Major Finding: Patients taking 2 mg/kg of daclizumab every 2 weeks plus interferon beta had significantly fewer new or enlarged gadolinium-enhancing lesions after 24 weeks of treatment than did those taking interferon beta plus placebo (1.32 vs. 4.75).
Data Source: CHOICE study: Double-blind, randomized, placebo-controlled, phase II trial of 230 patients with active relapsing MS
Disclosures: Many investigators reported potential conflicts of interest with Biogen Idec Inc., maker of the MS medications, Tysabri and Avonex. Some of the investigators are employed by and own stock with either Biogen Idec or Facet Biotech Corp., both of which funded the trial. Dr. Greenberg and Dr. Stüve disclosed potential conflicts of interest with several manufacturers of MS drugs.
Multiple sclerosis patients who experience relapsing disease while taking interferon beta might be able to reduce their number of new or enlarging lesions by adding the humanized monoclonal antibody daclizumab.
Besides reducing the risk of lesion growth and formation, the antibody might exert at least part of its effects through a mechanism that is now suggested by several lines of evidence to be a potential drug target and an important part of further understanding the pathogenesis of the disease, Dr. Daniel Wynn of Consultants in Neurology Multiple Sclerosis Center, Northbrook, Ill., and his associates reported (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70033-8
Daclizumab (Zenapax) has been already approved by the Food and Drug Administration for the prophylaxis of acute organ rejection in patients receiving renal transplants.
“The true effects of this trial and previous observations on daclizumab might be more far-reaching than they seem at first glance,” Dr. Olaf Stüve and Dr. Benjamin M. Greenberg wrote in an editorial (Lancet Neurol. 2010 Feb. 16 [doi:10.1016/S1474-4422(10)70032-6
Daclizumab was thought to inhibit T-cell proliferation and activation by binding to the CD25 subunit of the human high-affinity interleukin-2 receptor, but in this and other studies of MS patients treated with daclizumab, T cells have shown normal proliferative and activation responses.
Rather than reduce the activation or proliferation of T cells, Dr. Wynn and his colleagues found that the reduction of disease activity with daclizumab appears to be associated with an expansion of a regulatory subset of CD56
In the 51-center CHOICE study, the investigators randomized 75 patients to daclizumab 2 mg/kg every 2 weeks, 78 patients to daclizumab 1 mg/kg every 4 weeks, and 77 patients to placebo. These patients had a mean age of about 40 years and continued to take their baseline interferon beta regimens. Patients in each treatment arm averaged about 2.5 relapses in the previous 2 years and had a mean Expanded Disability Status Scale score of 3 (0 = normal; 10 = death). All of the patients had experienced at least one relapse or at least one gadolinium-enhancing brain or spinal cord lesion in the previous year while on a stable interferon beta regimen.
No significant differences were noted between the low-dose daclizumab and placebo groups on any of the imaging or clinical end points.
However, at 24 weeks, significantly fewer new or enlarged gadolinium-enhancing lesions had developed in the high-dose daclizumab group, compared with the placebo-treated group (mean of 1.32 lesions vs. 4.75, respectively). Enlarged lesions were defined by at least a 50% increase in size for lesions measuring at least 5 mm in diameter and by at least a 20% increase in size for lesions less than 5 mm.
High-dose daclizumab also was associated with a significantly lower number of new gadolinium-enhancing lesions alone, compared with placebo (mean of 1.18 vs. 3.95).
By 24 weeks, the high-dose daclizumab patients developed significantly fewer T2 lesions than did placebo-treated patients (1.1 vs. 3.4).
None of the groups were significantly different in terms of the change in their T1 hypointensities, the change in the volume of their T2 lesions, or their annualized relapse rate or mean time to relapse.
When daclizumab treatment was discontinued in a 48-week posttreatment period, the formation of lesions returned to about the same level in all groups.
In a post hoc analysis, higher counts of CD56
Daclizumab-treated patients who were in the highest quartile of CD56
“Identifying the physiological mechanism or mechanisms that lead to the expansion of [CD56
Serious adverse events in patients treated with daclizumab most often consisted of infections and infestations, none of which were opportunistic or resulted in death. Two patients who received daclizumab developed malignant disease, one with breast cancer and one with a recurrence of pseudomyxoma peritonei.
My Take
Drug Is Good Candidate for Phase III
In this phase II trial, treatment with high-dose daclizumab significantly reduced the number of gadolinium-enhancing lesions in MS patients, which suggests that it is a good candidate to move forward into phase III clinical trials. However, because the treatment phase of the trial lasted only 6 months, we cannot know yet what effect the drug has on the rate of relapse and other clinical measures.