Alefacept

Alefacept is a fusion protein that impairs the activation of T cells by antigen-presenting cells and also causes the depletion of memory T cells.³⁵ Alefacept is approved for the treatment of moderate-to-severe psoriasis. A course of alefacept therapy consists of 12 weeks of 15 mg weekly intramuscular (IM) injections, followed by 12 weeks of follow-up. In some of the studies described below, patients were treated with 7.5 mg weekly intravenous (IV) infusions, but it is important to note that the IV formulation is no longer available for clinical use. The product labeling warns that lymphopenia can occur during alefacept therapy and that CD4⁺ and CD8⁺ T-lymphocyte counts should be monitored weekly during treatment. Alefacept should be withheld if CD4⁺ cell counts fall below 250 cells/µL and discontinued if they remain below 250 cells/µL for a month or more.³⁵

Performance in short-term studies

• During a single course of alefacept IM treatment in a double-blind clinical trial, 21% of patients achieved PASI 75 two weeks after the last dose (n=166),³⁶ and 33% of patients achieved PASI 75 at any time during the 12-week course of treatment and 12 weeks of follow-up (n=166).³⁷ Patients who achieved PASI 75 at any time during the course of treatment and follow-up maintained a PASI 50 for a median duration of 209 days.³⁸ The percentage of patients achieving PASI 75 at any time during a second 12- week course of treatment and follow-up was 43% (n=131) (Figure 8).³⁹
• In a pooled analysis of controlled clinical trials using one or two courses of either an IM or IV formulation of alefacept, the adverse events that occurred with an incidence at least 2% higher among alefacept-treated patients than placebo-treated patients were pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection-site pain, injection-site inflammation, and accidental injury (n=876).³⁵




Figure 8




• Patients who received a 16-week course of 15 mg alefacept IM once weekly continued to show improvements from baseline PASI through week 24, while the PASI responses in patients who switched to placebo after week 12 gradually declined (10 patients in each group) (Figure 9).⁴⁰




Figure 9

Performance in long-term studies

• Among patients who received multiple courses of 7.5 mg IV alefacept, the percentage of patients achieving PASI 75 or PASI 50 at any time during a treatment course increased with each additional course of treatment. In the 4 patients who were followed for several months off-treatment, the duration of remission seemed to increase slightly with the number of courses of treatment received. The safety findings in this study were similar to those seen in short-term clinical trials.^41,42

Performance in combination therapy

• With various agents. In an ongoing study, 201 patients have completed 12 weeks of therapy (but not the 12-week follow-up period) of alefacept in combination with one other psoriasis therapy, ie, cyclosporine, methotrexate, ultraviolet B (UVB), prednisone, a systemic retinoid, or a topical agent. When evaluated 2 weeks after the last dose, 61% of patients improved by one or more categories in the Physician's Global Assessment.⁴³ The adverse effects were similar to those associated with alefacept monotherapy, and there was no worsening of end-organ toxicity when alefacept was combined with cyclosporine or methotrexate.⁴⁴
• With methotrexate (MTX). Twelve patients who achieved PASI 50 during MTX treatment were transitioned onto alefacept therapy. MTX dosing was reduced by 2.5 mg each week during the first several weeks of alefacept therapy. All patients were able to discontinue MTX between 4 and 10 weeks after initiating alefacept (except for 1 patient who discontinued MTX before study entry). When evaluated 1 month after the last dose of alefacept, 6 patients showed improvement in PASI and 4 patients maintained their PASI relative to baseline; 1 patient had disease worsening after MTX discontinuation and had to restart MTX at week 12; and 1 patient restarted MTX 4 months after the last dose of alefacept.⁴⁵
• With cyclosporine (CsA). Eleven patients who had achieved a Physician's Global Assessment (PGA) of mild to clear on CsA treatment had their CsA dose tapered over 3 steps (current dose, 3 mg/kg/day, and 2.5 mg/kg/day) during 12 weeks of alefacept treatment. PGA scores remained stable in the 7 patients who completed CsA dose-tapering during alefacept therapy.⁴⁶

Other studies

• Nail psoriasis. Nine patients from an ongoing open-label study⁴⁷ of multiple courses of 15 mg IM alefacept therapy were found to have nail psoriasis. Of the 6 patients who had evaluable data, 3 had improvements in their nail disease and 3 had disease worsening after alefacept treatment. There was no correlation between changes in nail disease and improvements in PASI (Figure 10).⁴⁷




Figure 10




• Psoriatic arthritis. Eleven patients who had psoriatic arthritis in at least two joints were treated with 7.5 mg alefacept IV once weekly for 12 weeks. At week 12, 66.3% of patients achieved a 20% reduction from baseline in the American College of Rheumatology score (ACR 20) and 29.4% achieved an ACR 50. Adverse events were similar to those seen in psoriasis patients dosed with IV alefacept.^48,49
• Rheumatoid arthritis. Patients with rheumatoid arthritis who were on stable doses of methotrexate received either 3.75 mg or 7.5 mg IV alefacept or placebo once weekly for 12 weeks (n=12 in each group), followed by 12 weeks of observation. In the alefacept treatment groups at any time during treatment or follow-up, 67% of patients achieved ACR 20, 25% achieved ACR 50, and 8.3% achieved ACR 70. In the placebo group, 17% of patients achieved ACR 20, and no patients achieved ACR 50 or ACR 70. Adverse events were similar to those with IV alefacept dosing in psoriasis patients.^50,51
• Reduced CD4⁺ testing schedule. Selected patients whose weekly CD4⁺ cell counts were normal after one course of either IV or IM alefacept had their CD4⁺ cell counts monitored every other week during subsequent courses of alefacept therapy. The reduced schedule of CD4⁺ cell count monitoring did not increase the risks of alefacept treatment.⁵²

Snapshot of alefacept
Alefacept is a T-cell depleting agent that has shown efficacy in moderate-to-severe psoriasis and may also be effective in the treatment of psoriatic and rheumatoid arthritis. Alefacept has a fairly slow onset of action and a modest rate of clinical success when used as monotherapy, but, in those patients who do respond, long periods of disease remission can occur after a course of therapy is completed. Studies suggest that alefacept can be used safely in combination with other systemic antipsoriasis therapies or phototherapy for short periods of time, and this may be particularly useful during the first 12 weeks of alefacept treatment.^43-46 Alefacept has a low rate of mostly mild adverse effects, and studies suggest that multiple courses of treatment are safe and can increase the duration of remission. Weekly testing of CD4⁺ cell counts is required during alefacept therapy, but a study suggests that patients with stable CD4⁺ cell counts on alefacept therapy could be tested every other week with no adverse effect on safety.⁵²

Future directions for alefacept research
One of the more interesting remaining questions about alefacept concerns the role of T-cell depletion in the clinical response to alefacept. T-cell depletion is considered to be the primary mechanism of action for alefacept, but the degree of T-cell depletion is not entirely predictive of clinical response. Moreover, T-cell counts in the blood begin to fall shortly after alefacept therapy is initiated, but clinical effects are typically not seen until after 12 or more weeks of therapy. It may be that the effect of alefacept on T-cell levels in the skin may be more important in the clinical response in psoriasis than is the effect on T-cell levels in the blood. Future research in this area may provide insight into why different patients respond differently to alefacept therapy.

It will also be important to further investigate the optimal dosing regimen for alefacept. In particular, the possibility of basing a course of alefacept on 16 rather than 12 weeks of therapy should be further investigated. More studies are also needed on the use of adjunctive therapy during the first course of alefacept treatment. The slow onset of efficacy with alefacept is an acknowledged problem, and it has been suggested that combination therapy during the first few months of treatment could improve patient outcomes. A few studies have evaluated the concomitant use of methotrexate, cyclosporine, phototherapy, and other treatments with alefacept, but more information is needed about the efficacy and long-term safety of this approach.