皮膚科 劉權毅醫師

November 24, 2009 (San Diego, California) — A new fully human monoclonal antibody (MAb) against TNF, golimumab (CNTO148, Centocor/Schering-Plough), is close to entering the market. Results from a phase2 clinical trial of 172 patients with rheumatoid arthritis (RA) show encouraging safety and efficacy data, investigators reported at the 2005 ACR/ARHP Annual Scientific Meeting [ 1 ]. Phase 3 studies of RA, psoriatic arthritis, and ankylosing spondylitis are planned to start soon, the companies tell rheuma wire . Golimumab could be launched in 2007.
 

Being a fully human MAb directed against TNF, golimumab resembles adalimumab (Humira, Abbott), which was the first such product to reach the market. It has been claimed that adalimumab has advantages over infliximab (Remicade, Centocor & Schering-Plough), which is a chimeric part-human, part-mouse antibody, particularly in terms of eliciting less of an immunogenic response and hence the development of antidrug antibodies. That the manufacturers would go on to develop a fully human product is not surprising, because this is what the market is demanding, one rheumatologist commented to rheuma wire , but from a clinical standpoint, he says, golimumab does not represent a huge advance, there is already one fully human MAb product available. Golimumab will offer more of the same.

Results from the phase 2 trial "demonstrate the potential of golimumab as another therapy for the treatment of rheumatoid arthritis," comments lead investigator Dr Jonathan Kay (Massachusetts General Hospital, Boston) in a press release issued by the American College of Rheumatology (ACR). "When treating a debilitating disease like RA, it is important to have several treatment options, and we are encouraged by the safety and efficacy data we have seen thus far for golimumab," he adds in a statement issued by the manufacturers.

Golimumab is being investigated in both subcutaneous-injection and intravenous-infusion formulations. The companies are still exploring various dosage schedules, but preliminary data suggest that the subcutaneous injection could be given once every four weeks and the infusion once every three months, both of which offer an improvement over what is currently available ( etanercept [Enbrel, Immunex/Wyeth] is given as a subcutaneous injection once a week and adalimumab every other week; infliximab is given by infusion every eight weeks).

In the phase 2 study, golimumab was administered by subcutaneous injection at 50mg or 100mg every two or four weeks and was compared with placebo in patients who had active RA despite methotrexate treatment. Kay reported that although the placebo response was relatively high, significantly more patients on the drug achieved an ACR20 response at 16 weeks, the primary end point of the study. There were also significantly more patients on the drug with ACR50 and ACR70 responses.

Phase 2 trial efficacy results for golimumab at week 16 (n=172)

 

*significant compared with placebo (p<0.05)
 

Remission (as measured by disease activity score [DAS28]) at 16 weeks was achieved by 27% of patients in the golimumab group and 6% of those in the placebo group (p=0.007). Kay noted that no unexpected adverse events were reported. Serious adverse events (SAEs) were reported in 8% of patients in the golimumab group and 5.5% of those in the placebo group. The most common clinically relevant SAEs in the drug-treated patients were two cases of pneumonia and one case each of cardiac tamponade, cardiac failure, and lung cancer (unrelated). There were no deaths or cases of tuberculosis or lymphoma.

New oral anti-TNF product

Much earlier in the development process is an oral TNF inhibitor, which would offer a huge advantage over the products currently available, all of which are parenteral. However, this research is still at a very early stage. One such project was reported at the 2005 ACR/ARHP Annual Scientific Meeting by a group of researchers from the Nicholas Piramal Research Center (Mumbai, India), who described P979, an oral product with TNF-inhibitor properties [ 2 ]. They reported various in vitro studies, including tests of activity in synovial cells taken from RA patients undergoing knee replacement, in which the compound showed a dose-dependent inhibition of TNF release. They also reported studies of lipopolysaccharide-treated mice and collagen-induced arthritis in rats, in which oral dosing was followed by a "reduction in the severity of arthritis (articular index)." The group concluded that P979 "may turn out to be useful in the management of rheumatoid arthritis."

http://www.medscape.com/viewarticle/538424

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