An experimental subcutaneous and intramuscular formulation of the tumor necrosis factor-alpha (TNF-a) inhibitor infliximab (Remicade® ) is well tolerated and associated with a favorable American College of Rheumatology (ACR) response, according to a phase I study published online in the Journal of Rheumatology.¹ The new research sought to assess the safety, clinical response, and pharmacokinetics of subcutaneous (SC) and intramuscular (IM) doses of an experimental formulation of infliximab in patients with rheumatoid arthritis (RA) refractory to methotrexate (MTX).

In the open-label, three-stage design, 43 subjects were enrolled in seven dose groups. Specifically, stage I involved 15 subjects who received single SC doses of 0.5, 1.5, or 3.0 mg/kg. Stage II included 21 subjects who received one of three regimens: 100 mg SC every 2 weeks (three injections), 3 mg/kg commercially formulated IV infliximab every 2 weeks (two infusions) followed by 100 mg SC every 2 weeks (3 injections), or 100 mg IM every 2 weeks (three injections). Stage III involved 7 subjects who received 100 mg SC every 4 weeks (three injections).

According to the new findings, no serious injection site reactions were observed. Moreover, only one subject experienced serious adverse events, and these were not considered treatment-related by the investigators. A low-titer infliximab antibody response was detected in 27% of subjects receiving single SC doses, 5% receiving multiple SC doses, and 43% receiving IM doses. In addition, the exposure to SC infliximab was dose-proportional over the range of 0.3–3.0 mg/kg with a median half-life of 7.3–16.7 days. Finally, ACR20 criteria were reached in 80%–100% of subjects in all treatment groups. However, since the study was small and there was no placebo arm, more studies are needed before general conclusions can be made.

"Subjects receiving repeated subcutaneous infliximab doses experienced more rapid clinical response than those receiving repeated IM doses, as well as a lower incidence of antibody formation to infliximab," conclude the researchers, led by Rene Westhovens, MD, PhD, of UZ Gasthuisbeg in Leuven, Belgium. The pharmacokinetics of SC dosing were dose-proportionate, and detectable serum concentrations of infliximab appeared to be maintained with monthly 100 mg SC administration. "Definitive conclusions concerning the safety and efficacy of this investigative infliximab formulation in the treatment of RA, however, cannot be drawn in the absence of placebo-controlled studies of adequate sample size," the researchers note.

Choice in route of administration is important

"I was fascinated with this study and wasn't aware that anyone was looking at giving infliximab subcutaneously or via intramuscular injections," says Atul Deodhar, MD, associate professor of medicine and medical director of the rheumatology clinic in the division of arthritis and rheumatic diseases at Oregon Health & Science University in Portland, Oregon. "This study shows that subcutaneous [infliximab] does work, and giving it every month can maintain the blood level [of infliximab] and you can get the same efficacy as when it is given by the usual route," he says, adding that the findings must be confirmed in phase II and phase III studies.

Giving patients a choice in route of administration is important, however. "[Some] RA patients want to be independent and don't want to be going to the hospital and getting infusions for hours at a time, and [other] people can't fathom the idea of giving themselves repeated injections," Dr. Deodhar says. "There are pros and cons on both sides, but the fact that infliximab does work subcutaneously and has good effects is encouraging and will potentially add another option."

The new infliximab formulation is different than CNTO 148 (golimumab), an experimental fully human anti-TNF-a monoclonal antibody that is delivered subcutaneously. The second generation of biologics, golimumab is currently being developed by Centocor, Inc, and Schering-Plough, the manufacturers of infliximab. CIAOMed recently reported that preclinical studies suggest that CNTO 148 is two to four times more potent in in vitro and in vivo models than infliximab.²

References

1. Westhovens R, Houssiau F, Joly J, et al. A phase I study assessing the safety, clinical response, and pharmacokinetics of an experimental infliximab formulation for subcutaneous or intramuscular administration in patients with rheumatoid arthritis. J Rheumatol. 2006;33:5. First release April 1, 2006.
2. Kay J, Matteson EL, Dasgupta B, et al. Subcutaneous injection of CNTO 148 compared with placebo in patients with active rheumatoid arthritis despite treatment with methotrexate: a randomized, double-blind, dose-ranging trial. Presented at: 69th Annual Meeting of the American College of Rheumatology; November 12–17, 2005; San Diego, Calif. Abstract 1921.