SEATTLE, Wash. – Adding alefacept to methotrexate (MTX) greatly improved ACR20 response rates, tender joint counts (TJC), swollen joint counts (SJC), pain, and disability in psoriatic arthritis (PsA) patients, according to a randomized, controlled trial reported in the May issue of Arthritis & Rheumatism.¹

A fusion protein that combines the first extracellular domain of human lymphocyte function-associated antigen 3 (LFA-3) and the Fc portion of IgG1, alefacept inhibits T-cell activation by blocking co-stimulation, and was the first biologic agent approved for the treatment of chronic plaque psoriasis. Alefacept also facilitates apoptosis of memory T cells.

"These data underline the point that psoriasis and PsA are heavily T-cell-driven diseases, so it is appropriate to use a drug that is focused on inhibition of T-cell activation," lead author Philip J. Mease, MD, of the Swedish Medical Center in Seattle, told CIAOMed.

The placebo-controlled, double-blind trial randomized patients in a 2:1 randomization to alefacept 15 mg IM in combination with MTX (n = 123) or to placebo in combination with MTX (n = 62). All patients had persistently active PsA (defined as three or more swollen joints and three or more tender joints) despite at least 3 months of MTX prior to enrollment. Patients were on stable MTX doses of 10–25 mg/week and continued their usual dose throughout the study. Alefacept was administered at the US Food and Drug Administration (FDA)-approved dose for patients with psoriasis.

Alefacept associated with increased and more durable responses

Patients treated with 12 weeks of alefacept/MTX had significantly greater response rates to measures of disease activity in both PsA and psoriasis, and responses were not affected by the length of prior MTX treatment.

Specifically, the researchers found that the alefacept/MTX combination was not notably more toxic than MTX alone and was significantly more effective at 1) inducing ACR20 response at week 24 (following 12 weeks of treatments); 2) reducing tender joint count; 3) reducing swollen joint count; and 4) reducing the Psoriasis Area Severity Index (PSAI) by 50%, Dr. Mease said.

Observation continued for an additional 12 weeks after the end of the experimental treatment period. "Incremental improvement in ACR20 response was seen during the treatment-free observational phase, indicating that response to alefacept continues after therapy is completed, which is consistent with the response patterns seen in phase III trials evaluating alefacept for the treatment of psoriasis," the investigators report, noting that "this raises the possibility that an extended treatment period (<12 weeks) may offer additional clinical benefits for patients with PsA, as has been seen in patients with psoriasis."

Prior T-cell-focused PsA treatment unsuccessful

The results of this study are in notable contrast to a phase II trial of efalizumab(Raptiva®),²  which inhibits T-cell activation, trafficking, and reactivation in dermal tissues. That study failed to show a significant improvement in ACR20 response rate for efalizumab/MTX vs placebo/MTX at 12 weeks.

"I was not surprised at the results," Dr. Mease said. "I did expect a positive result based on the mechanism of action as well as the results in prior psoriasis work, although there could have been a question in some people's minds since efalizumab, another co-stimulatory blockade agent, did not show clear-cut efficacy in PsA, even though it has worked in psoriasis."

References

1. Mease PJ, Gladman DD, Keystone EC, et al. Alefacept in combination with methotrexate for the treatment of psoriatic arthritis. Results of a randomized, double-blind, placebo-controlled study. Arthritis Rheum. 2006;54:1636-1645.
2. Genentech, Xoma's Raptiva fails to meet endpoint in phase II psoriatic arthritis trial [press release]. FaxWatch; March 22, 2004.