Background: Monoclonal antibodies such as daclizumab could be a possible alternative immunotherapy to interferon beta treatment in people with multiple sclerosis (MS). It blocks the interleukin-2 receptor alpha subunit (CD25), and seems to be beneficial to patients with relapsing remitting multiple sclerosis (RRMS) in clinical and magnetic resonance imaging (MRI) measures of outcomes. This is an update of a Cochrane review first published in 2010, and previously updated in 2012. Objectives: To assess the safety of daclizumab and its efficacy to prevent clinical worsening in patients with RRMS. Search methods: The Trials Search Co-ordinator searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Specialised Register (17 May 2013). We handsearched the references quoted in the identified trials and reports (May 2013) from the most important neurological associations and MS societies. We contacted researchers participating in trials on daclizumab. Selection criteria: All randomised controlled clinical trials (RCTs) evaluating daclizumab, alone or combined with other treatments versus placebo, or any other treatment for patients with RRMS. Data collection and analysis: Two review authors independently assessed references retrieved for possible inclusion, extracted eligible data, cross-checked the data for accuracy and assessed the methodological quality. We resolved any disagreements by consensus among review authors. Main results: We included two trials with 851 patients that evaluated the efficacy and safety of daclizumab versus placebo for RRMS. We judged them to be at low risk of bias. Due to different time point evaluations and available data on primary studies, we were unable to undertake a meta-analysis. At 24 weeks, the median change was 0 (range -2 to 3) in the interferon beta and placebo group, 0 (-2 to 4) in the interferon beta and low-dose daclizumab group and 0 (-2 to 2) in the interferon beta and high-dose daclizumab group in 230 participants. The proportion of patients who had new clinical relapses were the following: 16 patients (21%) in the interferon beta and high-dose daclizumab group, 19 (24%) in the interferon beta and low-dose daclizumab group and 19 (25%) in the interferon beta and placebo group had relapses (P value = 0.87). At 52 weeks, the changes in Expanded Disability Status Scale (EDSS) from baseline was 0.09 ± 0.71 in placebo group, -0.08 ± 0.52 in low-dose daclizumab group and 0.05 ± 0.61 in high-dose daclizumab group in 621 participants. There was a significant difference between placebo and low-dose daclizumab groups (P value = 0.01), but no significant difference between placebo and high-dose daclizumab groups (P value = 0.49). The proportion of patients with new relapsing MS was significantly reduced in both daclizumab groups (19% in low-dose daclizumab group, 20% in high-dose daclizumab group) compared with placebo group (36%) (P value < 0.0001 and P value = 0.00032, respectively). There was no increased number of patients in any adverse events (risk ratio (RR) 0.98, 95% confidence interval (CI) 0.89 to 1.07) or serious adverse events in daclizumab groups compared with placebo (RR 1.15, 95% CI 0.29 to 4.54). Infections were the most frequent adverse events in treated participants and were resolved with standard therapies. One trial was still ongoing. Authors' conclusions: There was insufficient evidence to determine whether daclizumab was more effective than placebo in patients affected by RRMS in terms of clinical and MRI measures of outcomes. Daclizumab appeared to be relatively well tolerated. Infections were the most frequent adverse events, and were resolved with standard therapies. © 2013 The Cochrane Collaboration.

BACKGROUND:

Acute rejection is still a major problem in renal transplantation and is one of the most important causes of chronic graft dysfunction and late graft loss. Selective immunosuppression with a humanized antibody against the alpha-chain of the interleukin (IL)-2 receptor (CD25) was evaluated to demonstrate the efficacy of this type of immunoprophylaxis in combination with dual immunosuppression.

METHODS:

We studied the effect of daclizumab, a humanized monoclonal antibody against the alpha-chain of the IL-2 receptor, in a randomized double-blind, prospective phase III clinical trial in 275 patients receiving a first cadaveric renal allograft. Among them 111 (83%) in the placebo arm and 116 (82%) in the daclizumab arm received the full regimen of five doses (1.0 mg/kg) every other week. Baseline immunosuppression consisted of cyclosporine and corticosteroids.

RESULTS:

At 6 months, 39 (28%) of the patients in the daclizumab group had biopsy-proven rejections, as compared with 63 (47%) in the placebo group (P=0.001). The need for additional antilymphocyte therapy, antithymocyte globulin, antilymphocyte globulin (ATG, ALG, OKT3) was also lower in the daclizumab group (8% vs. 16%, P=0.02), and they required significantly lower mean (+/- SD) cumulative doses of prednisone (3750+/-1981 mg vs. 4438+/-2667 mg in the placebo group, P=0.01). Graft function was significantly better (P=0.02) in the daclizumab group (graft function rate: 58 vs. 51 ml/min, mean) as was patient survival (P=0.01, 99% vs. 94%). No specific adverse events were observed in daclizumab-treated patients. Patients receiving daclizumab experienced fewer cytomegalovirus infections (18% vs. 25%), and none died from severe infectious complications, compared to four patients in the placebo arm. No patient in the daclizumab group had a lymphoproliferative disorder or any other form of immunosuppression-related tumor during the first year after transplant.

CONCLUSIONS:

Administration of daclizumab in addition to dual immunosuppression therapy significantly reduced biopsy-proven acute rejection after renal transplantation, improved patient survival, and did not add to the toxicity of the immunosuppressive regimen.

BACKGROUND:

A new class of monoclonal antibodies (non-T-cell depleting) has gained favor for induction therapy after transplantation. This study evaluated the non-T-cell depleting antibody to the CD25 cell, daclizumab, as a single-dose induction agent immediately after pediatric liver transplantation to spare the use of the calcineurin inhibitor, tacrolimus, for 7 days in respect to both efficacy and renal function.

METHODS:

From January 1998 to November 2001, 81 pediatric orthotopic liver transplant recipients receiving 89 liver grafts were evaluated. The treatment arm (n=61) received daclizumab 1 mg/kg immediately after liver transplantation along with mycophenolate, steroids, and, on postoperative day 7, tacrolimus. The control group did not receive induction therapy, whereas tacrolimus, mycophenolate, and steroids were started immediately after surgery.

RESULTS:

The induction group had fewer patients with rejection within the first 30 days after liver transplantation (9 [14.8%] vs. 10 [50%]; P=0.003). The mean time to first rejection was similar between groups (12.1 [+/-7.8] days vs. 18.5 [+/-8.1] days; P=not significant). There was a 3.39 increase in relative risk to develop rejection within the first 30 days after orthotopic liver transplantation if the patient did not receive induction therapy (relative risk=3.39; 95% confidence interval [1.61, 7.14]). Two-year actuarial survival for the induction group was 93.2% compared with 85% in the control; graft survival was also similar between groups (87.8% vs. 72.7%) at 2 years.

CONCLUSION:

Daclizumab 1 mg/kg given immediately after pediatric liver transplantation and withholding tacrolimus, is safe, efficacious, and reduces rejections within the first 30 days after surgery.

BACKGROUND:

Interleukin-2 receptor antagonists (IL-2RAs) have been extensively used in kidney transplant patients to prevent the occurrence of acute rejection. The efficacy and safety of basiliximab and daclizumab, the 2 most commonly used IL-2RAs in clinics, have been compared in a number of randomized controlled trials, but no definite conclusions have been drawn.

OBJECTIVE:

This meta-analysis aimed to compare the efficacy and safety of basiliximab and daclizumab in kidney transplant patients.

METHODS:

We performed keyword searches in Pubmed, Embase, and the Cochrane library. In total, 6 randomized controlled trials with 509 patients were included in this meta-analysis. Data collected included patient survival, graft survival, acute rejection, infection, and cytomegalovirus infection. The outcome measure was the relative risk of basiliximab versus daclizumab.

RESULTS:

Therapy with basiliximab and daclizumab resulted in similar outcomes regarding acute rejection (6-month 95% confidence interval [CI], 0.09-1.14; 12-month 95% CI, 0.53-1.91), patient survival (95% CI, 0.97-1.04), graft survival (95% CI, 0.98-1.08), infection (95% CI, 0.66-1.01), and cytomegalovirus infection (95% CI, 0.45-1.14) within the follow-up period. There were no significant differences in safety and efficacy between the 2 drugs.

CONCLUSIONS:

The safety and efficacy of daclizumab and basiliximab are similar in kidney transplant recipients.

BACKGROUND:

Monoclonal antibodies that block the high-affinity interleukin-2 receptor expressed on alloantigen-reactive T lymphocytes may cause selective immunosuppression. Daclizumab is a genetically engineered human IgG1 monoclonal antibody that binds specifically to the alpha chain of the interleukin-2 receptor and may thus reduce the risk of rejection after renal transplantation.

METHODS:

We administered daclizumab (1.0 mg per kilogram of body weight) or placebo intravenously before transplantation and once every other week afterward, for a total of five doses, to 260 patients receiving first cadaveric kidney grafts and immunosuppressive therapy with cyclosporine, azathioprine, and prednisone. The patients were followed at regular intervals for 12 months. The primary end point was the incidence of biopsy-confirmed acute rejection within six months after transplantation.

RESULTS:

Of the 126 patients given daclizumab, 28 (22 percent) had biopsy-confirmed episodes of acute rejection, as compared with 47 of the 134 patients (35 percent) who received placebo (P=0.03). Graft survival at 12 months was 95 percent in the daclizumab-treated patients, as compared with 90 percent in the patients given placebo (P=0.08). The patients given daclizumab did not have any adverse reactions to the drug, and at six months, there were no significant differences between the two groups with respect to infectious complications or cancers. The serum half-life of daclizumab was 20 days, and its administration resulted in prolonged saturation of interleukin-2alpha receptors on circulating lymphocytes.

CONCLUSIONS:

Daclizumab reduces the frequency of acute rejection in kidney-transplant recipients.

BACKGROUND:

Daclizumab, a humanized monoclonal antibody against the interleukin-2 receptor, reduced the risk of rejection without increasing the risk of infection among renal-transplant recipients and, in a single-center trial, among cardiac-transplant recipients. We conducted a multicenter, placebo-controlled, double-blind study to confirm these results in cardiac-transplant patients.

METHODS:

We randomly assigned 434 recipients of a first cardiac transplant treated with standard immunosuppression (cyclosporine, mycophenolate mofetil, and corticosteroids) to receive five doses of daclizumab or placebo. The primary end point was a composite of moderate or severe cellular rejection, hemodynamically significant graft dysfunction, a second transplantation, or death or loss to follow-up within six months.

RESULTS:

By six months, 104 of 218 patients in the placebo group had reached the primary end point, as compared with 77 of the 216 patients in the daclizumab group (47.7 percent vs. 35.6 percent, P=0.007), a 12.1 percent absolute risk reduction and a 25 percent relative reduction. The rate of rejection was lower in the daclizumab group than in the placebo group (41.3 percent vs. 25.5 percent). Among patients reaching the primary end point, the median time to the end point was almost three times as long in the daclizumab group as in the placebo group during the first 6 months (61 vs. 21 days) and at 1 year (96 vs. 26 days). More patients in the daclizumab group than in the placebo group died of infection (6 vs. 0) when they received concomitant cytolytic therapy.

CONCLUSIONS:

Daclizumab was efficacious as prophylaxis against acute cellular rejection after cardiac transplantation. Because of the excess risk of death, concurrent or anticipated use of cytolytic therapy with daclizumab should be avoided.

The purpose of this study is to compare outcomes in patients undergoing lung transplantation, using 2 different induction therapies. Primary outcome is survival and secondary outcomes include freedom from infection and freedom from rejection.

In phase III trials daclizumab was used in a five-dose regimen of 1 mg/kg at 2-weekly intervals, resulting in saturation of IL-2Rα on circulating lymphocytes for up to 120days after renal transplantation. The purpose of this study was to evaluate daclizumab blood concentrations and the saturation of the IL-2Rα on the circulating lymphocytes with a limited dosing regimen of daclizumab. Twelve patients undergoing primary cadaver or living donor transplantation were randomized to either receive one dose (2mg/kg) or two doses (2nd dose, 1 mg/kg) of daclizumab in addition to maintenance immunosuppression therapy consisting of either tacrolimus or cyclosporine, mycophenolate mofetil and prednisone. Patients were followed for 6 months after the transplantation. Pharmacokinetic and pharmacodynamic studies were performed up to 20 weeks after the transplantation. In patients treated with a single dose of daclizumab, the blood concentrations of daclizumab declined to 1 μg/mL at 43 ± 7 days after the transplantation. In patients treated with two doses of daclizumab, the blood concentrations of daclizumab declined to 1 μg/mL at 45 ± 13 days after the second dose for a total of 59 ± 13 days after the transplantation. Daclizumab levels of 1 μg/mL or greater were associated with saturation of the IL-2Rα on the circulating lymphocytes. In the new era of effective maintenance immunosuppression, a limited dosing regimen of daclizumab may be desired, practical and economical.

Objective: The objective of this study was to compare efficacy and safety of alemtuzumab, antithymocyte globulin (ATG), and daclizumab for induction therapy in organ transplantation. Methods: We searched PUBMED, EMBASE, and Cochrane databases to identify randomized controlled trials that compared alemtzumab, ATG, and daclizumab for induction therapy in kidney as well as pancreas transplantation. According to the inclusion criteria, the collected data included general characteristics of the studies and their major outcomes. The meta-analysis was performed using RevMan 5.0.25 software. Results: We identified 9 studies involving 777 patients. No differences between alemtuzumab, daclizumab, and ATG were observed in terms of patient survival, graft survival, or acute rejection episodes at a 24-month follow-up (P =.62, P =.55, and P =.08, respectively). Infections within 36 months were greater between the alemtuzumab and the ATG group (P =.03). There was no significant difference in terms of infection at 24 months. Conclusions: Alemtuzumab and daclizumab appeared to be as effective as ATG for induction therapy in kidney transplantation at a follow-up of 24 months. However, alemtuzumab showed a lower rate of infection at 36 months compared with ATG. © 2012 Elsevier Inc.

Daclizumab and mycophenolate mofetil (MMF) decrease the incidence of acute allograft rejection. This double-blind, randomized, placebo-controlled trial was performed primarily to assess the pharmacokinetics of MMF in an immunosuppressive regimen incorporating daclizumab. At five centers, 75 renal transplant recipients were randomized 2 : 1 to receive either daclizumab 1 mg/kg or placebo pre-transplantation and every other week, for a total of five doses. All patients received cyclosporine, steroids, and MMF. Levels of mycophenolic acid (MPA), its glucuronide metabolite, and daclizumab were measured after dosing on days 28 and 56. Safety parameters evaluated included: adverse events, laboratory abnormalities, infections, patient/graft survival, incidence of lymphoproliferative disorders, and incidence of acute rejection at 12 months. The concomitant administration of daclizumab and MMF had no effect on the pharmacokinetics of

MPA:

AUC0-8 values (μg h/mL ± SD) on day 28 were 30.1 ± 13.3 for daclizumab-treat patients vs. 31.1 ± 12.4 for placebo and on day 56, 37.7 ± 18.2 for daclizumab-treated patients vs. 35.7 ± 14.0 for placebo. Adverse events were similar between the two groups. Acute rejection at 12 months occurred in 14% of patients receiving daclizumab and 20% of patients receiving placebo. The coadministration of daclizumab did not result in a pharmacokinetic interaction with MPA, the active metabolite of MMF.