By Chris Berrie PRAGUE, CZECH REPUBLIC -- October 13, 2007 -- The addition of the humanized antihuman interleukin-2 (IL-2) alpha receptor chain (CD25) antibody daclizumab to interferon beta (IFNbeta) therapy is safe and well tolerated by patients with multiple sclerosis (MS), and is associated with a significant reduction in new or enlarged Gd+ lesions. Coinvestigator Xavier Montalban, MD, Head, Neuroimmunology Clinic, Vall d'Hebron University Hospital, Barcelona, Spain, presented the results of the multicenter, randomized, double-blind, placebo-controlled, phase 2 CHOICE study here at the 23rd Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS). Daclizumab blocks interleukin 2 (IL-2)alpha receptor-mediated T- and B-cell activation, Dr. Montalban said in his presentation on October 12. Open-label studies of patients with relapsing multiple sclerosis who were refractory to IFNbeta therapies indicated that daclizumab reduced the number of new brain lesions. For the CHOICE study, Dr. Montalban and colleagues enrolled a total of 230 patients (aged 18-55 years) with an MS diagnosis confirmed using McDonald criteria, on at least 6 months of stable IFNbeta treatment, who satisfied the following criteria: expanded disability status scale (EDSS) of 5 or greater at screening; and one or more relapses or qualifying magnetic resonance imaging (MRI) scans within 12 months of screening. Patients were randomized to three treatment combinations with background IFNbeta: 77 received placebo, 78 received daclizumab 1 mg/kg SC every 4 weeks (low-dose); 75 received daclizumab 2 mg/kg every 2 weeks (high-dose). They were all treated for 24 weeks and were followed for 48 weeks. "Ninety percent completed the treatment period, which means that the drop-out was very low," Dr. Montalban noted. Baseline disease characteristics across the three treatment groups were similar for mean time since first MS symptoms, mean Expanded Disability Status Scale (EDSS), gadolinium contrast enhancing (Gd+) lesions, and mean number of relapses in the previous 2 years. The great majority in each group (>90%) were diagnosed as relapsing-remitting MS (RRMS). Dr. Montalban noted that the low-dose daclizumab group had a higher mean number of Gd+ lesions at baseline (1.1 vs 2.7 vs 0.8). The primary efficacy endpoint was total number of new or enlarged Gd+ lesions on monthly brain MRIs collected from weeks 8 to 24. The secondary efficacy endpoints were relapse rate from week 8 to week 24, and safety. For the intention-to-treat (ITT) population, the primary efficacy analysis shows a significant 72% reduction in mean number of new or enlarged Gd+ lesions in the high-dose daclizumab group ([P =.004). Low-dose daclizumab showed a 25% reduction, although this was not a significant difference (P =.501). "These positive effects were already evident, very early after just 4 weeks after the initiation of the trial," Dr. Montalban stressed.
Both the low- and high-dose daclizumab groups also achieved reductions in annualized relapse rates compared with placebo, although, these did not reach statistical significance (35%, P =.266; 33%, P =.317).
Safety analysis shows a similar incidence of overall infection rates across treatment groups (52% vs 51% vs 47%), although there was higher incidence of cutaneous adverse effects in the daclizumab treatment groups (27% vs 37% vs 31%). Conversely, there was a high incidence of injection-site reactions with placebo (24.7% vs 16.7% vs 18.7%). There were no deaths or opportunistic infections.
Dr. Montalban noted that there were higher rates of serious adverse events related to daclizumab treatment (2.6% vs 6.4% vs 6.7%); most of these were grade 3/4 serious infections (0% vs 2.6% vs 6.7%).
The higher dose of daclizumab in these patients who were nonresponders to their continuing IFNbeta therapy was associated with a significant reduction in Gd+ lesions that was accompanied by a favourable trend in reduction of relapse rates, Dr. Montalban stressed. "Daclizumab safety also supports moving forward into the next clinical studies," he added.
Funding for this study was provided by PDL BioPharma, Inc. and Biogen Idec Inc.
[Presentation title: Daclizumab in Patients With Active, Relapsing Multiple Sclerosis on Concurrent Interferon-Beta Therapy. Week 24 Data – Phase 2 (CHOICE) Study. Abstract 50]
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