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| Meetings/Links : Meeting Reports : Psoriasis and Biologic Therapy |
Update on the Safety of Biologic Agents in the Treatment of Psoriasis
At separate sessions of a recent national meeting, Drs. Gordon, Lebwohl, and Wolverton discussed the long-term safety of the biologic agents in patients with psoriasis. This was also the subject of several poster presentations.
Long-Term Safety Studies: Issues to Consider
Dr. Gordon analyzed the various databases available for assessing the long-term safety of biologic agents.1 While placebo-controlled trials provide the most reliable data, the numbers are often relatively small. In contrast, open-label trials are typically of longer duration, with larger numbers, but they lack a control arm. Voluntary reporting (such as the FDA reports) and long-term monitoring of use may underestimate the numbers in total, and the numbers, while often initially large, may decline due to lack of interest; there is also no control group or denominator. In addition, as the background incidence of many problems is unknown in psoriasis patients, a baseline for the evaluation of side effects is often difficult to establish. Further considerations in this patient population include the use of multiple medications and the possibility of other underlying conditions. These are highly relevant when evaluating the long-term safety data in the use of anti-TNF agents in the rheumatoid arthritis (RA) and Crohn's disease patient populations.
It was noted that physicians now recommend that a test for purified protein derivative of tuberculin (PPD) be performed on all patients about to receive an immunosuppressive agent, followed by a chest x-ray if the PPD test is positive. Exacerbation of tuberculosis (TB) with the use of infliximab or adalimumab has been observed, but most of these reports come out of trials in Europe and involve patients who were not properly screened for TB prior to entry.
Adverse Event Profiles of the Biologic Agents
The adverse event profiles of the biologic agents were reviewed in a presentation by Dr. Lebwohl.2 Whereas T-cell agents do not appear to increase infection, the causal relationship between the TNF agents and infections or lymphoma is not yet clear. Although there is a risk of TB reactivation with the TNF agents, especially with infliximab, this can be minimized with prescreening. In studies in patients with congestive heart failure (CHF), there was a clear indication with both infliximab and etanercept that the condition could be made worse. Although no clinical trials showed evidence of new-onset heart failure, there have been cases cited in postmarketing reports. The labeling of all of the TNF agents indicates that they should not be used in patients with heart failure. The available data are based on RA patients, who are already at increased risk for heart failure. Finally, data from trials of etanercept and infliximab indicate that there is an increased risk of demyelinating disorders with use of these agents in patients with a history of neurologic disorders. It is unclear as to whether demyelinating disorders are an unmasking of an existing condition or the creation of a new condition. Therefore, these agents should be used with caution in patients with a personal or family history of neurologic disorders.
No Apparent Increased Risk of Lymphoma With Biologics
A presentation by Dr. Wolverton discussed the risk of lymphoma with biologic therapy in light of the published 2- to 3-fold increased risk for lymphoma in psoriasis patients.3 A critical assessment of the data in RA patients showed that, while confidence intervals are wide given that the numbers are relatively low when compared to the appropriate control group, there appears to be no increased risk of lymphoma with the biologics.
Alefacept
Alefacept is a fusion protein that blocks the interaction of T cells with antigen-presenting cells, thereby preventing T-cell activation. Alefacept also causes apoptosis of memory T cells through the formation of "bridges" between T cells and natural killer cells. Alefacept is approved for the treatment of moderate to severe psoriasis.
The long-term safety of alefacept in 1,869 patients who have received up to 9 courses of therapy over a 5-year period was presented in a poster by Goffe et al.4 He concluded that the incidence of adverse events, discontinuations for adverse events, serious adverse events, and infections and malignancies did not increase over multiple courses of therapy (Table 1).
Table 1. Alefacept safety by course of therapy.4
Etanercept
Etanercept is a fusion protein that blocks TNF-a. It is approved for the treatment of moderate to severe psoriasis and psoriatic arthritis.
A poster by Tyring et al presented data from the first 3 months of a 2-year safety and efficacy study with etanercept 50 mg twice weekly.5 As early as week 4, the proportion of PASI 50 and 75 responders was statistically significantly greater in the etanercept treatment group compared to the placebo treatment group. The PASI 75 results from this study confirmed those of previous studies utilizing this dose. Seven-year safety data in RA, presented by Dr. Lebwohl, demonstrated that the rates of serious infections did not increase over time and that the number of observed malignancies was similar to that expected using external cohorts.6
Efalizumab
Efalizumab is a humanized monoclonal antibody that blocks T-cell activation, reactivation, and trafficking into the skin by binding to CD11a (an LFA-1 subunit) on T cells. It is approved for the treatment of moderate to severe psoriasis.
A poster by Gottlieb et al presented safety data from an open-label phase 3 study involving 36 months of continuous efalizumab therapy.7 In this trial, the concomitant use of topical therapies and/or UVB phototherapy was allowed. Only 6.2% of patients were given UVB at any time during the trial. Although the concomitant use of systemic psoriasis therapies was prohibited, safety analyses included all patients regardless of systemic use or indication. Results showed that there was no evidence of cumulative or end-organ toxicity, no increase in the overall incidence of adverse events during long-term therapy, no new adverse events, and no increase in infection or malignancy (Figures 1 through 4).
Figure 1. Efalizumab 3-year trial: adverse events of infection.7
Figure 2. Efalizumab 3-year trial: adverse events of psoriasis.7
Figure 3. Efalizumab 3-year trial: adverse events of arthritis.7
Figure 4. Efalizumab 3-year trial: serious adverse events and malignancy.7
The safety and tolerability data from another long-term open-label trial with efalizumab were also presented in a poster by Menter et al.8 Patients were given a single conditioning dose of 0.7 mg/kg efalizumab followed by 11 weekly doses of 1 mg/kg. After completing 12 weeks of treatment, patients in the placebo arm were allowed to enter an open-label extension study of up to 48 weeks of efalizumab therapy. Concomitant topical therapy or phototherapy was permitted. Only 21 (6.2%) patients were given UVB during therapy. Following completion of the extended treatment period, patients had the option of either entering a 12-week treatment-free observation period or continuing to receive efalizumab for another 12 weeks. The overall incidence of adverse events appeared to decrease with additional treatment during 60 weeks of continuous efalizumab therapy. No new common adverse events emerged with extended efalizumab exposure, and the incidence of infection, malignancy, and other clinically important adverse events was comparable to that observed in the placebo-controlled period of the trial and generally remained stable with increased exposure to efalizumab (Table 2).
Table 2. Efalizumab: clinically significant adverse events over 15 months of continuous therapy.8
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