CUSTOM DERMATOLOGY SEARCH:
The Use of Alefacept in the Treatment of Psoriasis
V.K. Wong, BA and M. Lebwohl, MD
Recent evidence clearly demonstrates that psoriasis is mediated by the activation of T-cells, which opens up a new array of therapeutic approaches to improve the clinical and social impact that it has on affected patients. This knowledge gives us the ability to create molecules that selectively target the steps in the activation of Tlymphocytes. Therefore, we will be able to treat psoriasis more specifically, and presumably with fewer side-effects.
Although most psoriasis patients are able to control their condition with topical treatments, there are significant numbers of patients who require phototherapy or systemic treatments. With the exception of PUVA, current phototherapy and systemic immunosuppressive therapies fail to provide long-term remissions. Apart from the inconvenience of frequent phototherapy visits, PUVAis associated with the development of skin cancers, and immunosuppressive therapies are associated with organ toxicities.1 Biogen, Inc. recently completed studies on the recombinant protein alefacept (a human LFA-3/IgG1 fusion protein, also known as AMEVIVE™ or LFA3TIP) for the treatment of chronic plaque psoriasis, the most common form of psoriasis.
Mechanism of Action
Alefacept is a selective immunomodulating anti-psoriatic drug that blocks the LFA-3/CD2 interaction necessary for the activation and proliferation of T-cells by binding to CD2 on T-cells. Alefacept also induces selective apoptosis of CD4 memoryeffector T-cells by binding to the Fc?RIII receptor on natural killer cells and macrophages.2,3 CD2 expression is higher on memory-effector (CD45RO+) than naïve (CD45RA+) T-cells. Thus, alefacept has a dual mechanism of action: it selectively binds to and reduces circulating levels of the memory-effector T-cell population. A correlation has been found between that reduction and the improvement of psoriasis.2 Since the CD4 count is reduced due to apoptosis, it must be monitored on a regular basis to ensure that it does not drop below 250cells/mm3.4
A Phase I study (n=28) showed that alefacept was welltolerated when administered as either an IM injection, an IV bolus injection (30-second), or an IV infusion (30-minutes); however, pharmacokinetic data support the administration of alefacept via IM or IV bolus injection as opposed to an IV infusion.5 A clinical study by Ellis, et al, (n=175) determined the safety and efficacy of repeated courses of 7.5mg alefacept administered by IV bolus. Tolerance was consistent with previous studies and no flares or rebounds were reported after treatment withdrawal.6 Lebwohl, et al, in a phase III study, (n=507) found that a dose of 15mg of alefacept given intramuscularly led to significant improvement in the symptoms and severity of plaque psoriasis, suggesting an alternative to IV administration.7 Both routes of administration are given once weekly for 12 weeks. These studies demonstrated the potential of alefacept as an effective therapy for chronic plaque psoriasis, for it was well-tolerated and provided a markedly durable clinical response, i.e., patients who responded to a 12-week course of alefacept maintained their improvement for over 7 months post-treatment on average.
Patient Selection and Management
Because this is a systemic therapy to be administered through 12 weekly injections, alefacept will undoubtedly be used in patients with moderate-to-severe psoriasis. The likeliest initial
Alefacept should be administered under the supervision of a dermatologist. In clinical trials, alefacept resulted in temporary reduction of T-cells and CD4+ cells. CD45RO+ memory-effector cells, which play a major role in the pathogenesis of psoriasis, were selectively reduced, whereas naïve T-cells were unaffected. Primary and secondary immunizations were not affected by alefacept therapy.
It is possible that regulatory agencies will request regular monitoring of lymphocyte or CD4+ cell counts during the baseline total lymphocyte count below the normal range should not begin treatment with alefacept. Patients should be advised to inform their primary care physician or dermatologist if they develop an infection while undergoing a course of therapy with alefacept.
Alefacept is categorized as US FDA Pregnancy Category B and should be used in pregnant females only if the benefits outweigh the risks. Alefacept has only been studied in patients 16 years and over. Although not approved for pediatric use, this is probably one of the safest systemic treatments for psoriasis. While it is not known if alefacept enters breast milk in nursing females, other antibodies do enter breast milk, so this should be considered in nursing mothers.
Alefacept was approved by the US FDA as an injection for adults with chronic plaque psoriasis. The recommended dose of alefacept is 15mg IM, or 7.5mg IV, once a week over a 12-week period, as supported by results from the Phase III trials.7 Patients may be retreated with alefacept on an as needed basis so long as their total lymphocyte and CD4+ Tcell counts are not below the normal range, and at least 12 weeks has passed since their last course of treatment.
While the drug has been studied in an IV and IM formulation, most dermatologists are used to administering IM drugs and may prefer that route of administration. The current developments of biologic therapy have led to infusion centers in some dermatologists’ offices, so IV alefacept may be used in these settings. Injection site reactions are avoided by using the IV route and some patients may find this route less painful, but some patients experience chills with the first IV injection, a side-effect that is very uncommon when the drug is administered intramuscularly.
The most commonly observed adverse events that occured more often with at least a 2% higher incidence in patients treated with alefacept when compared to those treated with placebo were: pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site pain, injection site inflammation, and accidental injury. Malignancies and serious infections were observed, but these did not appear to be related to CD4 levels. Most malignancies seen were cutaneous (basal and squamous cell carcinomas) and the rate of malignancy was not greater than what would be expected for the general population.
Alefacept selectively reduces memory-effector (CD45RO+) T-cells, which are involved in the pathogenesis of psoriasis. In clinical studies, alefacept provided significant improvements in patients’ psoriasis. Alefacept was well tolerated and, notably, produced long-lasting remissions. There were no reported opportunistic infections and no disease rebounds or flares after drug withdrawal. Alefacept appears to be a useful addition to the psoriasis armamentarium.
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Last modified: Thursday, 21-Jun-2012 16:51:28 MDT