By William Elliott, MD, FACP, and James Chan, PharmD, PhD

Dr. Elliott is Medical Director, Pharmacy, Northern California Kaiser Permanente, and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA.

Drs. Elliott and Chan report no financial relationships relevant to this field of study.

The FDA has approved a humanized monoclonal antibody for the treatment of multiple sclerosis (MS). Daclizumab, which targets the interleukin-2 receptor, is a long-acting injectable drug that is self-administered. It is marketed as Zinbryta.

INDICATION

Daclizumab is indicated for the treatment of adults with a relapsing form of multiple sclerosis (RMS) who have responded inadequately to two or more MS drugs.1

DOSAGE

The recommended dose is 150 mg administered subcutaneously once monthly. Daclizumab is available as a single-dose prefilled syringe containing 150 mg/mL.

POTENTIAL ADVANTAGES

Daclizumab provides another option, with a different mechanism of action, for the treatment of RMS.

POTENTIAL DISADVANTAGES

Daclizumab can cause severe liver injury, including life-threatening events, liver failure, and autoimmune hepatitis.1 It is contraindicated in patients suffering from pre-existing hepatic disease or hepatic impairment. It also has been associated with other immune-mediated disorders such as skin reactions, lymphadenopathy, and non-infectious colitis. Immune-mediated disorders occurred in approximately 30% of subjects compared to 12% for interferon-treated subjects.1

COMMENTS

Daclizumab binds to the alpha subunit of the high-affinity interleukin-2 receptor and increases signaling through the intermediate-affinity receptor (IL-2R α, CXD25).1,2 The exact mechanism of action is not clear but is postulated that modulation of IL-2 mediated activation of lymphocytes leads to suppression of MS disease activity. Researchers investigated the efficacy of daclizumab in two randomized, double-blind, controlled studies in patients suffering from RMS.1,3,4

In the first study, subjects experienced at least two relapses during the prior three years and at least one in the prior year, one or more clinical relapses, and one or more new image detected lesions (T1 gadolinium enhanced or T2 hyperintense MRI lesions) within the prior two years or at least one in the prior 12 months. Subjects presenting with progressive forms of MS (Expanded Disability Status Scale [EDSS] > 5) were excluded. Subjects were randomized to 150 mg of daclizumab monthly (n = 919) or 30 mg interferon-beta-1a intramuscularly weekly (n = 922). Annualized relapse rate (ARR) was the primary outcome. Secondary outcomes included the proportion of patients relapsed, the proportion who experienced confirmed disability progression, and the number of newly enlarged T2 hyperdense lesions. At baseline, the mean EDSS was 2.5 (minimum to mild disability) and mean annual relapse was 1.6. ARRs up to 144 weeks were 0.216 for daclizumab and 0.393 for interferon-beta-1a, a 45% reduction.1,3 The number of new or newly enlarged lesions at 96 weeks was reduced, 4.31 vs. 9.44 (54% reduction). There was no difference in the proportion of confirmed disability progression (16% vs. 20%). Infections, cutaneous events, and elevation of liver enzymes were more common in the daclizumab group.

The second study included subjects presenting with RMS who experienced at least one relapse in the prior year or who had one or more MRI-detected lesions within six weeks of randomization.1,4 Subjects were randomized to daclizumab (n = 208) or placebo (n = 204). Mean EDSS was 2.8 and number relapsed in the prior year was 1.4. ARR at week 52 was 0.211 for daclizumab and 0.458 for placebo (54% reduction). The relative reduction in new lesions was about 70%. Treatment effects were similar for highly active vs. less active patients.5 Long-term safety and efficacy are under evaluation in long-term extension studies.6,7

CLINICAL IMPLICATIONS

Currently FDA-approved drugs for the treatment of RMS include self-injected agents (interferon beta-1a, interferon beta-1b, peginterferon beta-1, and glatiramer), oral agents (dimethyl fumarate, fingolimod, and teriflunomide), and intravenous agents (alemtuzumab, mitoxantrone, and natalizumab). Results from a recent network meta-analysis suggest that alemtuzumab, natalizumab, and fingolimod are the most effective for preventing clinical relapse in the first 24 months.8 Daclizumab provides another potentially effective treatment of RMS, but because of potential serious adverse events, it is only recommended for patients who inadequately responded to two or more agents. Daclizumab is available through a restricted program under the ZINBRYTA Risk Evaluation and Mitigation Strategy program. Prescribers and pharmacies must be certified, and patients must enroll in the program. The cost of daclizumab was not available at the time of this review.

REFERENCES

  1. Zinbryta Prescribing Information. Biogen Inc. May 2016.
  2. D’Amico E, Messina S, Caserta C, et al. A critical appraisal of daclizumab use as emerging therapy in multiple sclerosis. Expert Opin Drug Saf 2015;14:1157-1168.
  3. Kappos L, Wiendl H, Selmaj K, et al. Daclizumab HYP versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2015;373:1418-1428.
  4. Gold R, Giovannoni G, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): A randomised, double-blind, placebo-controlled trial. Lancet 2013;381:2167-2175.
  5. Giovannoii G, Radue EW, Havrdova E, et al. Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis.
    J Neurol 2014;261:316-323.
  6. Safety and efficacy extension study of daclizumab high yield process (DAC HYP) (BIIB019) in participants who have completed study 205MS202 (NCT00870740) to treat relapsing remitting multiple sclerosis (SELECTED). Available at: http://1.usa.gov/28YczaE. Accessed June 16, 2016.
  7. Long-term extension study in participants with multiple sclerosis who have completed study 205MS301 (NCT01064401) to evaluate the safety and efficacy of BIIB019 (EXTEND). Available at: http://1.usa.gov/28YTyb9. Accessed June 16, 2016.
  8. Tramacere L, Del Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis. Cochran Database Syst Rev 2015; Sept 18:CD011381.