Medical Policy

 

Subject: Daclizumab (Zinbryta®)
Document #: DRUG.00089 Publish Date:    12/27/2017
Status: Revised Last Review Date:    11/02/2017

Description/Scope

This document addresses the uses of subcutaneous daclizumab (Zinbryta, Biogen Inc., Cambridge, MA) for the treatment of multiple sclerosis (MS). Daclizumab is a humanized, monoclonal antibody that inhibits interleukin-2 (IL-2)’s high affinity response by blocking the receptor to its CD25-subunit. CD25 is expressed at high levels on T-cells that become activated in individuals diagnosed with MS.

This document does not address the clinical indications for intravenously administered daclizumab (Zenapax®; Roche, Nutley, NJ), which is U.S. Food and Drug Administration (FDA) approved for the prophylaxis of acute organ rejection in individuals receiving renal transplants.

Note: Please see the following related documents for additional information:

Position Statement

Medically Necessary:

Daclizumab (Zinbryta) is considered medically necessary for the single-agent treatment of individuals with relapsing-remitting multiple sclerosis (RRMS) who meet all of the following criteria:

  1. 18 years of age and older; and
  2. Received prior treatment with at least two alternative drug therapies indicated for the treatment of multiple sclerosis (for example, interferons, glatiramer) and failed to achieve an adequate response to those therapies.

Investigational and Not Medically Necessary:

Daclizumab (Zinbryta) is considered investigational and not medically necessary when the medically necessary criteria are not met and for all other indications including, but not limited to:

  1. Primary progressive multiple sclerosis (PPMS);
  2. Secondary progressive multiple sclerosis (SPMS);
  3. Combination treatment with other disease modifying biologic MS drug therapies (for example, interferons, glatiramer, alemtuzumab, natalizumab and ocrelizumab);
  4. Individuals with hepatic disease, hepatic impairment and autoimmune conditions involving the liver.
Rationale

In 2016, daclizumab received FDA approval as a therapy for individuals with relapsing-remitting MS (RRMS) who have failed at least two alternative therapies for the treatment of MS (FDA Product Information [PI] Label, 2017). The decision to limit daclizumab’s approval to third-line therapy or later, was based on the unfavorable safety profile demonstrated in clinical trials relative to alternative therapies for relapsing forms of MS. Zinbryta is available only through a Risk Evaluation Mitigation Strategy (REMS) restricted distribution program.

The FDA approval of daclizumab was based on two phase III, randomized, double-blind, controlled clinical trials; both trials were funded, designed and analyzed by the manufacturers of Zinbryta. In the most recent pivotal trial by Kappos and colleagues (2015), a total of 1841 individuals diagnosed with RRMS were randomized to receive either 150 mg of daclizumab once every 4 weeks and once weekly injections of placebo (n=919), or once weekly injections of interferon beta-1a and monthly injections of placebo (n=922). Study enrollees were followed for up to 144 weeks and no less than 96 weeks, at 244 study sites across 28 countries. Notable inclusion criteria included a diagnosis of RRMS according to the 2005 McDonald criteria, age 18-55 years, cranial magnetic resonance imaging (MRI) showing lesions consistent with MS, and an Expanded Disability Status Scale (EDSS) score of 0-5.0 (EDSS steps 0 to 5.0 refer to people with MS who are able to walk up to 200 meters without any aid). Key study exclusion criteria included a diagnosis of primary progressive MS (PPMS), secondary progressive MS, or progressive relapsing MS, major co-morbidity, history of intolerance, noncompliance, or contraindication to interferon beta-1a, and previous treatment with other CD25 monoclonal antibodies. The primary outcome of interest was the annual relapse rate. Secondary study endpoints included the number of new, or newly enlarged lesions (on MRI), the proportion of study participants with confirmed progression of disability, the proportion of participants who did not relapse during the 144 week study period, and the proportion who had an increase from baseline in negative MS effects as measured by the Multiple Sclerosis Impact Scale (MSIS)-29 physical impact score. The characteristics of participants were well balanced between the two study arms as were the rates of study withdrawal and treatment discontinuation. The primary outcome of interest was met with a statistically significant lower annualized relapse rate in the daclizumab arm (0.22 versus 0.39; p<0.001). Of the objective secondary outcomes, only the number of new or newly enlarged lesions on MRI was reduced at week 96 in the daclizumab arm (54% lower; p<0.001). The overall incidence of adverse events was identical in each group (91% in both arms). Excluding relapse of MS, the most commonly reported adverse events (> 10% report in either group) were nasopharyngitis, headache, upper respiratory tract infection, pyrexia, injection-site pain, urinary tract infection and influenza-like illness. Hepatic events occurred in 16% of the daclizumab arm and 14% of the interferon beta-1a arm. The most common serious adverse events, excluding MS relapse, were infections and cutaneous events. A total of 4 study participants in the interferon beta-1a group, and 1 in the daclizumab group, died during the study period; no deaths were thought to be attributable to study treatments. The study authors conclude that daclizumab demonstrated superior efficacy to that of interferon beta-1a with respect to the annualized relapse rate and lesions (on MRI) but was not associated with a significantly lower risk of disability progression at 12 weeks. The rates of infection, cutaneous events, and abnormal liver function tests were higher in those treated with daclizumab versus interferon beta-1a and an acute case of hepatic failure/toxic hepatitis was also reported in the daclizumab group.

The second pivotal clinical trial conducted by Gold and colleagues (2013), evaluated the annualized relapse rate (primary endpoint) of 621 individuals diagnosed with RRMS who were randomized to one of three study arms to receive monthly injections of either, (1) daclizumab 150 mg (n=208), (2) daclizumab 300 mg (n=209), or (3) placebo (n=204); 92-94% of enrollees from each study arm completed follow-up through study end (52 weeks). Study participants were aged 18-55 years, had a confirmed diagnosis of RRMS (as assessed by the 2005 McDonald criteria), had a baseline EDSS score of 5.0 or less, and either at least one confirmed relapse in the previous 12 months or one new gadolinium-enhancing lesion on brain MRI in the previous 6 weeks. Diagnosis of progressive forms of MS (including primary, secondary or progressive-relapsing) was an exclusion criterion. Secondary and tertiary outcomes included the number of new or enhancing brain lesions on MRI, change in quality of life as measured by the MSIS-29 physical impact score, and disability progression (as measured by the EDSS). The three groups were similar in demographics and baseline disease characteristics at enrollment, with the exception of the daclizumab 150 mg group who had a higher mean number of gadolinium-enhancing lesions at baseline. At study end, investigators reported that the annualized relapse rate was lower for the daclizumab 150 mg arm (54% reduction, 95% confidence interval [CI], 33-68%; p<0.0001) and the daclizumab 300 mg arm (50% reduction, 95% CI, 28-65%; p=0.00015) than for those in the placebo arm. Furthermore, a higher proportion of individuals were relapse free in the daclizumab 150 mg arm (81%; p<0.0001) and 300 mg arm (80%; p=0.0003) than in the placebo arm (64%). More favorable point estimates with statistical significance were reported in the daclizumab 150 mg group versus the 300 mg group. Administration of daclizumab was associated with an increased risk of infection and of cutaneous and hepatic events compared to placebo. In the daclizumab 150 mg group, 1 death occurred in an individual who was recovering from a serious rash; the death was attributed to local complication of a psoas abscess.

Giovannoni and colleagues (2014a) published results of an extension trial in which participants in the placebo arm were randomized to receive 150 mg or 300 mg of daclizumab for an additional 52 weeks of follow-up; those already receiving daclizumab continued with their previous dose. A total of 517 individuals with RRMS participated in this extension study. Authors concluded that adverse events and immunogenicity were not increased in the second year of continuous treatment with daclizumab. Post-hoc analyses have been conducted from the data collected in the original clinical trial. The previously determined efficacy of daclizumab was found to be similar in highly active disease (> 2 relapses per year) versus less active disease (Giovannoni, 2014b) and associated with a meaningful increase in the proportion of subjects who were disease-activity free at 1 year follow-up, versus placebo (Havrdova, 2014).

The safety and efficacy of combination therapy with daclizumab and other biologic MS drug therapies has not been established.

Background/Overview

Multiple Sclerosis

According to the National Institute of Neurological Disorders and Stroke (NINDS, 2015), there are currently 250,000 to 350,000 people in the US diagnosed with MS. This estimate includes approximately 200 new cases diagnosed every week. Studies of the prevalence of individuals with MS indicate that the rate of the disease has increased steadily during the twentieth century.

MS is an autoimmune disease of the central nervous system (CNS). During the MS disease process, inflammation of nervous tissue causes the loss of myelin, a fatty material that acts as a protective insulation for the nerve fibers in the brain and spinal cord. This demyelination leaves multiple areas of hard scarred tissue (plaques) along the covering of the nerve cells. Another characteristic of MS is the destruction of axons, which are the long filaments that carry electric impulses away from a nerve cell. The demyelination and axon destruction disrupts the ability of the nerves to conduct electrical impulses to and from the brain, and produces the various symptoms. Common symptoms of the disease include fatigue, numbness, coordination and balance problems, bowel and bladder dysfunction, emotional and cognitive changes, spasticity, vision problems, dizziness, sexual dysfunction, and pain. Classifications of MS are relapsing remitting (RRMS), primary progressive (PPMS), progressive relapsing (PRMS), and secondary progressive MS (SPMS). Most individuals with MS have a relapsing course and their first attack may present as a clinically isolated syndrome (CIS). A CIS is a single demyelinating episode with consistent MRI findings (indicating inflammation/demyelination in one or more sites in the CNS). Individuals with this syndrome are at high risk for developing clinically definite MS.

Diagnostic criteria for MS have evolved in recent years. Although the diagnosis can be made on clinical grounds alone, MRI of the CNS can support, supplement, or even replace some clinical criteria (Pohlman, 2011). The McDonald Criteria, a tool for the diagnosis of MS, was updated in 2010 by the International Panel on Diagnosis of MS (the Panel). The Panel stressed that the McDonald criteria should only be applied in those individuals who present with a typical CIS suggestive of MS or symptoms consistent with a CNS inflammatory demyelinating disease. This is because the development and validation of the criteria was limited to individuals with such a presentation. The 2010 McDonald criteria as documented in the table below include clinical presentations as well as additional data needed for MS diagnosis including MRI findings for demonstration of dissemination of CNS lesions in space and time.

The treatment of MS varies depending upon individual disease characteristics. RRMS is the most common type and is characterized by clearly defined exacerbations followed by periods of remission. There is no disease progression during the periods between disease relapses. RRMS is generally associated with a better prognosis than progressive disease courses. Certain immunomodulatory agents, including interferon beta preparations, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, alemtuzumab and teriflunomide, have shown beneficial effects for individuals with RRMS, including a decreased relapse rate and a slower accumulation of brain lesions on MRI.

Daclizumab (Zinbryta) is a long-acting, subcutaneous injection that is self-administered monthly. The active ingredient in Zinbryta, daclizumab, is also FDA-approved as Zenapax for the prophylaxis of acute organ rejection in individuals receiving renal transplants. In addition to the divergent FDA approved clinical indications, Zenapax’s glycosylation, cytotoxic activity, route of administration, dosing, frequency, and duration differ significantly from Zinbryta (Zenapax PI Label, 2005; Zinbryta PI Label, 2017).

The 2010 McDonald Criteria for Diagnosis of MS
(Polman, 2011)

 

Clinical Presentation

Additional Data Needed for MS Diagnosis

2 or more attacksa; objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attackb.

Nonec

 

2 or more attacksa; objective clinical evidence of one lesion

 

Dissemination in space, demonstrated by:

  • 1 or more T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)d; or
  • Await further clinical attacka implicating a different CNS site

1 attacka; objective clinical evidence of two or more lesions

 

Dissemination in time, demonstrated by:

  • Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or
  • A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or
  • Await a second clinical attacka

1 attacka; objective clinical evidence of one lesion (clinically isolated syndrome)

 

Dissemination in space and time, demonstrated by:
For dissemination in space (DIS):

  • 1 or more T2 lesion in at least 2 of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord)d; or
  • Await a second clinical attacka implicating a different CNS site; and

For dissemination in time (DIT), demonstrated by:

  • Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time; or
  • A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan; or
  • Await a second clinical attacka

Insidious neurological progression suggestive of MS (typical presentation of PPMS)

 

1 year of disease progression (retrospectively or prospectively determined) plus
2 of 3 of the following criteriad:

  1. Evidence for DIS in the brain based on one or more T2 lesions in the MS-characteristic (periventricular, juxtacortical, or infratentorial) regions
  2. Evidence for DIS in the spinal cord based on 2 or more T2 lesions in the cord
  3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

If the Criteria are fulfilled and there is no better explanation for the clinical presentation, the diagnosis is ‘‘MS’’; if suspicious, but the Criteria are not completely met, the diagnosis is ‘‘possible MS’’; if another diagnosis arises during the evaluation that better explains the clinical presentation, then the diagnosis is ‘‘not MS.’’
aAn attack (relapse; exacerbation) is defined as patient-reported or objectively observed events typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours, in the absence of fever or infection. It should be documented by contemporaneous neurological examination, but some historical events with symptoms and evolution characteristic for MS, but for which no objective neurological findings are documented, can provide reasonable evidence of a prior demyelinating event. Reports of paroxysmal symptoms (historical or current) should, however, consist of multiple episodes occurring over not less than 24 hours. Before a definite diagnosis of MS can be made, at least 1 attack must be corroborated by findings on neurological examination, visual evoked potential response in patients reporting prior visual disturbance, or MRI consistent with demyelination in the area of the CNS implicated in the historical report of neurological symptoms.
bClinical diagnosis based on objective clinical findings for 2 attacks is most secure. Reasonable historical evidence for 1 past attack, in the absence of documented objective neurological findings, can include historical events with symptoms and evolution characteristics for a prior inflammatory demyelinating event; at least 1 attack, however, must be supported by objective findings.
cNo additional tests are required. However, it is desirable that any diagnosis of MS be made with access to imaging based on these Criteria. If imaging or other tests (for instance, CSF) are undertaken and are negative, extreme caution needs to be taken before making a diagnosis of MS, and alternative diagnoses must be considered. There must be no better explanation for the clinical presentation, and objective evidence must be present to support a diagnosis of MS.
dGadolinium-enhancing lesions are not required; symptomatic lesions are excluded from consideration in subjects with brainstem or spinal cord syndromes.

MS = multiple sclerosis; CNS = central nervous system; MRI = magnetic resonance imaging; DIS = dissemination in space; DIT = dissemination in time; PPMS = primary progressive multiple sclerosis; CSF = cerebrospinal fluid; IgG = immunoglobulin G.

2010 McDonald MRI Criteria for Demonstration of DIS:
DIS can be demonstrated by one or more T2 lesiona in at least two of four areas of the CNS:

  1. Periventricular
  2. Juxtacortical
  3. Infratentorial
  4. Spinal cordb

Based on Swanton et al 2006, 2007.
aGadolinium enhancement of lesions is not required for DIS.
bIf a subject has a brainstem or spinal cord syndrome, the symptomatic lesions are excluded from the Criteria and do not contribute to lesion count.
MRI = magnetic resonance imaging; DIS = lesion dissemination in space; CNS = central nervous system

2010 McDonald MRI Criteria for Demonstration of DIT:
DIT can be demonstrated by:

  1. A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, with reference to a baseline scan, irrespective of the timing of the baseline MRI
  2. Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time

Based on Montalban et al 2010.
MRI = magnetic resonance imaging; DIT = lesion dissemination in time.

2010 McDonald Criteria for Diagnosis of Multiple Sclerosis in Disease with Progression from Onset:

  1. One year of disease progression (retrospectively or prospectively determined)
  2. Plus two of the three following criteriaa:
    1. Evidence for DIS in the brain based on one or more T2b lesions in at least one area characteristic for MS (periventricular, juxtacortical, or infratentorial)
    2. Evidence for DIS in the spinal cord based on two or more T2b lesions in the cord
    3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index)

aIf a subject has a brainstem or spinal cord syndrome, all symptomatic lesions are excluded from the Criteria.
bGadolinium enhancement of lesions is not required.
MS = multiple sclerosis; PPMS = primary progressive MS; DIS = lesion dissemination in space; CSF = cerebrospinal fluid; IgG = immunoglobulin G.

Adverse Events and Warnings

Black box warnings from the FDA PI Label (2017) include the following:

Additional warnings and recommendations from the FDA PI Label (2017) include:

Definitions

Clinical lesion: An area of inflamed or demyelinated central nervous system tissue; synonymous with plaque.

Expanded Disability Status Scale (EDSS): A method of quantifying disability in MS and monitoring changes in the level of disability over time. The scale ranges from 0 to 10 in 0.5 unit increments; increasing units represent higher levels of disability. Scoring is based on examination by a neurologist.

Primary progressive MS (PPMS): A clinical course of MS characterized by progression of disability from onset without superimposed relapses. The term progressive-relapsing multiple sclerosis or PRMS, previously used to characterize individuals who had progressive disease from onset and clear acute relapses, is no longer preferred. An acute relapse in an individuals with progressive disease from onset is now considered to be PPMS with active disease, whereas those with progressive disease from onset without acute relapses are considered to have PPMS, not active but with progression.

Relapse: The appearance of new symptoms or the aggravation of old ones, lasting at least 24 hours in the absence of fever or infection (synonymous with exacerbation, attack, flare-up, or worsening); usually associated with inflammation and demyelination in the brain or spinal cord.

Relapsing-remitting MS (RRMS): A clinical course of MS characterized by clearly defined, acute relapses with full or partial recovery; no disease progression or worsening of disability develops between relapses.

Secondary progressive MS (SPMS): A clinical course of MS demonstrating sustained progression of physical disability occurring separately from relapses in individuals who previously had RRMS.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes. Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy. Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

When services may be Medically Necessary when criteria are met:

HCPCS

 

J3490

Unclassified drugs [when specified as Zinbryta]

J3590

Unclassified biologics [when specified as Zinbryta]

 

 

 

ICD-10 Diagnosis

 

 

G35

Multiple sclerosis

 

When services are Investigational and Not Medically Necessary:
For the procedure and diagnosis codes listed above when criteria are not met or for all other diagnoses not listed; or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

References

Peer Reviewed Publications:

  1. Giovannoni G, Gold R, Selmaj K, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECTION): a multicentre, randomised, double-blind extension trial. Lancet Neurol. 2014a; 13(5):472-481.
  2. Giovannoni G, Radue EW, Havrdova E, et al. Effect of daclizumab high-yield process in patients with highly active relapsing-remitting multiple sclerosis. J Neurol. 2014b; 261(2):316-323.
  3. 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(9884):2167-2175.
  4. Gold R, Radue EW, Giovannoni G, et al. Safety and efficacy of daclizumab in relapsing-remitting multiple sclerosis: 3-year results from the SELECTED open-label extension study. BMC Neurol. 2016; 16:117.
  5. Havrdova E, Giovannoni G, Stefoski D, et al. Disease-activity-free status in patients with relapsing-remitting multiple sclerosis treated with daclizumab high-yield process in the SELECT study. Mult Scler. 2014; 20(4):464-470.
  6. 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):1418-1428.
  7. Krueger JG, Kircik L, Hougeir F, et al. Cutaneous adverse events in the randomized, double-blind, active-comparator DECIDE study of daclizumab high-yield process versus intramuscular Interferon Beta-1a in relapsing-remitting multiple sclerosis. Adv Ther. 2016; 33(7):1231-1245.
  8. Liu Y, Vollmer T, Havrdova E, et al. Impact of daclizumab versus interferon beta-1a on patient-reported outcomes in relapsing-remitting multiple sclerosis. Mult Scler Relat Disord. 2017; 11:18-24.
  9. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2):292-302.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. Daclizumab. In: DrugPoints® System (electronic version). Truven Health Analytics, Greenwood Village, CO. Updated September 7, 2017. Available at: http://www.micromedexsolutions.com. Accessed on September 30, 2017.
  2. Daclizumab Monograph. Lexicomp® Online, American Hospital Formulary Service® (AHFS®) Online, Hudson, Ohio, Lexi-Comp., Inc. Last revised March 19, 2017. Accessed on September 29, 2017.
  3. Tramacere I, Giovane C, Salanti G, et al. Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2015;(2):CD011381.
  4. Zenapax®.[Product Information]. Hoffmann-La Roche Inc., Nutley, NJ; September 15, 2005. Available at http://www.accessdata.fda.gov/drugsatfda_docs/label/2005/103749s5059lbl.pdf. Accessed on September 30, 2017.
  5. Zinbryta® .[Product Information]. Biogen Inc., Cambridge, MA; August 28, 2017. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761029s007lbl.pdf. Accessed on September 30, 2017.
Websites for Additional Information
  1. American Academy of Neurology. Multiple Sclerosis: Practice Guidelines. March 2014 Available at: https://www.aan.com/Guidelines/Home/ByTopic?topicId=18. Accessed September 30, 2017.
  2. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis: Hope through research. Last Updated November 19, 2015. Available at: http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm. Accessed on September 30, 2017.
  3. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis Information Page. Last Updated on November 19, 2015. Available at: https://www.ninds.nih.gov/Disorders/All-Disorders/Multiple-Sclerosis-Information-Page. Accessed on September 30, 2017.
  4. National Multiple Sclerosis Society. What is MS? Available at: http://www.nationalmssociety.org/about-multiple-sclerosis/index.aspx. Accessed September 30, 2017.
  5. Tarver, M. Kurtzke Expanded Disability Status Scale (EDSS). Department of Veterans Affairs: Multiple Sclerosis Centers for Excellence. Last Updated on July 2015. Available at: http://www.va.gov/MS/Professionals/Diagnosis/Kurtzke_Expanded_Disability_Status_Scale.asp. Accessed on September 30, 2017.
Document History

Status

Date

Action

Revised

11/02/2017

Medical Policy & Technology Assessment Committee (MPTAC) review. Updated header language from “Current Effective Date” to “Publish Date.” Added combination therapy to the INV&NMN criteria. Updated Rationale, Background/Overview, References and Websites sections

Reviewed

11/03/2016

MPTAC review. Updated Rationale, Reference and Websites sections. 

New

08/04/2016

MPTAC review. Initial document development.