Efalizumab

Efalizumab is a novel immunomodulator that blocks T-cell migration and activation. The drug was initially approved in October 2003 for the treatment of adult patients with chronic moderate to severe plaque psoriasis. This review will discuss the efficacy and safety data for efalizumab in the treatment of psoriasis. In clinical use, efalizumab has utility as a first-line biologic therapy for plaque psoriasis, as well as a first-line choice for hand and foot psoriasis, overweight patients, and those who have had inadequate response to a TNF inhibitor. In addition, several off-label applications of efalizumab will be reviewed.     

Efalizumab in the treatment of psoriasis

BACKGROUND: Efalizumab (anti-CD11a), a targeted, reversible T-cell modulator, is a humanized monoclonal antibody that provides a rapid onset of action of clinical benefit and has been studied up to 36 months, showing continuous control of plaque-type psoriasis. Efalizumab has recently been approved in Canada for this indication. OBJECTIVE: To examine the efficacy and safety of efalizumab by presenting the latest data in the treatment of psoriasis. METHODS: We searched MEDLINE (1966-2005) for randomized, double-blind studies of efalizumab (1 mg/kg for 12 weeks) using the following key words: psoriasis, efalizumab, biologics, and treatment. RESULTS: It was found that the proportion of patients who achieved Psoriasis Area and Severity Index (PASI) 75 and PASI 50 ranged from 22 to 39% and 52 to 61%, respectively. PASI 75 improvement was achieved in 44% of patients, who continued to receive efalizumab by week 24. Following 36 months of continuous treatment, a PASI 75 response was achieved by 45% (intent-to-treat [ITT] analysis), 59% (maintenance group analysis), and 73% (as-treated analysis). Its safety profile was similar during the 12-week and 36-month treatment periods. CONCLUSIONS: Currently, more than 3,500 patients have received efalizumab in clinical trials. Efalizumab may be an important treatment option for dermatologists seeking to provide a well-tolerated and effective treatment modality for patients with moderate to severe chronic plaque psoriasis.     

Treatment of nail psoriasis with efalizumab: a preliminary study

Nail involvement is common in psoriasis, affecting 50% to 80% of all patients with the disorder. Pain may accompany nail involvement, restricting daily living activities, and therapy is limited by issues of efficacy and safety. The cases of 4 participants who had been enrolled in a 3-year study of efalizumab for the treatment of chronic moderate to severe plaque psoriasis are presented in this preliminary study. In addition to the diagnosis of moderate to severe plaque psoriasis, each participant discussed in this report presented with nail involvement. These participants achieved clearance of their nail psoriasis within 19 to 33 weeks of efalizumab therapy. None of the participants demonstrated adverse effects during efalizumab therapy. Our experience with these participants suggests that efalizumab may help to improve psoriasis affecting the nails when used for the treatment of chronic moderate to severe plaque psoriasis.     

Efalizumab for the treatment of psoriatic arthritis

BACKGROUND: Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis. Efalizumab, a T cell-targeted, recombinant human monoclonal antibody, is approved for the treatment of adult patients with chronic moderate to severe plaque psoriasis. The effect of efalizumab therapy on PsA has not previously been investigated. OBJECTIVE: This phase II randomized, double-blind, placebo-controlled multicenter study evaluated the efficacy and safety of efalizumab for the treatment of PsA. METHODS: Patients were required to be on at least one of the following concomitant systemic therapies for PsA: nonsteroidal anti-inflammatory drugs, corticosteroids, and/or sulfasalazine or methotrexate. One hundred fifteen patients with active PsA were enrolled and randomized in the study. Of these, 107 were treated weekly with efalizumab 1 mg/kg or placebo for 12 weeks, followed by 12 additional weeks of open-label efalizumab. RESULTS: At week 12, 28% of efalizumab-treated patients achieved ACR-20 response (a 20% reduction from the baseline in the American College of Rheumatology response criteria), the primary end point, compared with 19% of placebo patients (p = .27). The safety profile was comparable between efalizumab- and placebo-treated patient groups, regardless of methotrexate background therapy, and no worsening of joint disease occurred with efalizumab therapy. CONCLUSIONS: Efalizumab was not effective in treating PsA; efalizumab therapy did not worsen PsA. The efalizumab safety profile does not appear to be altered with the concomitant use of methotrexate therapy.     

A favourable benefit/risk ratio with efalizumab: a review of the clinical evidence

Moderate to severe plaque psoriasis has traditionally been treated with agents that have toxicities associated with long-term use. Many patients therefore cannot be treated safely, conveniently or effectively with traditional therapies. Recent phase 3 clinical trials for efalizumab, a biological agent targeted specifically at the T-cell-based pathology of psoriasis, have demonstrated its short- and long-term efficacy and safety for the treatment of psoriasis. This article reviews results from 12-week, six-month, and three-year trials, focusing on the drug's safety, efficacy, and therapeutic response time, as well as the phenomenon of rebound in non-responding patients. Efalizumab emerges as an important addition to the dermatological pharmacopeia for the long-term treatment of psoriasis.     

T-cell modulation for the treatment of chronic plaque psoriasis with efalizumab (Raptiva): mechanisms of action

Psoriasis is a chronic, incurable, auto-immune disorder with cutaneous manifestations. New evidence on the central role of the immune system in the pathogenesis of psoriasis increasingly provides insight into pathogenic steps that can be modulated to provide disease control. Numerous biological therapies are in various stages of clinical development, with expectation of providing enhanced safety and efficacy over currently available psoriasis therapies. Efalizumab, a recombinant humanized monoclonal IgG1 antibody, is a novel targeted T-cell modulator that inhibits multiple steps in the immune cascade that result in the production and maintenance of psoriatic plaques, including initial T-cell activation and T-cell trafficking into sites of inflammation, including psoriatic skin, with subsequent reactivation in these sites. This article reviews the pharmacodynamic, pharmacokinetic and clinical effects observed during phase I, II and III efalizumab trials in patients with moderate to severe chronic plaque psoriasis.     

Safety of efalizumab in adults with chronic moderate to severe plaque psoriasis: a phase IIIb, randomized, controlled trial

Background To provide safety data for efalizumab, a recombinant humanized monoclonal IgG₁ antibody, in adults with chronic plaque psoriasis. Methods A 12‐week, Phase IIIb, randomized, double‐blind, parallel‐group, placebo‐controlled trial. At 58 study sites in the USA and Canada, 686 patients with moderate to severe chronic plaque psoriasis received an initial conditioning dose of efalizumab 0.7 mg/kg subcutaneously (SC) followed by either 11 weekly doses of efalizumab 1 mg/kg SC or matching placebo. Main outcome measures were safety and tolerability outcomes (primary) and efficacy outcomes (secondary). Results During 12 weeks of therapy with efalizumab or placebo, the incidence of clinical adverse events was 82.2% and 72.9%, respectively; the incidence of serious adverse events was 1.8% and 3.4%, respectively; and the incidence of nonserious adverse events leading to withdrawal was 1.8% and 1.7%, respectively. In the efalizumab group, there were no clinically significant changes in vital signs or laboratory parameters and no evidence of end‐organ toxicities. A significantly higher proportion of patients receiving efalizumab than those receiving placebo achieved ≥ 75% improvement in the Psoriasis Area and Severity Index (PASI) (P < 0.001), ≥ 50% improvement in PASI (P < 0.001), and a static Physician's Global Assessment rating of Minimal or Clear (P < 0.001). The mean improvement in the Psoriasis Symptom Assessment was significantly greater in the efalizumab group (P < 0.001). Conclusions Efalizumab treatment SC for 12 weeks was safe, well tolerated, and effective in patients with moderate to severe chronic plaque psoriasis.     

A favourable benefit/risk ratio with efalizumab: A review of the clinical evidence

Moderate to severe plaque psoriasis has traditionally been treated with agents that have toxicities associated with long-term use. Many patients therefore cannot be treated safely, conveniently or effectively with traditional therapies. Recent phase 3 clinical trials for efalizumab, a biological agent targeted specifically at the T-cell-based pathology of psoriasis, have demonstrated its short- and long-term efficacy and safety for the treatment of psoriasis. This article reviews results from 12-week, six-month, and three-year trials, focusing on the drug’s safety, efficacy, and therapeutic response time, as well as the phenomenon of rebound in non-responding patients. Efalizumab emerges as an important addition to the dermatological pharmacopeia for the long-term treatment of psoriasis.

     

Clinical considerations of efalizumab therapy in patients with psoriasis

Psoriasis is a chronic, incurable disease that often requires decades of therapy to maintain disease control. Efalizumab is a recombinant monoclonal IgG1 antibody approved for use in patients with chronic moderate-to-severe plaque psoriasis. To date, efalizumab has been evaluated extensively in more than 3500 patients, including in studies that have evaluated its efficacy and safety during extended use. Just as psoriasis fluctuates in severity, the response to treatment with efalizumab can vary among patients. On the basis of my personal experience managing patients in and out of clinical trials, most patients benefit from efalizumab. The possibility exists of intercurrent events during efalizumab therapy, such as the development of a transient localized papular eruption or mild arthralgia or, in a few patients, a generalized inflammatory flare or severe arthralgia. However, there are techniques to potentially manage these events in a manner that maximizes patient comfort and compliance. If dermatologists become comfortable recognizing the subset of patients who are overall excellent responders but develop a papular eruption or mild and manageable arthralgia, they will be able to readily incorporate this effective biologic into their daily practice. In this article, clinical trial data and case reports illustrate recommended patient management techniques and the substantial long-term benefits that psoriasis patients may realize with efalizumab therapy.     

Efalizumab: results of a 3-year continuous dosing study for the long-term control of psoriasis

BACKGROUND: Efalizumab, a T-cell-targeted, recombinant, humanized, monoclonal IgG1 antibody, inhibits key T-cell-mediated steps in the pathogenesis of psoriasis. Efalizumab is approved for the treatment of moderate-to-severe chronic plaque psoriasis in adults in more than 50 countries. OBJECTIVES: To evaluate the efficacy and safety of long-term, continuous efalizumab therapy in patients with psoriasis. METHODS: This open-label, multicentre phase III study enrolled 339 patients with moderate-to-severe chronic plaque psoriasis. During the initial 3-month phase, patients received subcutaneous efalizumab 2 mg kg(-1) weekly with randomization to receive concomitant fluocinolone acetonide or placebo ointment during month 3. The second phase was a long-term observational period; patients achieving a >or=50% improvement in the Psoriasis Area and Severity Index (PASI) score were eligible to receive efalizumab 1 mg kg(-1) weekly for up to 33 months. The final 3-month treatment period was an optional transition period for patients who completed the 33-month segment before efalizumab became commercially available. RESULTS: After 3 months, 41.3% of patients achieved a >or=75% improvement in PASI (PASI-75) and 13.0% achieved a >or=90% improvement (PASI-90). Continued improvement was observed: 45.4% and 24.5% achieved PASI-75 and PASI-90, respectively, at the end of the observational phase. The safety profile was stable, with no new or no increase in common events over 36 months of treatment. CONCLUSIONS: This was the longest continuous study using a biologic therapy for psoriasis. Clinical benefit of efalizumab improved over the first 18 months and was maintained during 36 months of continuous therapy. Long-term efalizumab therapy is appropriate for many patients with plaque psoriasis.     

Efalizumab

Efalizumab is a humanized monoclonal antibody that binds to CD11a, the alpha-subunit of lymphocyte function-associated antigen-1, and consequently inhibits T-cell activation. In randomized, double-blind, placebo-controlled trials, efalizumab 1.0 mg/kg, administered subcutaneously once weekly for 12 weeks, significantly reduced disease activity in patients with chronic, moderate-to-severe plaque psoriasis. Significantly more efalizumab recipients had a > or =75% decrease in the Psoriasis Area and Severity Index (PASI) score [22.4-38.9%] than placebo recipients (2.4-4.9%); an additional 12 weeks of treatment resulted in sustained or increased PASI responses. The efficacy of weekly subcutaneous efalizumab was maintained during 15 months of treatment. Efalizumab significantly improved health-related quality of life in patients with chronic plaque psoriasis, with significant improvements in all the Dermatology Life Quality Index domains. Efalizumab was generally well tolerated in patients with chronic, moderate-to-severe plaque psoriasis, with few serious adverse events or treatment withdrawals. The most common adverse events were headache, chills, myalgia, pain, and fever; these most often occurred within 2 days of administration of the drug, were most frequent after the first or second dose, and decreased in frequency over time.     

Long‐term efalizumab therapy for patients with moderate‐to‐severe,chronic plaque psoriasis: results from an Australian expanded access program

Background Psoriasis is a chronic skin disease that can impact heavily on a patient’s well‐being. Efalizumab, a unique, targeted, biological therapy, has demonstrated efficacy in treating moderate‐to‐severe, chronic plaque psoriasis with ≤36 months of continuous therapy. The objective of this Extended Access Program (EAP) was to evaluate further the benefit of efalizumab as long‐term therapy in a real‐world clinical setting. Methods After an initial conditioning dose of efalizumab (0.7 mg/kg subcutaneously), a weekly dose of efalizumab (1.0 mg/kg) was administered for ≤21 months. Patients with reduced Psoriasis Area and Severity Index (PASI) scores (≥50%, or a score ≤8) at month 3 entered the long‐term maintenance treatment period. Results In total, 101 patients (>18 years) with severe plaque psoriasis enrolled on the EAP, of these 93 (92.1%) met all the inclusion criteria. After 3 months of treatment, 84/101 (83.2%) patients had evaluable data and entered the maintenance period. After 3 months, 57/84 (67.9%) patients had achieved PASI‐50. Using an intent‐to‐treat analysis, after 21 months of treatment, PASI‐75 and PASI‐50 were achieved by 43/101 (42.6%) and 69/101 (68.3%) of patients, respectively. Efalizumab was generally well tolerated during the 21 months of continuous therapy. Conclusion Efalizumab, 1.0 mg/kg/week, is effective and well tolerated in a ‘real world’ clinical setting, providing enduring reduction of psoriasis symptoms for up to 21 months.     

Efalizumab: Integrating a new biologic agent into the long-term management of moderate to severe plaque psoriasis

Efalizumab, one of a new generation of biological agents, has been approved for use in moderate to severe psoriasis in over 35 countries including Canada. It may hold the promise of a new level of safe, long-term disease control for psoriasis patients, who have had few adequate options to date. Dermatologists and other caregivers may require some background regarding the mechanisms of action and the optimal use of this drug before integrating it into their standard repertoire of treatment. The present supplement discusses efalizumab’s biological basis and reviews its clinical safety and efficacy. The salient differences amongst the various biologicals, with regard to safety, efficacy and convenience, are also considered. The supplement concludes with a practical guide to initiating and maintaining patients on efalizumab treatment.     

Efalizumab: Integrating a new biologic agent into the long-term management of moderate to severe plaque psoriasis

Efalizumab, one of a new generation of biological agents, has been approved for use in moderate to severe psoriasis in over 35 countries including Canada. It may hold the promise of a new level of safe, long-term disease control for psoriasis patients, who have had few adequate options to date. Dermatologists and other caregivers may require some background regarding the mechanisms of action and the optimal use of this drug before integrating it into their standard repertoire of treatment. The present supplement discusses efalizumab’s biological basis and reviews its clinical safety and efficacy. The salient differences amongst the various biologicals, with regard to safety, efficacy and convenience, are also considered. The supplement concludes with a practical guide to initiating and maintaining patients on efalizumab treatment.

     

From conventional to cutting edge: the new era of biologics in treatment of psoriasis

ABSTRACT:  Psoriasis is a chronic T-cell-mediated inflammatory disease of the skin and joints that affects 1–3% of the world population. Conventional treatments for moderate to severe psoriasis are associated with broadband immunosuppression and/or organ toxicities that can be problematic when used long term. Advances in the understanding of psoriasis pathogenesis have led to targeted therapy in the form of biologics. These agents have gained popularity as safe, effective, and convenient alternatives for the treatment of chronic, moderate to severe plaque psoriasis. This review will focus on the five main biologics used in the treatment of moderate to severe plaque psoriasis: efalizumab, alefacept, etanercept, infliximab and adalimumab. Mechanisms of action, guidelines for usage, efficacy data, and safety concerns will be discussed for each biologic. In addition, the new Th17 biologics and their role in psoriasis pathogenesis will also be examined.     

Efalizumab-induced autoimmune pancytopenia

Efalizumab is a recombinant, humanized monoclonal anti-CD11a antibody used for the treatment of moderate to severe plaque psoriasis. Immune-mediated thrombocytopenia and anaemia have previously been reported with this therapy. We describe the first case of immune-mediated pancytopenia in a patient treated with efalizumab. Close monitoring of all blood cell counts is warranted in light of this case.     

Efalizumab in the treatment of psoriasis: mode of action, clinical indications, efficacy, and safety

Efalizumab is a humanized monoclonal antibody directed against the CD11a subunit of the lymphocyte function-associated antigen 1. It has been approved for the treatment of moderate-to-severe plaque psoriasis. Efalizumab has been shown in several clinical trials to be effective and well tolerated in the treatment of patients with moderate-to-severe psoriasis. The safety profile of continuous therapy with efalizumab—as far as it is currently available—is favorable. Mode of action, pharmacological profile, clinical indications and efficacy, safety, and tolerability as well as practical considerations of efalizumab are reviewed in this article.     

CLinical experience acquired with the efalizumab (Raptiva) (CLEAR) trial in patients with moderate-to-severe plaque psoriasis: results from a phase III international randomized, placebo-controlled trial

BACKGROUND: Efalizumab (anti-CD11a), a humanized monoclonal antibody, blocks multiple T-cell-dependent functions implicated in the pathogenesis of psoriasis, including T-cell activation, migration to the skin, reactivation in psoriatic skin and interactions with keratinocytes. OBJECTIVES: This multinational, randomized, double-blind, placebo-controlled, parallel-group trial was designed to evaluate the safety and efficacy of subcutaneous efalizumab 1.0 mg kg-1 once weekly for 12 weeks compared with placebo in a population that included high-need patients, defined as those for whom at least two systemic therapies were unsuitable because of lack of efficacy, intolerance or contraindication. PATIENTS/METHODS: Patients with moderate-to-severe plaque psoriasis [involvement of >or=10% of total body surface area and Psoriasis Area and Severity Index (PASI)>or=12.0 at screening] were randomized in a 2:1 ratio to receive efalizumab or placebo. The primary efficacy endpoint was the proportion of patients achieving >or=75% PASI improvement (PASI-75 response) at week 12 in the intention-to-treat population; secondary endpoints included changes in PASI, static Physician's Global Assessment, Physician's Global Assessment of change from baseline and percentage of body surface area affected. Results We enrolled 793 patients (529 received efalizumab and 264 placebo), including 526 high-need patients (342 received efalizumab and 184 placebo). Week 12 PASI-75 rates were 29.5% for efalizumab compared with 2.7% for placebo among high-need patients (P<0.0001) and 31.4% for efalizumab compared with 4.2% for placebo in the full study population (P<0.0001). RESULTS: for all secondary efficacy endpoints showed superiority of efalizumab over placebo in both the high-need and the full populations. Efalizumab demonstrated a favourable safety profile, without evidence of systemic toxicity, in both the high-need group and the overall study population. CONCLUSIONS: The efficacy and safety of efalizumab therapy were comparable between high-need patients and the more general moderate-to-severe psoriasis patient population. In view of its demonstrated efficacy and safety profile, efalizumab represents a valuable option for the treatment of adult patients with moderate-to-severe plaque psoriasis, including high-need patients.     

Efalizumab-induced guttate psoriasis. Successful management and re-treatment

Psoriasis is a chronic, immunologically based inflammatory skin disease. Efalizumab (Raptiva) is a humanized monoclonal immunoglobulin G1 antibody that binds with high specificity and affinity to the alpha subunit of leucocyte function-asssociated antigen-1 (LFA-1) on the surface of T cells. Therefore, efalizumab is an effective biologic therapy for the long-term treatment of chronic moderate-to-severe plaque psoriasis. This drug demonstrated a good safety profile, whereas most adverse events were mild to moderate in severity. During efalizumab treatment, a small percentage of patients experienced protocol-defined psoriasis adverse events (e.g. worsening of psoriasis or the onset of new psoriasis morphologies). We present the case of a patient who experienced a new onset of guttate psoriasis and a mild worsening of pre-existing psoriatic lesions during treatment with efalizumab. Restarting with the same drug did not induce any adverse events.     

The lymphocyte: protagonism in the new era of the biological therapies

Psoriasis is a systemic type T cell mediated immune system chronic inflammatory skin disease. These cells play an important role in the immune system and in the inflammatory response that determines the development and maintenance of the psoriasis lesions. However, greater understanding of the pathophysiology of this disease has led to the development of specific and selective biological treatments. Efalizumab is a humanized IgG1 monoclonal antibody that binds to the Leukocyte-Function-Associated Antigen 1 (LFA-1). When it binds to the CD11a--alpha subunit of LFA1--it inhibits the binding of this ligand to the intercellular adhesion molecule 1. This inhibits several processes related with the T cells that are fundamental in the pathogenesis of psoriasis: activation of the T cells in the lymph nodes, the migration of the T cells towards the dermis and epidermis and finally the reactivation of these in the inflammatory focus. The clinical studies have demonstrated that efalizumab, administered subcutaneously only once a week, provides a clinical benefit as well as improvement in the quality of life in patients with psoriasis with chronic, moderate or severe plaques. Long-term treatment studies suggest that continuous therapy with efalizumab is more beneficial in the maintenance of the improvement of the response and demonstrate that efalizumab may be administered safely for prolonged periods. Given its efficacy, rapid onset action, safety profile due to its selective action mechanism and convenience in its subcutaneous self-administration weekly, efalizumab offers a new therapeutic option, especially of interest for the treatment of psoriasis.