Immunosuppressant - CP-690550
Successful organ transplantation relies on suppressing the immune system to prevent the body rejecting the new tissue. Numerous drugs are already in use, including cyclosporin, sirolimus and steroids, but because they are not particularly tightly targeted serious side-effects are common, including kidney toxicity and hypertension.
Successful organ transplantation relies on suppressing the immune system to prevent the body rejecting the new tissue. Numerous drugs are already in use, including cyclosporin, sirolimus and steroids, but because they are not particularly tightly targeted serious side-effects are common, including kidney toxicity and hypertension.
An alternative approach would be to target pathways that are specific to the body's immune response. Pfizer has been looking for an inhibitor of JAK3, one of the Janus kinases that are involved in the creation of sites for docking of signal transducers and activators of transcription. This particular kinase is fairly well restricted to part of the immune response, and hence has potential as a target for novel immunosuppressants.
The compound CP-690550 is specific for JAK3, and hence may have fewer side-effects than current drugs, and may also have potential in autoimmune conditions such as rheumatoid arthritis.1 Several trials have been carried out. Its safety and efficacy were evaluated in a six month Phase IIa open label trial in 61 patients who had had a kidney transplant.2 Subjects were given 15 or 30mg of the new agent or tacrolimus alongside an IL-2 receptor antagonist, MMF and steroids. More patients given the higher dose developed infections, but there were no significant differences in haemoglobin or white blood cell counts after six months.
Another trial was carried out in 264 rheumatoid arthritis patients.3 In the randomised, double blind placebo controlled Phase IIa trial, RA sufferers who were resistant to or intolerable to tumour necrosis factor inhibitors or methotrexate were given 5, 15 or 30mg of the drug or placebo twice a day for six weeks. The most common side-effects were nausea and headache, which appeared to be dose dependent. All three doses improved the symptoms of arthritis and functional disability, and the improvements were significantly better than those seen in the placebo group. The two highest doses gave significant improvement in remission rates.
The drug is also being investigated as a potential treatment for psoriasis.4 In a multiple dose randomised, double blind, placebo controlled trial, its safety and tolerability were investigated in the treatment of psoriatic lesions. A total of 59 subjects with psoriasis were given 5, 10, 20, 30 or 50mg of the drug twice a day for 14 days, 60mg once a day, or placebo. Again, the most common side-effects were nausea and headache, and all doses except the lowest gave a significant improvement in the symptoms of psoriasis after the two week period. Trials are continuing.