Trade Name Drug: Raptiva
Generic Name Drug: Efalizumab
Indication/Use: Plaque Psoriasis
Approval Date: Oct. 28, 2003
FDA Class: B
Efalizumab (Raptiva), a humanized therapeutic antibody designed to selectively and reversibly block the activation, reactivation, and trafficking of T cells, was approved by the FDA in October 2003 for the treatment of chronic, moderate to severe plaque psoriasis in adults age 18 or older.
Psoriasis is an autoimmune skin disease. It is characterized by accelerated skin growth that leads to skin cells building up on the surface of the skin, forming red, raised scaly plaques. Psoriasis can involve large areas of skin and is often itchy and painful. Approximately 1.5 million Americans suffer from moderate to severe psoriasis, which means they have psoriasis on more than 2% of their body’s surface. The PASI (Psoriasis Area and Severity Index) is a widely used scale in clinical trials for assessing the severity of psoriasis and the effectiveness of treatment. It assesses four main body areas (the head, upper extremities, lower extremities, and torso) and, for each of these areas, provides a methodically derived score of 0 72 based upon both the extent of psoriatic coverage and the severity of psoriatic lesions. The four subscores are then combined, providing the composite PASI, which ranges from 0.0 (no psoriasis) to 72.0 (the worst possible severity) in steps of 0.1. Plaque psoriasis is the most common type of psoriasis, accounting for 80% of all psoriasis cases. It is characterized by raised, reddened, scaly patches of skin. Plaque psoriasis is commonly found on the scalp, knees, elbows, and torso, but it may appear anywhere on the body and can involve extensive areas of the skin.
While there are a number of medications that may help control the symptoms of psoriasis, there is currently no cure. Mild cases are usually treated at home with OTC shampoos, hydrocortisone cream, antifungal medications, antibiotics, and other topical anti-infectives. The cause of psoriasis is not fully known. There is evidence that activated T cells are involved in the pathogenesis of psoriasis with excessive keratinocyte proliferation as a secondary phenomenon. Therefore, oral or injected immunosuppressive medications, such as corticosteroids or methotrexate, have had some success in treating very severe cases of psoriasis. Other medications may include retinoids or cyclosporine.
Alefacept, approved in early 2003 for the treatment of moderate to severe chronic plaque psoriasis, represents a new generation of biologic therapies for this disorder. Alefacept, utilizing its LFA-3 binding domain, complexes with T-cell CD2 sites resulting in prevention of T-cell activation. The recent approval of efalizumab offers a second biologic therapy of plaque psoriasis.
Mechanism of Action
Efalizumab (Raptiva) is an immunosuppressive recombinant humanized monoclonal antibody directed against the CD11a alpha subunit of leukocyte functionassociated antigen-1 (LFA-1). Blocking the interaction between LFA-1 on lymphocytes and intracellular adhesion molecule-1 (ICAM-1) on antigen-presenting/vascular endothelial cells results in a saturation of available CD11a binding sites and down-regulation contributing to inhibition of T-cell activation, reactivation, and trafficking to the dermis and epidermis.
Activation of T cells and their migration into the skin are known to contribute significantly to the lesions of psoriasis. LFA-1 is a heterodimeric adhesion molecule expressed on leukocytes, and is involved in T-cellmediated processes; it is required for initial activation of T cells, as well as leukocyte extravasation to inflammatory sites. LFA-1 binds to ICAM-1 located on keratinocytes, endothelial cells, and antigen-presenting cells; in inflamed psoriatic plaques, the interaction of LFA-1 with ICAM-1 facilitates T-cell extravasation into lesional skin, exacerbating inflammation. Effective inhibition of the LFA-1/ICAM-1 adhesion mechanism can explain the efficacy of efalizumab in disrupting the disease process. CD11a is also expressed on the surface of B lymphocytes, monocytes, neutrophils, natural killer cells, and other leukocytes. Therefore, the potential exists for efalizumab to affect the activation, adhesion, migration, and numbers of cells other than T lymphocytes.
In patients with moderate to severe plaque psoriasis, subcutaneous (SC) efalizumab in an initial dose of 0.7 mg/kg followed by 11 weekly SC doses of 1 mg/kg/wk, achieves steady-state serum concentrations at four weeks with a mean trough concentration of approximately 9 µg/mL. After the last dose, the mean peak concentration is approximately 12 µg/mL. Mean steady-state clearance was 24 mL/kg/day (range = 5-76 mL/kg/day). Mean time to eliminate efalizumab after the last steady-state dose is 25 days (13-35 days, n = 17). The mean estimated efalizumab SC bioavailability is 50%. In a population pharmacokinetic analysis of 1,088 patients, body weight was found to be the most significant covariate affecting efalizumab clearance. In patients receiving weekly SC doses of 1 mg/kg, efalizumab exposure was similar across body weight quartiles; efalizumab (Raptiva) clearance was not significantly affected by gender or race. The pharmacokinetics of efalizumab in pediatric patients has not been studied. The effects of renal or hepatic impairment on the pharmacokinetics of efalizumab have not been studied.
Efalizumab (Raptiva) is approved for the treatment of chronic moderate-to-severe plaque psoriasis in adults age 18 or older who are candidates for systemic therapy or phototherapy. Data from four randomized, placebo-controlled phase III studies enrolling more than 2,700 psoriasis patients treated with efalizumab were submitted in support of the application for approval of the new drug. The studies had a primary efficacy endpoint of greater than or equal to 75% improvement in PASI (PASI-75). Secondary endpoints for the phase III studies included physician assessment and patient-reported outcomes. Efalizumab demonstrated efficacy and maintained response in most patients after 12 weeks of treatment. Sustained responses to efalizumab have also been observed in uncontrolled open-label extension treatment trials when patients received efalizumab without interruption for 24 weeks.
A phase III, double-blind trial recently reported in JAMA enrolled 556 adult patients at 30 study centers in the US between January and July 2002. Patients were randomized 2:1 to receive 12 weekly doses of SC efalizumab, 1 mg/kg, or placebo equivalent. At baseline, all patients had stable, moderate to severe plaque psoriasis. Improvement was defined as at least PASI-75 as well as improvement on the overall Dermatology Life Quality Index (DLQI), Itching Visual Analog Scale (VAS), and Psoriasis Symptom Assessment (PSA) at week 12 compared with baseline.
The efalizumab group had significantly greater improvement on all end points than did the placebo group, including achievement of PASI-75 (27% vs 4%), percentage improvement on the overall DLQI (47% vs 14%), Itching VAS (38% vs -0.2%), PSA frequency subscale (48% vs 18%), and severity subscales (47% vs 17%; P < .001 for all comparisons). Study limitations were short duration of follow-up and lack of active comparator drug.
Common adverse events that occurred at least 2% more frequently in efalizumab patients than in placebo in clinical trials included headache, infection (mostly upper respiratory infections), chills, nausea, pain, myalgia (muscle pain), flu syndrome, fever, back pain, and acne. Five of these events (headache, chills, fever, nausea, and myalgia) were predominantly acute adverse events and were principally seen following the first two injections of efalizumab. For the third and subsequent doses, the incidence of acute adverse events was similar between the efalizumab and placebo groups. Less than 1% of patients were discontinued from treatment due to acute adverse events.
Serious adverse events occurring in clinical studies with efalizumab (Raptiva) were serious infections (0.4% in efalizumab vs 0.1% in placebo), malignancy (the overall incidence of malignancies of any kind was 1.8 per 100 patient-years for efalizumab-treated patients compared with 1.6 per 100 patient-years for placebo-treated patients), thrombocytopenia (0.3% efalizumab vs 0.0% placebo), and worsening of psoriasis, typically upon discontinuation (0.7% in efalizumab vs 0.0% in placebo).
No formal drug interaction studies have been performed with efalizumab. Efalizumab (Raptiva) should not be used with other immunosuppressive drugs. Acellular, live, and live-attenuated vaccines should not be administered to patients during their treatment with efalizumab.
Dosage and Administration
Efalizumab is supplied as a lyophilized, sterile powder to deliver 125 mg of efalizumab per single-use vial. The recommended dose of efalizumab is a single 0.7 mg/kg SC conditioning dose followed by weekly SC doses of 1 mg/kg (maximum single dose not to exceed a total of 200 mg). Efalizumab is intended for use under the guidance and supervision of a physician. If it is determined to be appropriate, patients may self-inject efalizumab (Raptiva) after proper training in the preparation and injection technique and with medical follow-up.