Daclizumab approved for relapsing forms of multiple sclerosis

Kevin W. Chamberlin, PharmD

Adam S. WhalleyOn May 27, 2016 the FDA announced the approval of Zinbryta(daclizumab) by Biogen for the treatment of adults with relapsing forms of MS. Daclizumab is the first subcutaneous injectable monoclonal antibody to be approved for the treatment of MS. However, due to its safety profile daclizumab should be reserved for patients with inadequate response to two or more MS medications. Daclizumab is an interleukin-2 antagonist monoclonal antibody, increasing the level of natural killer cells which appears to be a biomarker for reductions in brain inflammatory activity in MS patients.

Efficacy

The effectiveness of daclizumab was shown in two randomized, double-blind trials in patients with relapsing-remitting MS. In the SELECT trial patients between 18-55 years of age with relapsing-remitting MS were randomly assigned (1:1:1) to subcutaneous injections of daclizumab 150mg, daclizumab 300mg or placebo administered every 4 weeks for 52 weeks. One hundred eighty-eight patients were randomized to placebo, 192 to daclizumab 150mg, and 209 to daclizumab 300mg and completed follow up at week 52. The relapse rate was lower for daclizumab 150mg (0.21, 95% CI 0.16–0.29 p<0.0001) and 300 mg (0.23, 0.17–0.31, p=0.00015) than for placebo (0.46, 0.37–0.57).  The percentage of patients with confirmed disability progression at week 52 was 6% with daclizumab and 13% with placebo. It was determined that daclizumab 150mg was the most appropriate dose based on the similar efficacy outcomes and fewer serious adverse events, 15(7%) for daclizumab 150mg and 19 (9%) for daclizumab 300mg.

The DECIDE trial compared daclizumab 150mg subcutaneous injection every 4 weeks with interferon (INF) beta-1a (Avonex) 30mcg once weekly for up 144 weeks. A total of 1841 patients (919 patients on daclizumab and 922 on INF beta 1a) with at least 2 relapses during the previous 3 years or at least 1 new brain lesion within the last 2 years were included. The adjusted annualized relapse rate was lower in the daclizumab group (0.22, 0.19-0.24, P<.001) than the INF beta-1a group (0.39, 0.35-0.44). The estimated percentage of patients with disability progression at week 144 was decreased with daclizumab but was not statistically significant (16% vs. 20% P=0.16).

Safety

Daclizumab labeling contains a black box warning for an increased risk for hepatic injury including autoimmune hepatitis as well as other immune mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis. In the SELECT trial, 4% experienced ALT/AST elevations more than 5 times the upper normal limit, 3% of patients experienced serious infections, and less than 1% experienced serious cutaneous events. In the DECIDE trial, more patients experienced depression related events with daclizumab than INF beta-1. Other common side effects included injection site reactions, rash, and pharyngitis. Due to the risk of hepatic injury, daclizumab should not be used in combination with other hepatotoxic agents.

The effects of daclizumab during pregnancy and lactation of humans has not been studied. In monkeys administered daclizumab at 50mg/kg weekly, which produced an AUC approximately 30-50 times greater than the expected AUC in humans, no negative effects on fetal development were observed. It is not known if daclizumab is present in human milk, the effects on the breastfed child, or the effects on milk production.

Dosing

The recommended dose of daclizumab is a 150mg subcutaneous injection every 4 weeks. If a dose is missed it should be administered no more than 2 weeks late. Daclizumab is available in 150mg single dose pre-filled syringes. Prior to administration the patient should remove the syringe from the refrigerator to allow the drug to warm to room temperature. If refrigeration is unavailable, daclizumab may be stored protected from light for up to 30 days at room temperature (86^◦F). The drug should not be placed back in the refrigerator after being allowed to warm to room temperature and should be discarded after 30 days without refrigeration.

Daclizumab is contraindicated in patients with pre-existing hepatic disease. Daclizumab should not be started in patients with liver function tests showing ALT or AST at least 2 times greater than upper limit of normal.

Adam S. Whalley, PharmD is a PGY-1 pharmacy resident at UConn John Dempsey Hospital at UConn Health, Farmington, CT Kevin W. Charmberlin, PharmD is an associate clinical professor and assistant department head, pharmacy practice, UConn School of Pharmacy, Storrs, CT.