Introduction 23 26 ® 1 1 10 11 21 25 4 6 12 17 22 27 27 8 12 8 Methods 4 6 12 17 22 4 6 12 17 22 3 http://www.meddramsso.com/NewWeb2003/index.htm Treatment groups analyzed 1 Table 1 Summary of the Phase III data from five placebo-controlled clinical trials (including data from two open-label extension studies of two of these trials) and two open-label clinical trials of efalizumab included in the pooled safety analysis Publication (protocol number) Study design Number of patients in each analysis First treatment (0–12 weeks) Efalizumab sc 1–4 mg/kg qw or 2 mg/kg qow  Extended treatment (13–24 weeks) a  Re-treatment Placebo Efalizumab 1 mg/kg Efalizumab 2 mg/kg 13 Randomized, double-blind, parallel-group, placebo-controlled 170 162 166 462 123 – 55 12 Randomized, double-blind, parallel-group, placebo-controlled  122 232 243 579 289 – – 4 Randomized, double-blind, parallel-group, placebo-controlled  187 368 – 368 – – – 17 Randomized, double-blind, parallel-group, placebo-controlled  236 449 – 449 – 449 – 22 Randomized, double-blind, parallel-group, placebo-controlled 264 529 – 772 308 – 145 16 Open-label – – – 34 137 – 365 5 6 Open-label – – – b 290 339 – 14 c  4 – – – 174 342 – – 15 c  17 – – – 217 622 d –  Pooled analysis  979 1740 409 3,394 2,111 e 565 qow qw sc a b n n c d 17 e 6 17 15 It is worth noting that most of the studies included in this pooled analysis were designed and conducted before efalizumab had received regulatory approval and before it was known that doses of more than 1 mg/kg once weekly (the approved dose) did not confer additional treatment benefit (EMEA, Raptiva Summary of Product Characteristics; FDA US, FDA Prescribing Information for Raptiva). For this reason, only the efalizumab 1 mg/kg once-weekly dose data are reported for the ‘first treatment phase’ of the analysis. Due to the wide variety of study designs included in the pooled analysis, data for patients receiving any dose of efalizumab are combined for all other treatment phases analyzed. The ‘first treatment phase’ analysis included 0–12-week data from patients in the five placebo-controlled studies who received either efalizumab 1 mg/kg once weekly or placebo. This analysis allows a comparison between the efalizumab and placebo treatment groups. The ‘first exposure phase’ included 12-week data from all studies in patients who had their first exposure to any dose of efalizumab and, thus, did not include placebo data. This analysis was conducted to include the maximum number of patients who received efalizumab for their first 12 weeks of treatment (i.e., it included those patients who first received efalizumab treatment after crossing over from a placebo group, as well as the patients who first received efalizumab during weeks 0–12). The ‘extended treatment phase’ analysis included 13–24-week data in patients given any dose of efalizumab who had already received efalizumab during the first treatment phase. 6 15 17 The ‘re-treatment phase’ analysis included all patients who re-started treatment with efalizumab following a treatment-free observation period. Statistical analyses Descriptive statistics were used to explore the association between efalizumab and the occurrence of arthropathy AEs. Results are expressed as point-estimates of the incidence rates (ratio of the number of patients with an arthropathy AE to the total number of patient-years at risk of an arthropathy AE) with their 95% confidence intervals (CIs). Descriptive comparisons are provided; no formal statistical tests were performed. 22 1 Baseline demographics and psoriasis characteristics and the proportion of patients with a previous history of arthropathy (as reported by patients at the baseline visit) were tabulated by presence/absence of an arthropathy event. Results 1 12 13 2 Table 2 Baseline demographic and disease characteristics for patients in the placebo-controlled first treatment phase Characteristics n n n Mean age (years), mean (SD) 45 (12) 45 (12) 45 (13) Weight (kg), mean (SD) 90.0 (20.0)  89.4 (19.6) 93.6 (20.5) a 2 30.4 (6.4) 30.2 (6.3) 31.4 (6.6)  n  Caucasian 891 (91) 1,569 (90) 356 (87)  Other 88 (9) 171 (10) 53 (13) Duration of psoriasis, mean number of years (SD) 19.2 (11.4) 19.1 (11.4) 17.6 (11.7)  n 286 (29.2) 529 (30.4) 141 (34.5) BMI a First treatment phase (weeks 0–12) 1 1 Fig. 1 a b  22 First exposure phase 1 1 The incidence of arthropathy AEs in this group of patients was similar to that in the placebo group in the first treatment phase, as indicated by the overlap in CIs. Extended treatment phase (weeks 13–24) 1 1 Long-term treatment phase 2 Fig. 2 a 5 6 b 15 17  6 2 6 7 17 15 6 2 Re-treatment phase  1 1 Baseline characteristics and previous history of arthropathy There were no differences in baseline demographics or disease characteristics between the patients who had arthropathy AEs and those who did not. Patients who experienced an arthropathy AE during treatment with efalizumab appeared to be more likely to have a history of arthropathy prior to treatment. Of the patients who never developed an arthropathy AE during efalizumab treatment, 27% reported a previous history of arthropathy compared with 59% in patients who did have an arthropathy AE. n n Arthropathy AEs and clinical response to efalizumab 3 Fig. 3 a b  3 Discussion The placebo-controlled results of this large-scale pooled analysis of arthropathy data from seven clinical trials show that efalizumab does not appear to increase the risk of developing arthropathy AEs compared with placebo during the first 12 weeks of treatment. In addition, for patients treated with efalizumab, the incidence of arthropathy AEs did not appear to increase over time. The proportion of patients who had an arthropathy AE within any 12-week treatment period was low (<4.1%) through all treatment phases (first treatment, first exposure, extended treatment, re-treatment, long-term treatment). http://www.emea.eu.int/pdfs/human/press/pus/444500en.pdf 2 18 19 http://www.fda.gov/ohrms/dockets/ac/02/slides/3865S1_04_Biogen-Safety/sld007.htm 20 24 http://www.emea.eu.int/humandocs/PDFs/EPAR/Enbrel/014600en6.pdf http://www.fda.gov/ohrms/dockets/ac/02/slides/3865S1_04_Biogen-Safety/sld007.htm 18 24 http://www.emea.eu.int/humandocs/PDFs/EPAR/Enbrel/014600en6.pdf 22 To put the results of this pooled analysis, which by its very nature included select patient populations (determined by the inclusion/exclusion criteria and study designs), in the context of routine clinical practice, post-marketing surveillance data were assessed. During post-marketing surveillance of efalizumab, which accounts for approximately 17,500 patient-years to date, serious arthropathies requiring hospitalization were reported with a frequency of about 4.8 per 1,000 patient-years in patients receiving efalizumab. It should be noted, however, that underreporting of AEs in routine clinical practice setting may lead to an underestimate of the true incidence of arthropathy. For both the 12-week first treatment and first exposure phases of the current analyses, the proportions of patients reporting an arthropathy AE appeared to be lower in the efalizumab groups than in the placebo group in the first treatment phase. Correspondingly, the incidences of AEs per patient-year in these treatment phases were also lower in the efalizumab groups than that observed in the placebo group in the first treatment phase. However, the proportion of AEs that were moderate or severe was greater in the efalizumab groups than in the placebo groups; too few patients had events to draw any meaningful conclusions. During the extension phase (weeks 13–24), the incidence of arthropathy AEs in efalizumab-treated patients remained similar to the placebo group in the first treatment phase. Previous history of arthropathy and poor clinical response may potentially indicate a risk for occurrence of new arthropathy AEs during treatment. Indeed, arthropathy AEs were most frequent in patients who did not respond to therapy with efalizumab or in patients with a history of arthropathy. 5 6 7 2 6 In patients who re-started treatment for a further 12 weeks following an intervention-free period, the proportion of patients who had an arthropathy AE was lower than during the first treatment phase; the same was true for the incidence of arthropathy AEs per patient-year in re-treated patients. Although this scenario is likely to occur infrequently in clinical practice, these data show that if a patient needs to stop (e.g., during pregnancy) and then restart treatment, there appears to be no increased risk of arthropathy AEs. 9 27 8 8 In conclusion, the results of this pooled analysis show that efalizumab does not appear to increase the risk of developing arthropathy AEs compared with placebo. Long-term studies of efalizumab indicate that the incidence of arthropathy AEs remains stable and low for up to 3 years of continuous treatment.