Zinbryta ™ - daclizumab Manufacturer: Biogen, Inc. FDA Approval Date: May 27, 2016 Jenna W. Bartlett, PharmD Candidate

Zinbryta™ - daclizumab Objectives At the end of this presentation participants will be able to: 1. Appropriately recommend Zinbryta ™ - (daclizumab) 2. Effectively educate patients on the purpose, proper use and potential adverse effects of Zinbryta ™ - (daclizumab)

Zinbryta™ - daclizumab Clinical Application Indications: Treatment of relapsing forms of multiple sclerosis (MS), generally in patients that have had an inadequate response to ≥2 drugs indicated for the treatment of MS Place in therapy: Another option for 3 rd line (or later) treatment of relapsing MS with the advantage of being a once-monthly self- injection Zinbryta [package insert].

Zinbryta™ - daclizumab Clinical Application Contraindications: Preexisting hepatic disease or hepatic impairment, including ALT or AST ≥2x ULN History or autoimmune hepatitis or other autoimmune condition involving the liver Black Box warnings: Hepatotoxicity including autoimmune hepatitis Other immune-mediated disorders Precautions: Acute hypersensitivity Increased risk of infections Depression-related events Zinbryta [package insert].

Zinbryta™ - daclizumab Clinical Application Pregnancy: No human data available Fetal death and reduced growth seen in monkeys at maternal exposures >30 times than that expected clinically Lactation: No data available Zinbryta [package insert].

Zinbryta™ - daclizumab Drug Facts Pharmacology: Humanized monoclonal antibody that binds to CD25, a subunit of the IL-2 receptor Involves modulation of IL-2 mediated activation of lymphocytes The exact mechanism for therapeutic effect is unknown Zinbryta [package insert].

Zinbryta™ - daclizumab Drug Facts Pharmacokinetics: A Steady state: 4 months D V d = 6.34L M Catabolism to peptides and amino acids E T 1/2 = 21 days Zinbryta [package insert].

Zinbryta™ - daclizumab Drug Interactions Drug Interactions – Object Drugs: Live vaccines: enhanced toxicities and diminished efficacy Inactivated vaccines: diminished efficacy Immunosuppressants: enhanced toxicities and immunosuppressive effect UpToDate Accessed 09/07/16 Zinbryta [package insert].

Zinbryta™ - daclizumab Drug Interactions Drug Interactions – Precipitant Drugs: Immunosuppressants may enhance toxicities of Zinbryta Hepatotoxic drugs may increase risk of hepatotoxicity UpToDate Accessed 09/07/16 Zinbryta [package insert].

Zinbryta™ - daclizumab Adverse Effects Zinbryta [package insert]. Common Adverse Effects: (daclizumab%)[placebo%] Upper respiratory tract infection (9) [7] Rash (7) [3] Pharyngitis (6) [4] Serious Adverse Effects: (daclizumab%)[placebo%] Depression (7) [3] Increased ALT (5) [2] Increased AST (3) [<1]

Zinbryta™ - daclizumab Monitoring Parameters Toxicity Monitoring: AST ALT Total bilirubin Monitor at baseline, then monthly up to 6 months after the last dose Zinbryta [package insert].

Zinbryta™ - daclizumab Prescription Information Dosing: 150 mg SubQ monthly Remove prefilled syringe from refrigerator 30 min prior to injection to allow drug to warm Do not use if it is cloudy or has visible particles Inject into the thigh, abdomen, or back of the upper arm Cost: $8200/month Source – UpToDate 08/26/2016 Zinbryta [package insert].

Zinbryta™ - daclizumab Literature Review Purpose: To compare the efficacy of daclizumab versus interferon beta-1a in the treatment of relapsing- remitting MS Design: Randomized, double-blind, phase 3 study Group 1: daclizumab 150 mg SubQ every 4 weeks + placebo IM once weekly Group 2: interferon beta-1a 30 µg IM once weekly + placebo SubQ once monthly Kappos L, et al. N Engl J Med. 2015;373:

Zinbryta™ - daclizumab Literature Review Inclusion Criteria: Confirmed diagnosis of relapsing-remitting MS Age years Cranial MRI with lesions consistent with a diagnosis of MS Expanded Disability Status Scale score of 0-5 History of clinical relapses within the previous year Kappos L, et al. N Engl J Med. 2015;373:

Zinbryta™ - daclizumab Literature Review Patient Characteristics: N=1841 patients Mean 36 years old 68% female, 90% white 41% previous disease-modifying therapy 34% previous interferon beta therapy 4 years since diagnosis 1.6 relapses in previous year Kappos L, et al. N Engl J Med. 2015;373:

Zinbryta™ - daclizumab Literature Review Efficacy Results: Kappos L, et al. N Engl J Med. 2015;373: End PointDaclizumab Interferon beta-1a P value Adjusted annualized relapse rate <0.001 New or enlarged lesions <0.001 Disability progression

Zinbryta™ - daclizumab Literature Review Safety Results: Kappos L, et al. N Engl J Med. 2015;373: Event Daclizumab (%) Interferon beta-1a (%) Any event (excluding relapse) 9089 Serious ADE (excluding relapse) 1510 Infection6557 Cutaneous event3719 Hepatic event1614 Influenza-like illness1038

Zinbryta™ - daclizumab Literature Review Conclusions: Daclizumab has superior efficacy vs interferon beta-1a with respect to relapse and lesion activity No significant difference between treatments with respect to disability progression Daclizumab has increased ADE vs interferon beta-1a, so the net clinical benefit should be carefully considered Kappos L, et al. N Engl J Med. 2015;373:

Zinbryta™ - daclizumab Summary Zinbryta™, daclizumab, is indicated for relapsing MS, as 3 rd line (or later) treatment Contraindicated in preexisting hepatic disease or impairment Because of hepatotoxicity risk, monitor AST/ALT and bilirubin monthly up to 6 months after last dose (REMS program) Dosing is 150mg SubQ once monthly

Zinbryta™ - daclizumab References 1. multiple-sclerosis/zinbryta/pat/en_us/pdfs/zinbryta- prescribing-information.pdf) 2. Zinbryta [package insert]. Cambridge, MA: Biogen Inc; Daclizumab. UpToDate. Accessed 09/07/ Kappos L, et al. Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med 2015;373: Gold R, et al. Daclizumab high-yield process in relapsing-remitting multiple sclerosis (SELECT). Lancet 2013; 381: