Alefacept: a novel and selective biologic agent for the treatment of chronic plaque psoriasis

ARTICLE

Auteur(s) : Jean-Paul ORTONNE¹, Jörg C. PRINZ²

¹ Department of Dermatology, Hôpital L'Archet II, 15 rue de Saint Antoine de Ginestiere, BP 079, Nice, France
² Department of Dermatology, Ludwig-Maximilians University, Munich, Germany

Article accepted 07/10/2003

Psoriasis is a chronic inflammatory skin disease that follows a waxing and waning course, but generally continues to affect patients throughout their lives. It affects up to 3% of the world's population and is associated with medical costs of nearly $650 million each year in the United States alone [1, 2]. In the United Kingdom, the annual total treatment cost of plaque psoriasis, the most common form of the disease, has been estimated at 54,413,812 (approximately 82,013,694.57 EUR), assuming a 2% prevalence rate [3]. This excludes the significant economic burden associated with hospital admissions, ambulatory and primary care, as well as indirect costs (e.g. time off work).

Characteristic symptoms of plaque psoriasis include dry, red, scaly, raised lesions that may be localized or appear over widespread areas of the body. Patients often suffer from related problems such as chronic skin pain, itching, cracking, infection, and even disabling arthritis. In addition, psoriasis often has a negative effect on patient quality of life, a fact that may be underappreciated by many clinicians [4, 5]. Patients with psoriasis report decreases in quality of life comparable to those caused by cancer, arthritis, heart disease, diabetes, and major depression [6]. It is not surprising, then, that up to 10% of patients with psoriasis experience disease-related quality-of-life compromises grave enough to consider suicide [4]. Studies have also found a positive correlation between alcohol intake and psoriasis [7]. Therefore, it is extremely important that clinicians consider both the psychosocial and physical aspects of psoriasis when selecting therapy.

Treatments available for psoriasis include topical agents, light therapy (UVA and UVB), and systemic drug treatment. Unfortunately, most of these therapies are associated with substantial drawbacks, such as lack of long-lasting disease remission, safety concerns, and treatment inconvenience [8-14]. In addition, many patients fail existing treatments or reach the maximum recommended lifetime exposure. Novel biologic agents are being developed with the goal of prolonging the duration of remission of psoriasis symptoms, improving tolerability, and enhancing treatment convenience. The objective of this article is to briefly highlight the clinical profile of the recombinant human fusion protein, alefacept (Amevive^®, Biogen, Inc., Cambridge, MA, USA), and to describe several case studies based on the authors' personal experience with this drug. Phase 3 clinical trials have been recently completed with alefacept [15, 16] and, in the United States, it has been approved for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.

Alefacept – mechanism of action

Psoriasis is now recognized as an immune-mediated disease, and activated memory T cells play a pivotal role in its pathogenesis [17]. These T cells infiltrate the skin where they secrete the T1-type cytokines that drive the underlying inflammatory process causing keratinocytes to proliferate rapidly. Alefacept, which consists of the first extracellular domain of LFA-3 fused to the hinge, CH2, and CH3 domains of human IgG1, interferes with two key events in the immunological cascade leading to psoriasis. The LFA-3 domain of alefacept binds CD2 on T cells to inhibit T cell activation and proliferation, and the IgG1 domain of alefacept binds FcγRIII on accessory cells to induce apoptosis of T cells (Fig. 1) [18, 19]. Because CD2 is up-regulated on memory T cells [20, 21], alefacept has selective effects on this T cell subset while leaving other T cell populations relatively intact [22].

Alefacept – clinical profile

The efficacy and safety of alefacept were evaluated in two multicenter, randomized, double-blind, placebo-controlled, phase 3 trials including more than 1,000 patients with chronic plaque psoriasis [15, 16]. Alefacept was administered by intravenous (IV) bolus or intramuscular (IM) injection to patients at least 16 years of age suffering from chronic plaque psoriasis for at least one year. All enrolled patients had normal CD4⁺T cell counts at baseline and had not received systemic agents or light therapy within 4 weeks of beginning alefacept treatment. Each course of treatment consisted of alefacept 7.5 mg IV or 15 mg IM administered once weekly for 12 weeks followed by 12 weeks of observation.
In the IV study, 56% of patients (n = 367) treated with one course of alefacept 7.5 mg achieved a ≥ 50% decrease in PASI (PASI 50), and 28% achieved a  75% improvement in PASI (PASI ≥ 75) during the study period (both P <.001 versus placebo) (Fig. 2) [15]. In the IM study, 57% of patients (n = 166) treated with a single course of alefacept 15 mg achieved PASI 50, and 33% achieved a PASI 75 during the study period (both P <.001 versus placebo) [16]. Patients receiving two courses of IV or IM alefacept experienced additional symptomatic improvement (Fig. 2) [15, 23].
The IV study was designed to evaluate duration of response to alefacept [15]. In course 1, remission in patients who achieved a = 75% decrease in PASI persisted for a median of 216 days (> 7 months) without the use of significant topical therapy, phototherapy, or systemic therapy. The median duration of response could not be determined among patients who received two courses of IV alefacept because more than 50% of patients were still in remission at the time of analysis, and this appears to be extended beyond that obtained with a single course of therapy.
Quality of life was assessed in both of the phase 3 trials using the Dermatology Life Quality Index (DLQI), which was completed at baseline and at 2 and 12 weeks after the last alefacept dose [24, 25]. The results of the DLQI demonstrated that alefacept 7.5 mg IV and 15 mg IM significantly improved patient quality of life (Fig. 3). A second course of IV alefacept provided additional improvements. Regardless of the route of administration of alefacept, patients who achieved a reduction in PASI between = 50% and < 75% at 2 weeks after the last dose in course 1 experienced a significant improvement in their quality of life, and this benefit was maintained 12 weeks after treatment cessation. The combination of visible clinical amelioration and quality-of-life benefit achieved when PASI was reduced by at least 50% demonstrates that PASI 50 is an endpoint that reflects a considerable improvement for patients. The results obtained using the DLQI were similar to those achieved using another dermatology-specific quality-of-life instrument, the Dermatology Quality of Life Scales (DQOLS).
Alefacept was well tolerated [15, 16]. The most common adverse effects were headache, accidental injury, pharyngitis, and pruritus, with incidences similar to that associated with placebo. Injection site reactions were observed with IM administration and were typically classified as mild and did not lead to discontinuation of therapy. Chills were observed with IV alefacept but were limited to one or two occasions early during treatment; > 90% of episodes occurred within 24 hours of treatment. No clinically meaningful cases of sustained T cell suppression have occurred to date, and no significant increased risk of infection has been linked to alefacept use. No opportunistic infections, hypersensitivity reactions, or disease flares after drug discontinuation were noted. Alefacept has demonstrated minimal potential for immunogenicity.

Case studies

Our experiences with alefacept result from participating in three studies evaluating the efficacy of treatment and retreatment of chronic plaque psoriasis with alefacept. Eleven patients with PASI ranging from 11.4 to 44 (mean, 24.2) were included in the first double-blind study receiving either placebo or 10 mg or 15 mg alefacept IM once weekly for 12 weeks with a 12-week follow-up. All patients had a long history (= 15 years) of psoriasis with frequent disease relapses and at least one systemic and/or phototherapeutic regimen.
Five of seven patients who received active drug improved significantly, while two showed little improvement. Improvement of disease tended to occur at about 6 – 8 weeks, and continued during the follow-up period. Quality of life improved noticeably in these patients. The trial design allowed patients to be retreated with alefacept if they had mild or worsening psoriasis by physician global assessment (PGA) that persisted or reappeared after the first treatment course. As observed in other trials [15, 22], the effect of alefacept therapy was long-lasting. Retreatment was initiated 4.5-6.5 months after the last alefacept dose of the first course in six patients who met the criteria for retreatment. Onset of remission occurred faster and more efficiently in the second course compared with the first course. After the follow-up period of the second course, two of the six patients had only mild psoriasis and three patients were clear or almost clear by PGA. One patient did not respond to the first or the second course of alefacept. Interestingly, another patient who had a minimal response to the first treatment course became clear at the end of the second course. Retreatment induced longer remission from disease than did the first treatment course.
Intramuscular drug administration was easy and well tolerated. No local side effects were observed. The overall effort that patients had to put into treatment was low. All patients were highly compliant and content with the mode of application.
As a specific example, we treated a 51-year-old psychotherapist who had been suffering from extensive plaque psoriasis since the age of 24, and the impact on his quality of life was very significant. He had an unremarkable medical history and did not take medication that could exacerbate psoriasis. His psoriasis was severe, involving the forearms, arms, back, and legs. On the face, the lesions on the sebaceous zones (ie, eyebrows, naso-labial) were very visible. The scalp was affected as well as the nails of the hands and feet (ie, subungual onchylosis and hyperkeratosis). The palms and soles were also affected, but the body folds were undisturbed. The patient did not complain of itching. He consulted a dozen dermatologists who proposed local treatments, essentially composed of corticosteroid ointments and lotions. The results were very scant, and the constraint of a local, daily treatment was accepted reluctantly by the patient who became progressively lax over time. Over these long years, in spite of everything, he achieved some improvement, but not a total clearing, in the summer after sunbathing.
In 1985, after 9 years of evolution of the psoriasis, a dermatologist proposed balneo-PUVA therapy (topical 8-MOP and ultraviolet light therapy) to the patient. A very significant improvement occurred after 10 sessions, and complete clearing was obtained by the 20th session. Ultraviolet light therapy was stopped. A relapse occurred after 3 months of remission, and it was as severe as before the treatment. After several unsuccessful attempts to treat his psoriasis through application of vitamin D3 analogs, the patient gave up and turned towards alternative medicine without much success. In 1999, he returned to traditional medicine by consulting our department. Taking into account the severity of his outbreak, several systemic treatment strategies were proposed to him. The patient decided to try alefacept by intramuscular injection once a week for 12 weeks. He obtained clearing of disease that was maintained for 4 months. The patient appreciated the convenience of the treatment compared with the topical and phototherapies he had previously received. In addition, he tolerated alefacept well, and he volunteered to renew this treatment for 12 weeks. This second course of treatment led to approximately 60% improvement that was maintained for 3.5 months. A third course of treatment was initiated and resulted in complete clearing that persisted 8 months after treatment was complete. The patient expressed satisfaction with alefacept therapy and stressed the ease of treatment because of the way the drug is administered and how well it is tolerated. Figure 4 shows change in PASI, PGA, and CD4⁺ T cell counts over the three treatment courses for this patient.
Alefacept therefore appears an effective treatment modality for many patients. Constraints may result only from three aspects: (1) Treatment response cannot yet be predicted. Because alefacept is a remittive therapy and results are apparent later in the treatment course, sometimes peaking after the end of treatment during the follow-up period, a full course is necessary to fully distinguish those patients who may best benefit. (2) Determination of CD4⁺ and/or CD8⁺ T cell counts in peripheral blood T cells before and during therapy may not be available in all settings. (3) Although there is a clear value for the use of biologics in the treatment of psoriasis, the cost of these products may require a change in the pharmacoeconomical perception of health care costs. Treatment with alefacept appeared to be safe. Future observations will have to confirm long-term safety and exclude an increased risk of malignancies.
According to our experience and the data published in treatment studies, alefacept represents a promising new addition to the dermatologist's armamentarium for the treatment of psoriasis. The challenge now is to position this new product in the context of existing treatments. In the authors' experience, patients who would make good candidates for alefacept therapy include those who (1) have a history of moderate to severe chronically relapsing psoriasis that requires regular visits to a dermatologist; (2) require a new treatment option because other treatment modalities have been ineffective; (3) have had tolerability problems with prior treatments or would be expected to experience problems with other systemic treatments; (4) have quality of life strongly influenced by their physical appearance (ie,exposed areas affected, face, hands) and are impaired by physical appearance and psychological pressure as well as by time constraints imposed by other treatment modalities; and (5) are likely to comply with the treatment regimen. Patients should be 16 years of age and older, should not be pregnant or breast feeding, and should be HIV-negative and without a recent history of malignancies.

Conclusions

Alefacept offers a new effective, safe, disease-remittive treatment option for adult patients with chronic plaque psoriasis. In clinical studies, more than 55% of patients achieved a decrease in PASI of  ≥ 50% after a single course of alefacept treatment and approximately 70% achieved a ≥ 50% decrease in PASI after two courses. Alefacept is unique among current therapies for psoriasis because of its ability to induce long-lasting clinical efficacy, its low incidence of adverse effects, and the convenience of treatment due to the lengthy periods spent without a need for therapy. The long-term safety of alefacept will be monitored to confirm that there is no increased risk of infection or malignancy with treatment. Alefacept also offers considerable quality-of-life enhancement to patients suffering the debilitating psychosocial and physical consequences of psoriasis. Alefacept is the first therapy that can provide long-lasting, safe clearance of disease with improved quality of life for patients with psoriasis. n

References

1. Barker JN. Psoriasis as a T cell-mediated autoimmune disease. Hosp Med 1998; 59: 530-3.

2. Javitz HS, Ward MM, Farber E, Nail L, Vallow SG. The direct cost of care for psoriasis and psoriatic arthritis in the United States. J Am Acad Dermatol 2002; 46: 850-60.

3. Piercy J, Mesrobian X, Viala M, Evans C, Prosek B. Estimating the cost of moderate to severe chronic plaque psoriasis in the UK. JEAV 2002; 16: 284. [Abstract P27-32].

4. Krueger G, Koo J, Lebwohl M, Menter A, Stern RS, Rolstad T. The impact of psoriasis on quality of life. Results of a 1998 National Psoriasis Foundation Patient-Membership Survey. Arch Dermatol 2001; 137: 280-4.

5. Wong C, Kirby B. Managing the patient with psoriasis. Practitioner 2001; 245: 913-22.

6. Rapp SR, Feldman SR, Exum ML, Fleischer AB, Jr., Reboussin DM. Psoriasis causes as much disability as other major medical diseases. J Am Acad Dermatol 1999; 41: 401-7.

7. Faber FM, Nall L. Psoriasis and alcoholism. Cutis 1994; 53: 21-7.

8. Messana JM, Johnson KJ, Mihatsch MJ. Renal structure and function effects after low dose cyclosporine in psoriasis patients: a preliminary report. Clin Nephrol 1995; 43:150-3.

9. Zachariae H, Kragballe K, Hansen HE, Marcussen N, Olsen S. Renal biopsy findings in long-term cyclosporin treatment of psoriasis. Br J Dermatol 1997; 36: 531-5.

10. Koo J, Lebwohl M. Duration of remission of psoriasis therapies. J Am Acad Dermatol 1999; 41: 51-9.

11. Lindelöf B, Sigurgeirsson B, Tegner E, Larkö O, Johannesson A, Berne B, Ljunggren B, Andersson T, Molin L, Nylander-Lundqvist E, Emtestam L. PUVA and cancer risk: the Swedish follow-up study. Br J Dermatol 1999; 141: 108-12.

12. Shephard SE, Panizzon RG. Carcinogenic risk of bath PUVA in comparison to oral PUVA therapy. Dermatology 1999; 199: 106-12.

13. Stern RS, the PUVA Follow-up Study. The risk of melanoma in association with long-term exposure to PUVA. J Am Acad Dermatol 2001; 44: 755-61.

14. McClure SL, Valentine J, Gordon KB. Comparative tolerability of systemic treatments for plaque-type psoriasis. Drug Safety 2002; 25: 913-27.

15. Krueger GG, Papp KA, Stough DB, Loven KH, Gulliver WP, Ellis CN, for the Alefacept Clinical Study Group. A randomized, double-blind, placebo-controlled phase III study evaluating efficacy and safety of 2 courses of alefacept in patients with chromic plaque psoriasis. J Am Acad Dermatol 2002; 47: 821-33.

16. Lebwohl M, Christophers E, Langley R, Ortonne J-P, Roberts J, Griffiths CEM, for the Alefacept Clinical Study Group. An international, randomized, double-blind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Arch Dermatol 2003; 139: 719-27.

17. Singri P, West DP, Gordon KB. Biologic therapy for psoriasis. The new therapeutic frontier. Arch Dermatol 2002; 138: 657-63.

18. Miller GT, Hochman PS, Meier W, Tizard R, Bixler SA, Rosa MD, Wallner BP. Specific interaction of lymphocyte function-associated antigen 3 with CD2 can inhibit T cell responses. J Exp Med 1993; 178: 211-22.

19. Majeau GR, Meier W, Jimmo B, Kioussis D, Hochman PS. Mechanism of lymphocyte function-associated molecule 3-Ig fusion proteins inhibition of T cell responses. Structure/function analysis in vitro and in human CD2 transgenic mice. J Immunol 1994; 152: 2753-67.

20. Sanders ME, Makgoba MW, Sharrow SO, Stephany D, Springer TA, Young HA, Shaw S. Human memory T lymphocytes express increased levels of three cell adhesion molecules (LFA-3, CD2, and LFA-1) and three other molecules (UCHL1, CDw29, and Pgp-1) and have enhanced IFN-g production. J Immunol 1988; 140: 1401-07.

21. Majeau GR, Whitty A, Yim K, Meier W, Hochman PS. Low affinity binding of an LFA-3/IgG1 fusion protein to CD2⁺ T cells is independent of cell activation. Cell Adhes Commun 1999; 7: 267-79.

22. Ellis CN, Krueger GG, for the Alefacept Clinical Study Group. Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 2001; 345: 248-55.

23. Ortonne J-P, Prinz JC, Bos JD, Wozel G, Lahfa M, Dubertret L, O'Gorman J. Efficacy and tolerability of retreatment with intramuscular alefacept in psoriasis patients. JEAV 2002; 16: 283. [Abstract P27-30].

24. Finlay AY, Salek MS, Haney J, for the Alefacept Clinical Study Group. Intramuscular alefacept improves health-related quality of life in patients with chronic plaque psoriasis. Dermatology 2003; 206: 307-15.

25. Feldman SR, Menter A, Koo JY. Improved health-related quality of life following alefacept treatment in patients with chronic plaque psoriasis. Br J Dermatol in press.