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This article reports on the combined use of alefacept and etanercept in 3 patients whose psoriasis failed to respond adequately to etanercept. All patients maintained improvement for at least 8 weeks after completing 12 weeks of alefacept. No adverse events or infections were reported, and CD4+ T-cell counts remained above normal limits.
Among patients with psoriasis who did not achieve Psoriasis Area and Severity Index 50 during the first course of alefacept therapy, 53% achieved Psoriasis Area and Severity Index 50 during the second course (odds ratio [95% confidence interval] vs placebo 2.30 [1.26-4.19]). Alefacept provided incremental efficacy over 5 successive 12-week treatment courses.
Alefacept is a bioengineered fusion protein of soluble lymphocyte function antigen (LFA-3) with Fc fragments of IgG1. It is marketed in many countries for the treatment of moderate to severe psoriasis. This paper reviews the data supporting the use of alefacept in psoriasis and psoriatic arthritis.
Alefacept (B-9273) is an LFA-3-Ig fusion protein CD2 antagonist under development by Biogen for the potential treatment of autoimmune diseases, including psoriasis and transplant rejection [270267]. It is in phase III trials for psoriasis [349467]. In October 2000, the company reported that Amevive was on track for regulatory filing in the second half of 2001 [385250], with a possible launch in the second half of 2002 [395628]. The company began a pivotal phase III trial in the US in December 1999, involving patients with chronic plaque psoriasis [349467]. A second phase III trial has also been initiated [362199], [374040]. Results from both trials are expected in mid-2001 [396544]. In April 2001, SalomonSmithBarney confirmed that a regulatory filing was expected in Europe and the US in the second half of 2001 and stated that alefacept would be critical to the future earnings growth of the company [407796]. In June 1999, Merrill Lynch estimated product launch in 2001 [327145], [344773]. Sales in 2001 and 2002 were anticipated to be US $20 million and US $100 million, respectively [327145].
Alefacept is a lymphocyte function-associated antigen-3/IgG1 fusion protein that inhibits T-cells by antagonizing CD2, which has been developed and launched by Biogen for the potential treatment of psoriasis. In February 2003, Biogen launched alefacept in the US for use in adults with moderate-to-severe chronic plaque psoriasis, and by March 2003, the company was preparing for psoriasis trials to commence in Japan by the end of December 2003.
Alefacept belongs to the new generation of drugs applied in the treatment of psoriasis. It is an immunomodulatory recombinant, fully human lymphocyte function associated antigen-3/immunoglobulin G1 fusion protein (LFA-3-Ig) CD2 antagonist that targets memory-effector T cells by binding CD2 on the T cell surface. It blocks the interactions of leukocyte functional antigen (LFA)-3 with CD2 interaction. This drug is used to treat moderate-to-severe chronic plaque psoriasis and there was conducted a pilot study of psoriatic arthritis. It was observed that Alefacept had reduced peripheral-blood memory effector T-lymphocyte (CD45RO+) counts, cells which are responsible for sustaining the disease. Pharyngitis, dizziness, increased cough, nausea, pruritus, myalgia, chills, injection site inflammation, and accidental injury were recorded. So far, in the conducted trials no generalised immunosuppression or increased risk of infection or malignancy were observed. The possibility of increased risk of infections and malignancies must be considered because of reduced lymphocyte counts.
Recently, dermatologists have witnessed a revolution in our therapeutic armamentarium with the development of several novel biologic immunomodulators. Although psoriasis remains the only condition in dermatology for which the use of biologic immunomodulators has been approved by the Food and Drug Administration, these drugs have the potential to significantly impact the treatment of several inflammatory conditions in dermatology. This article includes a review of the mechanism of action, dosing, and side-effect profile, as well as a review of the current literature on off-label uses of the CD20-positive B-cell antagonist rituximab, the IgE antagonist omalizumab, the tumor necrosis factor-alpha antagonists infliximab, etanercept, and adalimumab, and the T-cell response modifiers efalizumab and alefacept.
Psoriasis vulgaris, a skin disease that is considered to be the result of a type 1 autoimmune response, provides an opportunity for studying the changes that occur in a target-diseased tissue during innovative immunotherapies. To gain a more comprehensive picture of the response to an approved biological therapy, we studied alfacept, which is a CD2 binding fusion protein. We examined T cells, dendritic cells (DCs), and expression of a number of inflammatory genes. In 22 patients, 55% demonstrated a clear histological remission of the disease, with a 73% reduction in lesional lymphocytes and a 79% decrease in infiltrating CD8+ cells. Only histological responders showed marked reductions in the tissue expression of inflammatory genes IFN-gamma, signal transducer and activator of transcription 1, monokine induced by IFN-gamma, inducible NO synthase, IL-8, and IL-23 subunits. Parallel decreases in CD83+ and CD11c+ DCs also were measured by immunohistochemistry. Because we observed that alefacept binds primarily to T cells and not DCs, we suggest that T cells are the primary target for therapy, but that DCs and a spectrum of type 1 inflammatory genes are coordinately suppressed.
Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to review the progress of the biologic agents which are available, or under investigation for clinical use: infliximab, etanercept, efalizumab, alefacept, and adalimumab. In addition, two other investigational therapies, oral tazarotene and oral pimecrolimus will be discussed. Clinical data for these agents, including the most recent phase II and/or III study results, will be discussed, as well as the most recent safety data.
During the past several years, a new generation of therapies for psoriasis has been in development. These biologic therapies target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. The first article of this 2-part update reviewed the tumor necrosis factor (TNF) inhibitors, infliximab and etanercept. In this article, we will review 2 therapies that target the T cell, efalizumab and alefacept.
Over the last several years, a new generation of therapies for psoriasis has been in development. These biologic therapies target the activity of T lymphocytes and cytokines responsible for the inflammatory nature of this disease. In this review, we present an update on the progress of the four biologic agents in the forefront: infliximab, etanercept, efalizumab, and alefacept. The mechanism of each drug will be reviewed, as well as the most recent efficacy and safety data.
Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years one of the major foci in psoriasis research has been the development of biological therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. This article will review the progress of four biological agents that are available or under investigation for clinical use: infliximab (Centocor Inc), etanercept (Amgen Inc/Wyeth), efalizumab (Genentech Inc/XOMA Ltd/Serono SA) and alefacept.
Combinations of therapeutic modalities have been utilized to meet the challenge of difficult to treat psoriasis. We report two cases of psoriasis, resistant to methotrexate and monotherapy with UVB, treated effectively with alefacept and concomitant narrow band UVB resulting in total disease clear.
Psoriasis is a chronic skin disorder that affects approximately 2% of the US and European population. Over the last several years, one of the major focuses in psoriasis research has been the development of biologic therapies for this disease. The aim of these therapies is to provide selective, immunologically directed intervention with fewer side effects than traditional therapies. The goal of this article is to update the progress of the tumor necrosis inhibitors which are available, or under investigation, for clinical use in psoriasis: infliximab, etanercept, and adalimumab, as well as the T-cell-targeted therapies efalizumab and alefacept (Table 1).
Nail psoriasis can be debilitating and as therapeutic options are limited, it can be notoriously difficult to treat. As there are many new medications currently undergoing clinical trials in psoriasis, questions have arisen concerning the effectiveness of these new therapies with regard to psoriatic nail disease. We present the results of a prospective, open-label, proof of concept study to determine the efficacy and safety of alefacept in subjects with moderate to severe nail psoriasis.
The chronic skin disease psoriasis frequently requires long-term systemic treatment with agents that suppresses the immune system with little specificity, which can lead to systemic side effects. Today, using recombinant techniques, it is possible to produce modified proteins, the so-called biologicals, that target specific molecules in the inflammatory process. For the biologicals etanercept, infliximab, adalimumab, efalizumab and alefacept, the clinical efficacy expressed in the rates of partial remission (75% reduction in skin lesions) in patients with plaque psoriasis range from 12 to 88%, compared with 22 to 87% for existing systemic therapies for psoriasis. The side effects of biologicals are usually mild to moderate, but can sometimes be severe. The biologicals should be prescribed with caution, given that they have been on the market for a relatively short period, and because all forms of immune suppression carry an increased risk of oncologic degeneration. The guideline of the Dutch Society of Dermatology and Venereology states that the use of a biological may be considered when a patient cannot tolerate or is unresponsive to conventional systemic therapy, or has an increased risk of adverse events. Biologicals increase the number of options for treatment-resistant plaque psoriasis, which allows therapy to be tailored to the individual patient.
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