MTX) treatment in adult patients with active rheumatoid arthritis (RA).. Patients were randomly assigned to 1 of 4 treatment groups and received 12 weeks of double-blind treatment. One group received MTX (7.5 mg/week with planned escalation to 20 mg/week), and 3 groups received pamapimod (50, 150, or 300 mg) once daily. The primary efficacy end point was the proportion of patients meeting the American College of Rheumatology 20% improvement criteria (achieving an ACR20 response) at 12 weeks. Secondary end points included ACR50 and ACR70 responses, change from baseline in the Disease Activity Score in 28 joints (DAS28), categorical analyses of DAS28/European League Against Rheumatism response, and change from baseline in each parameter of the ACR core set of measures. Safety monitoring included recording of adverse events (AEs), laboratory testing, immunology assessments, administration of electrocardiograms, and assessment of vital signs.. Patients assigned to receive MTX and pamapimod had similar demographics and baseline characteristics. At week 12, fewer patients taking pamapimod had an ACR20 response (23%, 18%, and 31% in the 50-, 150-, and 300-mg groups, respectively) compared with patients taking MTX (45%). Secondary efficacy end points showed a similar pattern. AEs were typically characterized as mild and included infections, skin disorders, and dizziness. Pamapimod was generally well tolerated, but the 300-mg dose appeared to be more toxic than either the 2 lower doses or MTX.. The present results showed that pamapimod was not as effective as MTX in the treatment of active RA.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; C-Reactive Protein; Double-Blind Method; Female; Health Status; Humans; Male; Methotrexate; Middle Aged; p38 Mitogen-Activated Protein Kinases; Pyridones; Pyrimidines; Severity of Illness Index; Treatment Outcome

The development of a new series of p38α inhibitors resulted in the identification of two clinical candidates, one of which was advanced into a phase 2 clinical study for rheumatoid arthritis. The original lead, an lck inhibitor that also potently inhibited p38α, was a screening hit from our kinase inhibitor library. This manuscript describes the optimization of the lead to p38-selective examples with good pharmacokinetic properties.

Topics: Administration, Oral; Arthritis, Rheumatoid; Biological Availability; Cell Line; Clinical Trials as Topic; Drug Discovery; Humans; Mitogen-Activated Protein Kinase 14; Models, Molecular; Protein Conformation; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Structure-Activity Relationship; Substrate Specificity

Topics: Arthritis, Rheumatoid; Chronic Disease; Clinical Trials, Phase II as Topic; Crystallography, X-Ray; Enzyme Inhibitors; Humans; Indoles; Inflammatory Bowel Diseases; Models, Molecular; Molecular Structure; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Protein Binding; Psoriasis; Pyridones; Pyrimidines; Treatment Outcome

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Enzyme Inhibitors; Humans; Indoles; Naphthalenes; p38 Mitogen-Activated Protein Kinases; Phenylurea Compounds; Pyrazoles; Pyridazines; Pyridones; Pyrimidines; Rheumatology

P38alpha is a protein kinase that regulates the expression of inflammatory cytokines, suggesting a role in the pathogenesis of diseases such as rheumatoid arthritis (RA) or systemic lupus erythematosus. Here, we describe the preclinical pharmacology of pamapimod, a novel p38 mitogen-activated protein kinase inhibitor. Pamapimod inhibited p38alpha and p38beta enzymatic activity, with IC(50) values of 0.014 +/- 0.002 and 0.48 +/- 0.04 microM, respectively. There was no activity against p38delta or p38gamma isoforms. When profiled across 350 kinases, pamapimod bound only to four kinases in addition to p38. Cellular potency was assessed using phosphorylation of heat shock protein-27 and c-Jun as selective readouts for p38 and c-Jun NH(2)-terminal kinase (JNK), respectively. Pamapimod inhibited p38 (IC(50), 0.06 microM), but inhibition of JNK was not detected. Pamapimod also inhibited lipopolysaccharide (LPS)-stimulated tumor necrosis factor (TNF) alpha production by monocytes, interleukin (IL)-1beta production in human whole blood, and spontaneous TNFalpha production by synovial explants from RA patients. LPS- and TNFalpha-stimulated production of TNFalpha and IL-6 in rodents also was inhibited by pamapimod. In murine collagen-induced arthritis, pamapimod reduced clinical signs of inflammation and bone loss at 50 mg/kg or greater. In a rat model of hyperalgesia, pamapimod increased tolerance to pressure in a dose-dependent manner, suggesting an important role of p38 in pain associated with inflammation. Finally, an analog of pamapimod that has equivalent potency and selectivity inhibited renal disease in lupus-prone MRL/lpr mice. Our study demonstrates that pamapimod is a potent, selective inhibitor of p38alpha with the ability to inhibit the signs and symptoms of RA and other autoimmune diseases.

Topics: Animals; Arthritis, Rheumatoid; Drug Evaluation, Preclinical; Humans; Inflammation; Inhibitory Concentration 50; Interleukin-1beta; Interleukin-6; Kidney Diseases; Mice; Monocytes; Osteoporosis; p38 Mitogen-Activated Protein Kinases; Protein Isoforms; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Synovial Fluid; Treatment Outcome; Tumor Necrosis Factor-alpha