One more thing when we are talking about JB honesty (and I will stop here).
Read abstract from EU and judge for yourself. Was CNS toxicity in animal model real reason for trial stop, or something else???
p38 Map Kinase Inhibition
FRI0018 A DOUBLE-BLIND, PLACEBO-CONTROLLED TRIAL OF VX-745, AN ORAL P38 MITOGEN ACTIVATED PROTEIN KINASE (MAPK) INHIBITOR, IN PATIENTS WITH RHEUMATOID ARTHRITIS (RA)
Weisman M, Furst D, Schiff M, Kauffman R, Merica E and Martin-Munley S
VX-745 is an oral inhibitor of p38 mitogen activated protein kinase (MAPK), blocking the synthesis of TNF-á, IL-1Â and IL-6 in human whole blood and peripheral blood mononuclear cells (PBMCs) after lipopolysaccharide stimulation in both in vitro and ex vivo assays. Because VX-745 had shown significant anti-inflammatory activity in rodent arthritis models, a trial in human rheumatoid arthritis (RA) was warranted. VX-745 is known to penetrate the blood brain barrier (BBB) in animals.
Methods: 44 patients receiving 250 mg bid VX-745 were compared with 15 patients recieving placebo. Area under the curve (AUC) of the ACR20 score over a 12-week treatment period was used as the primary endpoint. Patients, with active RA > 6 months, were allowed to continue stable doses of NSAIDs, but no DMARDs were permitted. Patients previously on anti-TNF, anti-IL-1, or cyclophosphamide therapy were excluded.
Results: Data in the table below is for all patients that completed treatment through week 12.
ACR20 ACR50 ACR70 % Improvement
VX-745 Placebo VX-745 Placebo VX-745 Placebo VX-745 Placebo
43%
(13/30) 17%
(2/12) 17%
(5/30) 0%
(0/12) 3%
(1/30) 0%
(0/12) SJC 28.6%
TJC 42.9% SJC 9%
TJC 30%
The most common adverse events in patients treated with VX-745 were gastrointestinal (GI) effects (27% of patients) and asymptomatic elevations in liver transaminases (16% of patients). GI effects were intermittent and consisted of diarrhea and abdominal pain. Elevations in liver transaminases (max AST 82-258 IU [normal 9-34]; max ALT 30-297 [normal 6-34]) declined after discontinuation of treatment with the exception of one patient that required an additional drug modification.
Although a second cohort patients to receive 500 mg bid VX-745 vs. placebo was planned, the study was discontinued because of adverse neurological effects in long-term animal studies.
Summary: These data indicate that inhibition of p38 MAPK may prove beneficial in the treatment of human RA.
Editorial Comments: p38 MAP Kinase plays a role in the production and downstream effects of pro-inflammatory cytokines such as TNF and IL-1. Therefore, inhibition of p38 MAP Kinase makes therapeutic sense. The clinical efficacy of VX-745 in this early study is modest at best, however. Furthermore, the hepatic toxicity of some p38 inhibitors demonstrated in animal models of arthritis seems to have been reproduced in humans here. Rumor has it that further development of this drug for human RA has been cancelled. |
