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Student Submission: Daclizumab – A New Option for Relapsing Multiple Sclerosis

Tuesday, January 31, 2017  
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Anna Krupa, PharmD Candidate 2017

Carol Ly, PharmD Candidate 2018
Jennifer Andres, PharmD, BCPS – Faculty Advisor
Temple University School of Pharmacy

Multiple sclerosis (MS) is an unpredictable and potentially disabling disease of the central nervous system. It affects 2.3 million people worldwide and approximately 400,000 people in the US.1 MS is not linked to a specific genetic factor, but rather associated with many other different risk factors including urbanization, smoking, vitamin D deficiency, and excessive sodium intake among others.2-4 MS is an autoimmune disease, in which the body attacks the myelin sheath and oligodendrocytes, by activation of T-helper cells, causing damage to the spine and the brain. There are four types of MS: relapsing-remitting MS (RRMS), secondary-progressive MS (SPMS), primary-progressive MS (PPMS), and progressive-relapsing MS (PRMS). MS is not curable, instead treatment focuses on the protection of myelin sheaths and the suppression of T-cells.5  Only RRMS can be modified with use of medications including interferon β1a, interferon β1b, or glatiramer acetate.1 

Biogen Idec and AbbVie have recently developed a monoclonal antibody treatment for RRMS. Daclizumab (ZinbrytaTM) was approved by the Food and Drug Administration (FDA) in May 2016.6 Daclizumab is a long-acting, humanized monoclonal antibody of the immunoglobulin G that binds to the interleukin-2 receptor expressed on activated T-cells.7 Daclizumab is administered as a 150 mg subcutaneous injection, self-administered in a prefilled syringe monthly.6,8 In clinical trials, daclizumab caused liver damage; therefore, use is contraindicated in patients with severe hepatic impairment. Prior to initiation, serum transaminases and total bilirubin levels should be obtained and repeated before the second dose of daclizumab and then obtained every 6 months thereafter.8 Caution should be exercised when using daclizumab with other hepatotoxic drugs, including non-prescription products. Treatment with daclizumab also increases the risk of other immune-mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis.8 Due to the safety profile, daclizumab is only available through a Risk Evaluation and Mitigation Strategies (REMS). Daclizumab is not recommended for use in pregnant or lactating women, due to lack of data, and in pediatric patients, due to the risk of hepatic injury and immune-mediated disorders.8 

Two studies have demonstrated the effectiveness of daclizumab. SELECT was a randomized, double-blind, placebo-controlled trial that compared daclizumab (150 mg and 300 mg) with placebo in patients with RRMS. Study results demonstrated the superiority of daclizumab, particularly in the primary end point, the annualized relapse rate at 52 weeks. The cumulative number of relapses observed in the trial was 1 in daclizumab compared to more than 2 in the placebo group. Key study eligibility criteria included subjects aged 18 to 55 years old, a confirmed diagnosis of RRMS using McDonald criteria, and a disability progression defined as 1-1.5 point increase on the Expanded Disability Status Scale (EDSS).9 The results of SELECT led to a larger study, the DECIDE trial. DECIDE was a Phase III, randomized, double blind, double dummy, parallel group, active-control study comparing daclizumab with intramuscular (IM) interferon beta-1a in RRMS.7 Study results demonstrated the superiority of daclizumab, particularly with respect to the primary end point, the annualized relapse rate at 144 weeks. Refer to table 1 for comparison of endpoints between the two arms of the study. The adjusted annualized relapse rate was 45% lower in the daclizumab (150 mg) group compared to the interferon beta-1a group. Key study eligibility criteria was similar to SELECT trial and also included MRI with lesions consistent with MS and a score of 0 to 5 on EDSS. Patients must have had a recent relapse. The study excluded patients with cancer or abnormal lab results, pregnant or lactating women, children and patients aged > 55 years old. Adverse events were more common in daclizumab. Notably, infections and skin reactions were the most common adverse events seen with daclizumab, while influenza-like illness was seen in nearly 75% more patients using interferon β1a. Other adverse events, such as headache, hepatic events, urinary tract infections, and upper respiratory tract infections were similar between two groups.7

Daclizumab provides an additional option for patients who have failed first-line treatments. Daclizumab has been shown to decrease relapses by almost half compared to interferon beta 1a. In addition, daclizumab may assist these patients with adherence since it consists of a single, monthly injection compared to interferon medications that requires weekly injections (IM formulation) or three times weekly injections (SQ formulation). Due to the safety profile, daclizumab should be reserved for patients who have not responded to 2 or more treatments. Patients without a history of hepatic problems are candidates for daclizumab. Both DECIDE and SELECT demonstrated superior efficacy of daclizumab compared to interferon beta-1a and placebo in the reduction of relapse rates for RRMS. Prescribers should take into consideration the type of MS, treatment history, age of the patient, and note the exclusion/inclusion criteria of each of the clinical studies as well as the potential for adverse drug reactions. 

Table 1
. Comparison of clinical end points and adverse effects of daclizumab versus interferon β1a in DECIDE trial.8

   Daclizumab High Yield Process  Interferon beta 1a
Number of patients 
 922  919
 Median duration of treatment
 108.7 weeks

 111.4 weeks

 Adjusted annualized relapse rate
 .22  .39
 New or newly enlarged hyperintense lesions
 4.3  9.4
 Patients free from relapse at week 144
 67%  51%
 Incidence of Adverse Effects
 90%  89%
 Serious Adverse Effects
 15%  10%
 Hepatic events
 16%  14%
 Hepatobiliary disorder  3%  2%
 Elevation of LFTs > 5 upper limit normal  6%  3%
 

References
1. National Multiple Sclerosis Society. Multiple Sclerosis FAQs. http://www.nationalmssociety.org/What-is-MS/MS-FAQ-s. Accessed June 21, 2016.
2. Munger KL, Levin LI, Hollis BW, Howard NS, Ascherio A. Serum 25-Hydroxyvitamin D Levels and Risk of Multiple Sclerosis. JAMA. 2006;296(23):2832-2838. 
3. Zivadinov R, Weinstock-Guttman B, Hashmi K, et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology. 2009;73(7):504-510. 
4. Owens GP, Bennett JL. Trigger, pathogen, or bystander: The complex nexus linking Epstein–Barr virus and multiple sclerosis. Mult Scler 2012;18(9):1204–1248. 
5. Shackelford KB. Multiple Sclerosis: Treatment Guidelines in 2013. Healthline. http://www.healthline.com/health/multiple-sclerosis/treatment-guidelines. Accessed June 19, 2016. 
6. U.S. Food and Drug Administration. FDA approves Zinbryta to treat multiple sclerosis. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm504000.htm. Accessed June 21, 2016.
7. Kappos L, Wiendl, H, Selmaj K, et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2015;373(15):1418-28. 
8. Zinbryta [package insert]. Cambridge, MA: Biogen; 2016.
9. Phillips G, Guo S, Bender R, et al. Assessing the impact of multiple sclerosis disease activity and daclizumab HYP treatment on patient-reported outcomes: results from the SELECT trial. Mult Scler Relat Disord. 2016;6:66-72. doi:10.1016/j.msard.2016.02.001


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