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VBCN - July 2016 Volume 3, No 2 - Drug Update
Loretta Fala

Multiple sclerosis (MS) is a chronic, inflammatory disease of the central nervous system (CNS) that causes demyelination and axonal damage in the brain, spinal cord, and optic nerves.1,2 The demyelination in MS is thought to be the result of abnormal immune response in which activated lymphocytes (T-cells and possibly B-cells) impact the CNS myelin.3

Although its incidence and prevalence are not well-established because of inconsistent reporting and tracking, MS affects 250,000 to 350,000 or more people in the United States, with as many as 200 new cases diagnosed weekly.4,5 Approximately 85% of people with MS are diagnosed with relapsing-remitting MS (RRMS).6 As many as 60% to 70% of patients with relapsing forms of MS gradually progress to secondary progressive MS.2

The symptoms of MS include muscle weakness, numbness, visual problems, fatigue, dizziness, tremor, pain, coordination and speech problems, bowel and bladder function problems, and in severe cases, impaired mobility and disability.2 MS can have a profound impact on patients, their families, and caregivers, particularly when the disease affects functionality, productivity, and quality of life.7

MS is associated with substantial healthcare costs.7-9 A recent study showed that the per-patient annual all-cause healthcare costs for MS ranged from $8528 to $54,244, with direct costs accounting for 77% of the total.8 In an earlier study, intangible costs, including for health-related quality of life, accounted for 17.5% to 47.8% of the total costs of managing MS.9 Overall, evidence suggests that the patient burden and healthcare costs increase with the severity of disease and its related disability.7,8

The main treatment goals for patients with MS are to manage symptoms and to prevent or delay relapse, disability progression, and disease activity.10,11 In recent literature, no evident disease activity (NEDA), which is defined by clinical and magnetic resonance imaging (MRI) criteria, has been suggested as a goal for MS treatment and clinical trial design.12 NEDA involves a patient-individualized approach: active monitoring with a repeat baseline MRI once a specific disease-modifying therapy (DMT) has had time to work, and performing an annual (or more frequent, if necessary) MRI for subclinical relapse.12

A recent study showed that relapsing MS therapies demonstrating the highest NEDA values in clinical trials were the most cost-effective.13 Treatment adherence, a key aspect of MS management that improves clinical benefits for patients, is also associated with lower rates of emergency department visits, hospital stays, and work absences.14

Early diagnosis and treatment are crucial for achieving optimal patient outcomes: aggressive, early therapy with DMTs in the early stages of MS has been shown to reduce relapse rates and slow the formation of new lesions.15,16 DMTs are the cornerstone treatments for relapsing MS.11,15 These agents differ in their safety and efficacy profiles, mechanisms of action, formulation, mode of delivery, dose, and dosing frequency. DMTs are associated with drug class- or agent-specific adverse events; therefore, the risks and benefits of each therapy must be considered.

Until recently, DMTs for relapsing MS included alemtuzumab; the beta interferons interferon beta-1a subcutaneous injection, interferon beta-1a intramuscular injection, interferon beta-1b, and pegylated interferon beta; dimethyl fumarate; fingolimod; glatir­amer acetate; natalizumab; and teriflunomide.11 In 2016, a novel once-monthly DMT with a new mechanism of action became available for relapsing MS.17,18

Daclizumab: A New Once-Monthly Option for Multiple Sclerosis

On May 27, 2016, daclizumab (Zinbryta; Biogen/AbbVie), a long-acting, interleukin (IL)-2 receptor-blocking antibody, was approved by the US Food and Drug Administration (FDA) for the treatment of adults with relapsing forms of MS.17,19 Because of its safety profile, daclizumab should generally be used for patients who respond inadequately to ≥2 MS therapies.19 Daclizumab is available only through restricted distribution via a Risk Evaluation and Mitigation Strategy (REMS) program.17

Jeffrey English, MD, Director of Clinical Research, Multiple Sclerosis Center of Atlanta, said, “MS affects each person differently, so it is critical that people have additional therapeutic options to address their needs throughout the course of the disease. Zinbryta provides a meaningful new treatment option that demonstrates efficacy and offers once-monthly dosing.”18

Daclizumab is the first once-monthly, self-administered treatment for MS.18 One of the studies leading to its approval was the largest and longest head-to-head phase 3 trial conducted on a drug to treat MS, according to Biogen and AbbVie.18

Mechanism of Action

Daclizumab is a humanized monoclonal antibody. Although the precise mechanism of exerting therapeutic effects in MS is unknown, daclizumab is presumed to modulate IL-2-mediated activation of lymphocytes through binding to CD25, a subunit of the high-affinity IL-2 receptor.19 These IL-2 receptors are expressed on lymphocytes, which are cells implicated in the pathogenesis of MS.19,20 Over a 52-week course of treatment with daclizumab, the total lymphocyte/T-cell counts decreased by <10%.21

Dosing and Administration

The recommended dose of daclizumab is 150 mg once monthly administered subcutaneously. Patients must be trained in the proper technique for self-administration. Laboratory tests should be performed at baseline and at periodic intervals to monitor patients for early signs of potentially serious adverse reactions.19

Daclizumab injection is available as a 150-mg/mL solution in a single-dose prefilled syringe.19

Clinical Trials

The FDA approval of daclizumab was based on 2 randomized, double-blind, controlled studies (DECIDE and SELECT) in patients with relapsing MS. In both studies, patients with progressive MS or an Expanded Disability Status Scale score of >5 were excluded.19

The DECIDE study compared the safety and efficacy of subcutaneous daclizumab 150 mg every 4 weeks with intramuscular interferon beta-1a 30 mcg weekly in 1841 patients with relapsing MS (Table 1).19,20

The primary end point was the annualized relapse rate during 144 weeks.19,20 The secondary end points included the proportion of patients whose disease relapsed, the proportion of patients who had confirmed disability progression, and the number of new or newly enlarging T2 hyperintense lesions. The patients were evaluated every 12 weeks and after a relapse event; MRI scans were performed at weeks 24 and 96.19,20

Daclizumab demonstrated a 45% reduction in the annualized relapse rate and a 54% reduction in the number of new or newly enlarging T2 hyperintense lesions compared with interferon beta-1a. The effect of daclizumab on 12-week confirmed disability progression was not significantly better than with interferon beta-1a.19,20

The SELECT clinical trial was a 52-week, randomized, double-blind, placebo-controlled study that compared the safety and efficacy of daclizumab with placebo in 412 patients (mean age, 36 years) with relapsing MS (Table 2).19,21

The primary end point was the annualized relapse rate at week 52. Other end points included new T1 gadolinium (Gd)-enhancing lesions from week 8 to week 24 in a subset of patients, the proportion of patients with disease relapse, the proportion of patients who had 12-week confirmed disability progression, and the number of new or newly enlarging T2 hyperintense lesions.

Daclizumab demonstrated a significant 54% reduction in the annualized relapse rate compared with placebo. Significant reductions were also demonstrated with daclizumab versus placebo in the proportion of relapse-free patients (81% vs 64%, respectively), the number of new T1 Gd-enhancing lesions (69% reduction), and the number of new or newly enlarging T2 hyperintense lesions (70% reduction).19,21

Adverse Reactions

The safety data for daclizumab are based on 2235 patients with RRMS who received daclizumab for 5214 person-years. Overall, 1576 were exposed to daclizumab for ≥1 years, 1259 for ≥2 years, and 888 for ≥3 years.19

The most common adverse events (incidence ≥5% and ≥2% higher than the comparator) reported with dacliz­umab included nasopharyngitis (25%), upper respiratory tract infection (17%), rash (11%), influenza (9%), dermatitis (9%), oropharyngeal pain (8%), bronchitis (7%), eczema (5%), and lymphadenopathy (5%).

The most common adverse reactions with daclizumab were upper respiratory tract infection (9%), depression (7%), rash (7%), pharyngitis (6%), and increased alanine aminotransferase (ALT) levels (5%).19

Up to 5% of patients discontinued daclizumab treatment because of an adverse event; hepatic events, including elevated serum transaminases and cutaneous events, were the most common reasons for discontinuation.19

Restricted Distribution Program

Because of the risk for hepatic injury, including several immune disorders, daclizumab is only available through a restricted program—the Zinbryta REMS Program. The drug is therefore only available to certified prescribers, pharmacies, and patients enrolled in this program.19

Contraindications

Daclizumab is contraindicated in patients with preexisting hepatic disease or hepatic impairment, including ALT or aspartate aminotransferase at least twice the upper limit of normal, in patients with a history of autoimmune hepatitis or other autoimmune conditions involving the liver, and in patients with a history of hypersensitivity to daclizumab or any other component of its formulation.19

Drug Interactions

Caution should be exercised when hepatotoxic drugs, including nonprescription products, are used concomitantly with daclizumab. The patient's need for the use of herbal products or dietary supplements that can cause hepatotoxicity should be carefully considered.19

Warnings and Precautions

Boxed warning. Daclizumab was approved with a boxed warning about the risk for severe liver injury, including life-threatening events, liver failure, and autoimmune hepatitis. The patient's transaminase and bilirubin levels should be obtained before initiating daclizumab treatment. Transaminase and bilirubin levels should be monitored monthly and up to 6 months after the last dose. In addition, daclizumab can cause immune-mediated disorders, including skin reactions, lymphadenopathy, noninfectious colitis, and other immune-mediated disorders.19

Hypersensitivity reactions/infections. Daclizumab can cause anaphylaxis, angioedema, and urticaria, and can increase the risk for infections; withholding treatment should be considered for serious infections until the infection resolves.19

Depression/suicide. The discontinuation of daclizumab should be considered in patients who report symptoms of depression and/or suicidal thoughts.19

Use in Specific Populations

The developmental risk associated with the use of daclizumab in pregnant women has not been adequately studied. It is not known whether daclizumab is present in human milk or whether it has an effect on the breastfed child or on milk production.19 Daclizumab has not been studied in children; dacliz­umab should not be used in pediatric patients because of safety risks.19

Conclusion

With the FDA approval of daclizumab subcutaneous injection, a new disease-modifying therapeutic option became available for patients with relapsing forms of MS, in particular, those who have an inadequate response to ≥2 drugs. Daclizumab, a humanized IL-2 receptor-blocking antibody, demonstrated superior efficacy in annualized relapse rate compared with interferon beta-1a in the DECIDE trial and compared with placebo in the SELECT trial. Moreover, dac­lizumab showed superior efficacy in reducing the number of new or enlarging brain lesions compared with interferon beta-1a and placebo.

Daclizumab provides patients with relapsing MS a convenient and effective once-monthly treatment option that is self-administered.




References

  1. National Multiple Sclerosis Society. Definition of MS. www.nationalmssociety.org/What-is-MS/Definition-of-MS. Accessed June 12, 2016.
  2. Mayo Clinic staff. Multiple sclerosis: symptoms and causes. October 1, 2015. www.mayoclinic.org/diseases-conditions/multiple-sclerosis/home/ovc-20131882. Accessed June 12, 2016.
  3. National Multiple Sclerosis Society. T cells. www.nationalmssociety.org/What-is-MS/Definition-of-MS/T-cells. Accessed June 19, 2016.
  4. National Multiple Sclerosis Society. MS prevalence. www.nationalmssociety.org/About-the-Society/MS-Prevalence. Accessed June 14, 2016.
  5. National Institute of Neurological Disorders and Stroke. Multiple sclerosis: hope through research. NIH Publication No 12-75. June 2012. www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm#3215_5. Accessed June 14, 2016.
  6. National Multiple Sclerosis Society. Relapsing-remitting MS (RRMS). www.nationalmssociety.org/What-is-MS/Types-of-MS/Relapsing-remitting-MS. Accessed June 14, 2016.
  7. Naci H, Fleurence R, Birt J, Duhig A. Economic burden of multiple sclerosis: a systematic review of the literature. Pharmacoeconomics. 2010;28:363-379.
  8. Adelman G, Rane SG, Villa KF. The cost burden of multiple sclerosis in the United States: a systematic review of the literature. J Med Econ. 2013;16:639-647.
  9. Wundes A, Brown T, Bienen EJ, Coleman CI. Contribution of intangible costs to the economic burden of multiple sclerosis. J Med Econ. 2010;13:626-632.
  10. Fox EJ, Rhoades RW. New treatments and treatment goals for patients with relapsing-remitting multiple sclerosis. Curr Opin Neurol. 2012;25(suppl 1):S11-S19.
  11. Mayo Clinic staff. Multiple sclerosis: treatment. October 1, 2015. www.mayoclinic.org/diseases-condi tions/multiple-sclerosis/diagnosis-treatment/treatment/txc-20131903. Accessed June 14, 2016.
  12. Giovannoni G, Turner B, Gnanapavan S, et al. Is it time to target no evident disease activity (NEDA) in multiple sclerosis? Mult Scler Relat Disord. 2015;4:329-333.
  13. Ontaneda D, Henry O. Cost effectiveness of multiple sclerosis therapeutic strategies for achieving no evidence of disease activity. Neurology. 2016;86(16 suppl). Abstract P2.193.
  14. Remington G, Rodriguez Y, Logan D, et al. Facilitating medication adherence in patients with multiple sclerosis. Int J MS Care. 2013;15:36-45.
  15. The Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis: principles and current evidence. Updated March 2015. www.nationalmssociety.org/getmedia/5ca284d3-fc7c-4ba5-b005-ab537d495c3c/DMT_Consensus_MS_Coalition_color. Accessed June 14, 2016.
  16. Gold R, Wolinsky JS, Amato MP, Comi G. Evolving expectations around early management of multiple sclerosis. Ther Adv Neurol Disord. 2010;3:351-367.
  17. US Food and Drug Administration. FDA approves Zinbryta to treat multiple sclerosis. Press release. May 27, 2016. www.fda.gov/NewsEvents/Newsroom/PressAnnounce­ments/ucm504000.htm. Accessed June 2, 2016.
  18. AbbVie. Biogen and AbbVie receive FDA approval of once-monthly Zinbryta (daclizumab) for multiple sclerosis. Press release. May 27, 2016. https://news.abbvie.com/news/biogen-and-abbvie-receive-fda-approval-once-monthly-zinbryta-daclizumab-for-multiple-sclerosis.htm. Accessed June 13, 2016.
  19. Zinbryta (daclizumab) injection [prescribing information]. Cambridge, MA: Biogen Inc; May 2016.
  20. 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.
  21. Gold R, Giovannoni G, Selmaj K, et al; for the SELECT Study Investigators. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT): a randomised, double-blind, placebo-controlled trial. Lancet. 2013;381:2167-2175.

Copyright © 2016 American Health & Drug Benefits. Used with permission.

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