RESEARCH - Subcutaneous Remicade shows promise in treating RA

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Subcutaneous Infliximab Shows Promise in Treating RA

April 17, 2006

by Mann Kleinman

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).

" 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, " says Dr. Deodhar.

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.

http://www.ciaomed.org/articles.cfm?articleID=641

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