Efalizumab

General adverse effects and adverse reactions

Adverse reactions to efalizumab in clinical trials have been reviewed [ ]. The most common were a first-dose reaction complex that includes headache, chills, fever, nausea, and myalgia within 2 days after the first two injections. These reactions were mostly mild to moderate in intensity when a small dose of 0.7 mg/kg was used as the first dose. Adverse events that occurred at rates of 1–2% more with efalizumab than placebo were arthralgia, weakness, peripheral edema, and psoriasis. Withdrawal of efalizumab is associated with a rebound flare reaction in about 5% of patients. Anti-efalizumab antibodies develop in about 5% of subjects, but their clinical significance is not known. Immune-mediated thrombocytopenia (at or below 52 × 10 ⁹ /l) has been observed in 0.3% of cases, and monitoring of platelet counts monthly during the first 3 months and 3-monthly thereafter was recommended. There have been reports of hemolytic anemia after 4–6 months. New-onset or recurrent severe arthritis, including psoriatic arthropathy, was infrequently reported in clinical trials and postmarketing surveillance. Symptoms associated with hypersensitivity reactions (dyspnea, asthma, urticaria, angioedema, maculopapular rashes) were rare in the first 12 weeks of the controlled studies. The overall incidence of malignancies of any kind was 1.8 per 100 patient-years with efalizumab, compared with 1.6 per 100 patient-years with placebo. The following serious adverse reactions were also reported: transverse myelitis, bronchiolitis obliterans, aseptic meningitis, idiopathic hepatitis, sialadenitis, and sensorineural hearing loss. The overall incidence of hospitalization for infections was 1.6 per 100 patient-years with efalizumab, compared with 1.2 per 100 patient-years with placebo; the rates of infection were 29% and 26% respectively. The most common laboratory findings in patients receiving efalizumab were reversible increases in lymphocyte and total white blood cell counts.

In four placebo-controlled trials patients who received efalizumab for 13–60 weeks the most common adverse events were mild to moderate, self-limiting, flu-like symptoms, which were most frequent after the first two doses of efalizumab [ ]. By the third dose, the incidence was comparable to that with placebo. There were serious adverse events in 2.2% and 1.7% with efalizumab and placebo respectively. Non-serious adverse events that led to withdrawal were infrequent and similar to placebo (2.8% versus 1.8%).

Observational studies

In a 24-week, open, phase IIIb/IV Latin American study of efalizumab in 189 patients with moderate-to-severe plaque psoriasis, adverse events were reported by 161 (85%) and serious adverse events by 21 (11%); one patient died of meningoencephalitis [ ].

Placebo-controlled studies

Efalizumab 1 or 2 mg/kg/week was given subcutaneously to 597 patients with psoriasis in a phase III multicenter, double-blind, randomized, placebo-controlled study [ ]. Adverse events included non-specific infections in 13%, pruritus (6%), and arthritis (5%). Efalizumab antibodies developed in 5%. There were serious adverse events in 13 patients (3%), including five non-fatal infections. Acute adverse events (most commonly headache, chills, fever, nausea, and myalgia, which occurred on the day of administration or within 2 days after) were most frequent after the first dose, were generally mild to moderate, and fell in frequency over time. None of the adverse events resulted in study withdrawal.

The efficacy and safety of efalizumab was studied in a randomized, double-blind, parallel-group, placebo-controlled trial in 556 adults with stable moderate to severe plaque psoriasis [ ]. Efalizumab significantly improved both physician-assessed and patient-reported outcomes. There were five types of adverse events with efalizumab (headache, chills, fever, myalgia, and pain) in at least 5% more patients than with placebo. Serious adverse events (not further specified in the publication) were infrequent, occurring in 2% of patients who were given efalizumab and 1% of those who were given placebo. The rate of diagnosed infections was 27% with efalizumab and 23% with placebo. Infections that occurred in at least 1% more of the efalizumab-treated patients included mild to moderate upper respiratory tract infections, bacterial infections (for example impetigo, streptococcal pharyngitis, cellulitis), and fungal (yeast) infections. There were no clinically important laboratory abnormalities.

Systematic reviews

Efalizumab was evaluated based on five double-blind, placebo-controlled trials [ ]. In four of the trials the end-point for efficacy was the number of patients who had an improvement of at least 75% in the psoriasis area severity index (PASI) score after 12 weeks of treatment. With efalizumab 1 mg/kg per week, about 25% of patients reached this target, compared with about 4% of patients in the placebo group. Efficacy was not improved by doubling the dose of efalizumab. Another trial focused on adverse reactions. Most of the patients relapsed within an average of 2 months after withdrawal of treatment. The most frequent short-term adverse reaction was a flu-like syndrome, which affected about 50% of patients. Adverse events in clinical trials included skin cancers, severe infections, aggravation or rebound of psoriasis after withdrawal of treatment, thrombocytopenia, leukocytosis, hypersensitivity reactions, and raised liver enzymes.

In a systematic review of double-blind, randomized, controlled trials of alefacept (n = 3), efalizumab (n = 5), etanercept (n = 4), and infliximab (n = 4) in patients with psoriasis, the relative risks of one or more adverse events in were significantly increased compared with placebo:

• alefacept: RR = 1.09; NNT _H = 15;

• efalizumab: RR = 1.15; NNT _H = 9;

• infliximab: RR = 1.18; NNT _H = 9.

Serious adverse events were increased in a sensitivity analysis of four efalizumab trials (n = 2443; RR = 1.92; NNT _H = 60) [ ].