Information for Healthcare Professionals
Written by Rachelle Ramirez
Tuesday, 23 August 2016 18:09
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DACLIZUMAB (Zinbryta™) – Information for Healthcare Professionals

The Multiple Sclerosis Emerging Therapies Collaborative includes the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS), the MS Coalition, the American Academy of Neurology, and the VA Multiple Sclerosis Centers of Excellence East and West.

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What is the medication?
Generic: daclizumab
Brand name: Zinbryta™
Has the medication received US Food and Drug Administration (FDA) approval?
Yes. Daclizumab 150 mg for subcutaneous administration received FDA approval on May 26, 2016.
If so, what are the indications and uses?
Daclizumab is indicated to treat adult patients with relapsing forms of multiple sclerosis. It is generally reserved for people with MS who have had an inadequate response to two or more medications indicated for the treatment of MS. Daclizumab is not approved for use in patients with primary progressive or non-relapsing forms of multiple sclerosis.
What were the findings in the pivotal and supportive trials of this medication?

Two randomized, double-blind, controlled studies evaluated 150 mg subcutaneous daclizumab administered every four weeks in patients with relapsing multiple sclerosis.

Study one (DECIDE study – Kappos L, et al. N Engl J Med 2015;373:1418-1428) compared daclizumab 150 mg sc every four weeks to interferon beta-1a 30 mcg intramuscularly once weekly (Avonex) for up to 144 weeks in 1841 patients with relapsing-remitting MS. The primary endpoint was annualized relapse rate (ARR) over 144 weeks; daclizumab with an ARR of 0.22 was significantly more effective than the interferon beta-1a intramuscular comparator with an ARR of 0.39 (p < 0.001) (a relative risk reduction of 45% and an NNT [number needed to treat] to prevent one relapse of 5.88).

Secondary efficacy endpoints included proportion of patients with disability progression over 144 weeks, as measured by expanded disability status scale (EDSS) confirmed at 12 weeks, which was 16% for daclizumab compared to 20% for interferon beta-1a intramuscular, a nonsignificant difference. A secondary MRI endpoint was new or enlarged T2 lesions on MRIs over 96 weeks for which adjusted mean numbers were 4.3 for daclizumab compared to 9.4 for interferon beta-1a intramuscular, a relative reduction of 54% favoring Zinbryta (p < 0.001).

Study two (SELECT study – Gold R et al. Lancet 2013;381:2167-2175) compared daclizumab 150 mg sc or 300 mg sc every four weeks to placebo injections in a three-armed study for 52 weeks of 621 patients with relapsing remitting multiple sclerosis. The primary endpoint was annualized relapse rate, which was 0.21 for the 150 mg group and 0.23 for the 300 mg group, each compared to 0.46 for the placebo group. The relative reduction for the 150 mg sc dose was 54% with an NNT to prevent one relapse of 4.0. A secondary clinical endpoint was the estimated proportion of patients with relapse at 52 weeks, which was 19% for the 150 mg group and 20% for the 300 mg group, each compared to 36% for the placebo group (p < 0.0001 for 150 mg compared to placebo).

Secondary MRI endpoints included the cumulative number of new gadolinium enhancing lesions on MRI scans done every four weeks between week 8 and week 24 in a frequent MRI subset, and the number of new or enlarged T2 lesions between week 52 and baseline. The mean number of new or enlarged T2 lesions was 2.4 for the 150 mg group and 1.7 for the 300 mg group, each compared to 8.1 for the placebo group (p < 0.0001 for the 150 mg group compared to placebo). The mean cumulative number of new gadolinium enhancing lesions in the frequent MRI subset between weeks 8–24 was 1.5 in the 150 mg group and 1.0 in the 300 mg group compared to 4.8 in the placebo group (p < 0.0001 for the 150 mg group compared to placebo). A tertiary clinical endpoint evaluated disability progression at 52 weeks assessed by change in EDSS confirmed at 12 weeks compared to baseline EDSS. The estimated proportion with 12–week confirmed disability progression at 52 weeks was 6% for the 150 mg group and 8% for the 300 mg group compared to 13% for the placebo group (HR = 0.43, p =0.021 for the 150 mg group compared to placebo).

What is the mechanism of action and the rationale for the use in MS?
The precise mechanism of action by which daclizumab affects relapsing MS is not fully understood. Daclizumab binds the IL2α chain of the high affinity IL2 receptor (CD25), resulting in increased signaling of the intermediate affinity IL2 receptor. Binding of the IL2 intermediate receptor results in expansion of CD56bright NK cells that are believed to have important immune regulatory effects, and which some studies have correlated with measures of clinical response to the agent. However, some individuals responsive to daclizumab have not shown increased CD56bright NK cell numbers, suggesting other potential mechanisms of action that may include inhibition of dendritic cell activation of effector T cells and reduction in lymphoid tissue inducer cells (Pfender N, Martin R. Exp Neurol 2014;262:44-51)
What is the delivery route and recommended dosing?
150 mg administered by subcutaneous injection once monthly in a single dose pre-filled syringe.
Can this medication be used with other medications?
  • Disease-Modifying Therapies (DMTs):
    Daclizumab has not been tested in conjunction with any other treatment for MS and is not approved for use in combination with other DMTs. In previous studies, intravenous formulations of daclizumab have been given to small numbers of patients taking interferon beta agents who had evidence of continued MS disease activity on their interferon therapy (Bielekova B et al PNAS 2004;101:8705-8708; Rose JW et al. Ann Neurol 2004;56:864-867; . Rose JW et al. Neurology 2007;69:785-789).
  • Other Medications:
    There may be increased risk for hepatotoxicity when drugs with hepatotoxic potential are used concomitantly with daclizumab.
How does the expected treatment effect compare with the treatment effect provided by other available medications?
Direct comparison data is available demonstrating superiority of daclizumab compared to interferon beta-1a 30 mcg IM given once weekly in reducing annualized relapse rate and related MRI activity in patients with relapsing–remitting MS as summarized above (study 1). No other comparative studies have been done.
What are the possible short-term side effects? What is the range of severity of side effects, and what are the recommended management strategies?

Adverse effects noted in clinical trials with daclizumab included:

  • increased rates of infections, including nasopharyngitis, upper respiratory tract infection, bronchitis, influenza
  • cutaneous reactions including serious reactions (2% in study 1), some of which appear to be immune mediated
  • elevated hepatic transaminase and bilirubin levels in comparison to interferon beta-1a 30 mcg IM weekly or placebo in studies 1 and 2 described above.
  • additional adverse reactions including dermatitis, oropharyngeal pain, bronchitis, eczema, and lymphadenopathy
  • In study 2 above, one patient taking daclizumab 150 mg sc died from complications of a psoas abscess. Another patient participating in an extension of study 2 and taking 300 mg of daclizumab sc died of autoimmune hepatitis.

Cutaneous reactions are common with daclizumab and have been reported in up to 77% of patients with MS using the drug. Moderate to severe rashes may occur in up to 19%. Lesion biopsies may show eczematous dermatitis or features of psoriasis, and may contain CD56bright NK cells. (Cortese I et al. Neurology 2016;86:847-855). Serious skin reactions occurred in 2% of patients taking daclizumab in study 1. It is recommended that serious diffuse or inflammatory rashes be evaluated by a dermatologist prior to subsequent dosing with daclizumab and that discontinuation of the agent may be appropriate.

Depression-related events occurred more frequently with daclizumab than with interferon beta-1a 30 mcg IM weekly (10% compared to 8%) in study 1 and with daclizumab compared to placebo (7% compared to 2%) in study 2. Daclizumab should be used with caution in patients with previous or current depressive disorders, and patients and care givers are advised to report any new or worsening depression or suicidal ideation. Discontinuation of daclizumab should be considered in patients with severe depression or suicidal ideation.

What assessments are recommended prior to starting treatment?
  • Patients should be assessed and tested for evidence of hepatic impairment or injury including levels of hepatic transaminases and bilirubin and screening for hepatitis B and C. Initiation of daclizumab is contraindicated in patients with pre–existing hepatic disease or hepatic impairment including ALT or AST at least two times the upper limit of normal.
  • Patients at risk for tuberculosis should be evaluated for the disease and treated prior to use if positive.
  • Vaccination with live virus vaccines is not recommended during treatment and for four months following discontinuation of treatment with daclizumab. Any required live virus vaccinations should be administered prior to the start of treatment.
What are the known long–range (morbidity and mortality) health risks?
Unknown at this time.
Has the FDA included any boxed warnings about this medication?

Daclizumab carries a boxed warning for:

  • hepatic injury including autoimmune hepatitis and is contraindicated in patients with pre–existing hepatic disease or impairment
  • other immune mediated disorders including cutaneous reactions, lymphadenopathy, non-infectious colitis, and other immune-mediated disorders that may require treatment with systemic corticosteroids or other immunosuppressive medications
Has the FDA instituted a Risk Evaluation and Mitigation Strategy (REMS) for this medication?

Yes. The REMS program for daclizumab includes:

  • restricted distribution through approved prescribers and pharmacies
  • required patient registration in monitoring program
  • hepatic transaminase and total bilirubin testing monthly for assessment prior to each dose and for six months following discontinuation of daclizumab
  • monitoring of skin reactions and assessment of diffuse or inflammatory rashes by a dermatologist is recommended
What training is recommended or required for clinicians or patients before initiating this treatment?
The REMS program requires training and certification of prescribers of daclizumab, and registration of patients in a monitoring program.
What is the pregnancy rating for this medication, and what is known about possible carcinogenesis, mutagenesis, and impairment of fertility?

Pregnancy ratings are no longer assigned to new medications.

There are no adequate data on developmental risks associated with use of daclizumab in pregnant women. Administration of daclizumab in monkeys during gestation resulted in embryofetal death and reduced fetal growth at doses greater than 30 times the dose used clinically.

No data on the presence of daclizumab in breast milk, effects on a breastfed child, or effects on milk production are currently available. Daclizumab has been found to be excreted in breast milk of daclizumab–treated monkeys.

Does this medication interact or interfere with oral contraceptives?
No current data are available regarding interaction of daclizumab with oral contraceptives.
Are there any recommended limits on treatment duration with this medication?
None at this time.
What happens following termination of treatment with this medication?
  • As with discontinuing any DMT, MS activity may return following the discontinuation of daclizumab
  • Monitoring of hepatic transaminases and bilirubin is required monthly for six months after discontinuing daclizumab
What treatment options are available for patients who have been treated with daclizumab?
Other MS disease-modifying therapies could be used.
What is the washout period?

After administration of daclizumab every four weeks, serum daclizumab reaches steady state concentrations by the fourth dose. The agent is a protein and is expected to undergo catabolism to peptides and amino acids as for endogenous IgG proteins without renal elimination. The estimated elimination half-life is 21 days; however, this was 19% higher in patients who developed neutralizing antibodies.

In study 1 antidrug and neutralizing antibodies were observed in 19% and 8% of patients and were transient in 12% and 7%, respectively. The antibodies typically appeared in the first year and frequency declined with continued daclizumab treatment. There was no apparent correlation of antidrug or neutralizing antibodies with clinical response, adverse reactions or the pharmacodynamic profile other than the effect on clearance.

How can the provider identify a suboptimal treatment response?
By monitoring for evidence of clinical or subclinical (MRI) evidence of MS activity and assessing adherence to administration schedule
Is the manufacturer/distributor offering any financial assistance program for patients?
Biogen's Above MS™ program provides access to Support Coordinators at 1-800-456-2255 who can offer financial and insurance support. Their services include:
  • Clarification of coverage options
  • Prior authorization assistance
  • $0 copay program for eligible patients
  • Insurance counseling
  • Free drug program for eligible patients
  • Support finding assistance through charitable organizations.
Are there any special considerations with this medication?
Vaccination with live virus vaccines is not recommended during treatment and for four months following discontinuation of treatment with daclizumab. Any required live virus vaccinations should be administered prior to use.
COMMENTARY BY TEMPLATE AUTHORS:
  • The prescriber information (PI) suggests that any required live virus vaccinations should be administered prior to the start of daclizumab. Although the PI does not specify when daclizumab could be initiated after live virus vaccination, the authors recommend that initiation of daclizumab be postponed until one month after a live virus vaccination is completed.
  • VZV screening and vaccination if necessary are recommended prior to initiating treatment.
  • Caution is advised in using this agent in patients with psoriasis or other significant cutaneous condition.
  • Daclizumab should be used with caution, if at all, in a patient with any active chronic infection, including but not limited to HIV.
WEB LINKS PROVIDED IN THIS DOCUMENT:
  • Kappos et al., 2015: http://www.ncbi.nlm.nih.gov/pubmed/26444729
  • Gold et al., 2013: http://www.ncbi.nlm.nih.gov/pubmed/23562009
  • Pfender & Martin, 2014: http://www.ncbi.nlm.nih.gov/pubmed/24768797
  • Bielekova et al., 2004: http://www.ncbi.nlm.nih.gov/pubmed/15161974
  • Rose et al., 2007: http://www.ncbi.nlm.nih.gov/pubmed/17709711
  • Cortese et al., 2016: http://www.ncbi.nlm.nih.gov/pubmed/26843560
EDITOR:
Rosalind Kalb, PhD

DISCLAIMER:

The Emerging Therapies Collaborative is proud to be a source of information about multiple sclerosis. Our comments are based on published data and expert opinion, but do not represent individual therapeutic recommendations or prescriptions. For specific information and advice, consult your physician.

DISCLOSURES:
Christopher T. Bever, MD, MBA has received royalties from Lippincott and Johns Hopkins University Press. He is the co-holder on patent on the use of hematogenous stem cells in neurological diseases and has received grants from Department of Veterans Affairs and the National MS Society.

Bruce Cohen, MD has received consulting from EMD Serono, Genentech, Teva Neuroscience, Novartis and Sanofi Genzyme. He has common stock in Abbott Laboratories and CVS-Caremark and has received grants that were funded institutional research through Northwestern University from Biogen Idec, EMD Serono, Novartis, and Hoffman La Roche.

June Halper, APN-C, MSCN, FAAN has received consulting from Biogen. She has also received royalties from Demos Medical Publishing.

David Jones, MD has received consulting from Biogen and Novartis. He has also received grants from Biogen and the National MS Society.

Rosalind Kalb, PhD, has received royalties from Demos Medical Publishing and Wiley Publishing.

Ruth Whitham MD is a Data Safety Monitoring Board member for Chugai Pharmaceuticals for two clinical trials in neuromyelitis optica.
FOR COMPLETE DISCLOSURES AND OTHER INFORMATION:
Please visit our website at http://www.ms-coalition.org/emergingtherapies or email us at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .
For additional information, healthcare professionals are invited to email the National MS Society's Professional Resource Center at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .
Last Updated on Monday, 12 September 2016 14:25