Efalizumab

Efalizumab is a humanized monoclonal antibody that blocks T-cell activation, reactivation, and trafficking into the skin by binding to CD11a, a subunit of LFA-1. This binding is reversible after discontinuation of treatment.^3,4 Efalizumab is approved for the treatment of moderate-to- severe psoriasis and is administered subcutaneously (SC) once weekly at a dose of 1 mg/kg.The product labeling states that rare cases of thrombocytopenia have been reported during treatment, and it is therefore recommended that platelet counts be assessed monthly during the first 3 months of treatment and periodically (at the physician’s discretion) thereafter.⁴ The causal relationship between efalizumab and thrombocytopenia is unknown.

Performance in short-term studies

• In a double-blind trial, 27% of efalizumab-treated patients (n=369) achieved PASI 75 after 12 weeks of therapy.⁵ Statistically significant differences from placebo were seen in PASI responses as early as 2 weeks after the start of treatment. The same results were seen when data from three 12-week, double-blind, placebo-controlled trials (total of 1651 patients) were pooled.^6,7 Patients who completed the 12-week double-blind trial could enroll in an open-label extension in which all patients were treated with efalizumab and the investigators remained blinded to the therapy received during the first 12 weeks. Among patients who completed 24 weeks of continuous efalizumab therapy (n=368), 44% reached PASI 75 (Figure 2).^7,8




Figure 2




• In the pooled safety results from the three 12-week, double-blind, placebo-controlled trials described above and a fourth 3-month safety study (2335 total patients; 1620 treated with efalizumab), the most common adverse events were mild-to-moderate flu-like symptoms (headache, chills, fever, nausea, etc) occurring after the first one or two doses of efalizumab. By the third dose, the incidence of these acute adverse events among efalizumab-treated and placebo-treated patients was similar.^4,6 The incidence of serious adverse events, infection, and malignancy was low and similar for efalizumab and placebo.⁶
• Among the 1115 patients who had received at least 6 months of efalizumab therapy (pooled results of 13 controlled and uncontrolled clinical trials), the safety profile during the second 3 months of treatment was similar to that seen during the first 3 months, except for a decrease in flu-like symptoms. There was no indication of hepatotoxicity or nephrotoxicity with longer-term treatment.⁹

Performance in long-term studies

• During the first 3 months of a recently completed 36-month open-label clinical trial,¹⁰ all patients were treated with 2 mg/kg efalizumab SC once weekly. At 3 months, patients who had achieved a PASI 50 response or a Physician's Global Assessment (PGA) of mild, minimal, or clear were eligible to enter the maintenance treatment period (1 mg/kg efalizumab once weekly). This change in dose reflects the growing understanding of the appropriate use of efalizumab. It has been determined that 1 mg/kg/wk is the appropriate dose to use in all patients. Preliminary results demonstrate that efficacy was improved or maintained through 30 months of continuous efalizumab treatment (Figure 3). Among all patients who entered the trial, 41% had a PASI 75 at 3 months and 50% had a PASI 75 at 30 months; 13% had a PASI 90 at 3 months and 29% had a PASI 90 at 30 months (“intent-to-treat” analysis; n=339, with 159 completing 30 months of efalizumab). Among just those patients who entered the open-label treatment period, 41% had a PASI 75 at 3 months and 58% had a PASI 75 at 30 months; 13% had a PASI 90 at 3 months and 34% had a PASI 90 at 30 months (“maintenance group” analysis; n=290). Patients in the open-label extension portion of this study were allowed to use mid-potency topical steroids and ultraviolet phototherapy (UVB) to help control their psoriasis, but only 2 patients utilized UVB during the 30-month period. There was no increase in adverse events over time, no evidence of increased end-organ toxicity, and no trend toward an increasing incidence of infection or malignancy.^10-12




Figure 3




• The long-term safety of efalizumab was also evaluated in a recently completed 72-week study, in which all patients who completed the first 12 weeks of a double-blind comparison of efalizumab 1 mg/kg/wk versus placebo were eligible to receive efalizumab 1 mg/kg/wk during an open-label extension to 72 weeks.¹³ This study also allowed patients to use mid-potency topical steroids and ultraviolet phototherapy to help control their psoriasis. Approximately 59% of the 328 patients who received between 37 and 48 weeks of continuous treatment in this study achieved PASI 75 (“as-treated” analysis). There was no increase in adverse events and no emergence of new adverse events with long-term treatment.¹³

Occurrence and management of psoriasis adverse events

• Definitions of psoriasis adverse events.¹⁴ During therapy, some patients may experience a worsening of their psoriasis. This worsening can either be in the form of a transient neutrophilic dermatosis (TND; formerly referred to as a “papular eruption”) or a generalized inflammatory exacerbation (formerly referred to as a “generalized inflammatory flare”). Relapse following therapy discontinuation is defined as a loss of at least 50% of the improvement seen during therapy. A rebound of psoriasis is defined as a worsening of psoriasis to 125% of the baseline PASI score or new generalized pustular, erythrodermic, or more inflammatory psoriasis within 12 weeks of discontinuation of therapy.
• Psoriasis adverse events (including both serious and nonserious events) during efalizumab therapy were reported in 3.2% of efalizumab-treated patients and 1.4% of placebo-treated patients.⁴ Transient neutrophilic dermatosis can be managed by adding a topical treatment until the problem resolves. Generalized inflammatory exacerbations occurring during the first 12 weeks of treatment can be managed by transitioning the patient to another therapy or by adding another systemic therapy (generally cyclosporine or methotrexate) to efalizumab. The patient can then be tapered off of the second therapy once the exacerbation has resolved.¹⁴
• In many of the controlled clinical studies of efalizumab, the protocol called for the abrupt discontinuation of efalizumab therapy after 12 weeks of treatment. In these studies, the median time to relapse was 64 to 70 days, and disease rebound occurred in 14% (188/1316) of efalizumab-treated patients and 11% (53/479) of placebo-treated patients.^4,8 In patients who experienced PASI 125, the median time to PASI 125 was 36 days. The vast majority of rebound events among efalizumab-treated patients (182/188), and all of the rebound events in placebo-treated patients, were manifested as PASI 125 rather than as new psoriasis morphologies. Of the 188 efalizumab-treated patients who experienced rebound, 72% (135/188) were nonresponders to efalizumab therapy, 18% (34/188) were partial responders, and 10% (19/188) were responders (Figure 4).¹⁵ In some of the clinical trials included in this analysis, some patients who experienced disease recurrence were treated with another psoriasis therapy. Those therapies that successfully prevented rebound in at least 90% of patients included (starting with the most effective) cyclosporine, methotrexate, systemic corticosteroids, phototherapy, and high-potency topical steroids. Therapies that successfully prevented rebound in 75% to 90% of patients included systemic retinoids, vitamin D derivatives, and other topical therapies.¹⁵




Figure 4




• During clinical studies, serious worsening of psoriasis associated with treatment was rare (19/2859; 0.7%), and most of these serious events (14/19; <0.5% of all patients) occurred after discontinuation of study drug rather than during treatment (5/19; <0.2% of all patients).⁴
• A dose-tapering study of 556 patients demonstrated that tapering the dose of efalizumab prior to discontinuation of therapy did not decrease the incidence of psoriasis rebound.¹⁶

Other studies

• Psoriatic arthritis. A double-blind study¹⁷ of efalizumab in 107 patients with psoriatic arthritis did not show a statistically significant difference between the efalizumab and placebo treatment groups. Results of this study showed no worsening of psoriatic arthritis and no adverse events of psoriatic arthritis or psoriasis. The efficacy of efalizumab on the psoriasis in the subset of patients with moderate-to-severe psoriasis was consistent with the results seen in psoriasis clinical trials.¹⁷

Snapshot of efalizumab

Efalizumab is a T-cell–inhibiting agent that is effective in the treatment of moderate-to-severe psoriasis. Efficacy can become apparent as soon as 2 to 4 weeks after treatment is initiated. More psoriasis patients have been studied in clinical trials with efalizumab than with any of the other biologic agents, and efficacy in some of these patients has been maintained for 30 months or more. Efalizumab has a demonstrated safety profile, and the most common adverse events are mild and occur during the first few weeks of treatment. Some patients may experience mild, localized psoriasis flares during treatment that can be managed with topical therapy and generally do not require the discontinuation of therapy. Rarely, patients may experience generalized inflammatory exacerbations during efalizumab treatment that require a transition to another therapy or the addition of a second systemic agent for a period of time. Rebound, which can occur after efalizumab discontinuation but is most likely to occur in patients who did not respond well during treatment, can occur and may be preventable by transitioning the patient to another psoriasis therapy.

Future directions for efalizumab research

The cohort of patients that have received efalizumab therapy for over a year (in some cases, more than 3 years) provides an opportunity for investigating the effects of continuous biologic therapy on psoriasis patients. Short-term efalizumab therapy (12 weeks) is not generally associated with long-term disease remission; however, there are anecdotal reports of very long remissions (up to 1 year and longer) following long-term (3 years) efalizumab treatment. Some investigators state that it is possible that the long period of T-cell inhibition produced by long-term efalizumab therapy could be causing some fundamental change that is altering the nature of psoriasis in these patients. It will be important to investigate these questions with regard to all of the biologic agents, not just efalizumab.

During the first few clinical studies of efalizumab, disease worsening during, or after discontinuation of, efalizumab therapy was not well understood and raised some concerns. Ongoing research and the clinical experience of many physicians now allows us to better predict which patients may experience significant problems and to better manage any problems that do arise.^14-16 More research is still needed in this area and may also help shed light on the nature of psoriasis in general.