Committee Approval Date: December 12, 2014 Next Review Date: December 2015

Medication Policy Manual Policy No: dru381 Topic: Lemtrada TM, alemtuzumab Date of Origin: December 12, 2014 Committee Approval Date: December 12, 2014 Next Review Date: December 2015 Effective Date: January 1, 2015 IMPORTANT REMINDER This Medical Policy has been developed through consideration of medical necessity, generally accepted standards of medical practice, and review of medical literature and government approval status. Benefit determinations should be based in all cases on the applicable contract language. To the extent there are any conflicts between these guidelines and the contract language, the contract language will control. The purpose of medical policy is to provide a guide to coverage. Medical Policy is not intended to dictate to providers how to practice medicine. Providers are expected to exercise their medical judgment in providing the most appropriate care. Description Alemtuzumab (Lemtrada) is an intravenously administered medication used to prevent or lessen the severity of multiple sclerosis attacks. It works by destroying certain immune cells that are involved in the multiple sclerosis immune response. This policy and the coverage criteria below do not apply to alemtuzumab (Campath). Alemtuzumab (Campath) is used for the treatment of cancer and does not require prior authorization. dru381.0 Page 1 of 9

Policy/Criteria I. Most contracts require prior authorization approval of alemtuzumab (Lemtrada) prior to coverage. Alemtuzumab (Lemtrada) may be considered medically necessary when all of the following criteria A, B, and C are met: A. A definitive diagnosis of a relapsing form of multiple sclerosis (relapsingremitting or secondary progressive multiple sclerosis) that has been established by a specialist in neurology or multiple sclerosis. AND B. Alemtuzumab (Lemtrada) is prescribed by, or in consultation with, a specialist in neurology or multiple sclerosis. AND C. There is clinical documentation that at least three disease modifying therapies for multiple sclerosis were ineffective, contraindicated or not tolerated, as specified by criteria 1, 2, and 3. Ineffectiveness is defined as meeting at least two of the following three criteria (a, b, or c) during treatment with one of these medications: a. The patient continues to have clinical relapses (at least two relapses within the past 12 months). b. The patient continues to have CNS lesion progression as measured by MRI. c. The patient continues to have worsening disability. Examples of worsening disability include, but are not limited to, decreased mobility, decreased ability to perform activities of daily living due to disease progression, or EDSS > 3.5. 1. An interferon beta product (see Appendix A) AND 2. Glatiramer acetate (Copaxone) AND 3. Natalizumab (Tysabri). If natalizumab is contraindicated due to a positive JC virus antibody, then at least one oral disease modifying therapy [either dimethyl fumarate (Tecfidera), fingolimod (Gilenya), or teriflunomide (Aubagio)] must be ineffective, contraindicated or not tolerated. II. Administration, Quantity Limitations, and Authorization Period A. RegenceRx does not consider alemtuzumab (Lemtrada) to be a self-administered medication. B. When prior authorization is approved, alemtuzumab (Lemtrada) shall be authorized in quantities as follows: dru381.0 Page 2 of 9

a. Initial authorization Alemtuzumab (Lemtrada) shall be covered in quantities up to 12 mg/day on five consecutive days in a 12 month period. b. Second authorization Alemtuzumab (Lemtrada) shall be covered in quantities up to 12 mg/day on three consecutive days 12 months after the initial treatment course. Use beyond two years is considered investigational. C. Authorization may be reviewed after the initial authorization to confirm that current medical necessity criteria are met and that the medication is effective. III. Alemtuzumab (Lemtrada) is considered investigational when used for all other conditions, including but not limited to: A. Use for multiple sclerosis beyond two years B. Use in combination with other disease-modifying multiple sclerosis therapies (see Appendix A) C. Any cancer indication, including, but not limited to B-cell chronic lymphocytic leukemia D. Post-transplant antibody induction therapy Position Statement Summary - Alemtuzumab (Lemtrada) is a monoclonal antibody used as monotherapy for the treatment of patients with relapsing forms (relapsing-remitting and secondary progressing) of multiple sclerosis (MS) to reduce the frequency of clinical exacerbations and delay the accumulation of physical disability. [1] - Alemtuzumab (Lemtrada) is not recommended as a first or second-line option due to potentially serious safety concerns. * Package labeling for alemtuzumab (Lemtrada) includes a Black Box Warning describing an increased risk of autoimmunity, infusion reactions, and malignancies with its use. [1] * Because of these safety concerns, distribution of alemtuzumab is restricted. Prescribers, health care facilities, and pharmacies must be enrolled in the Lemtrada REMS program to prescribe, dispense/administer, and dispense alemtuzumab (Lemtrada) for MS, respectively. [1] - Alemtuzumab (Lemtrada) is considered a disease modifying multiple sclerosis treatment. Other disease modifying multiple sclerosis treatments include interferon beta products (Avonex, Rebif, Betaseron, Extavia, or Plegridy TM ), fingolimod (Gilenya ), glatiramer acetate (Copaxone ), teriflunomide (Aubagio ), and dimethyl fumarate (Tecfidera ). [1] dru381.0 Page 3 of 9

- It has not been studied in combination with other disease-modifying MS medications and is therefore not recommended that alemtuzumab (Lemtrada) be administered concomitantly with other disease-modifying MS medications as efficacy and safety has not been established. - Alemtuzumab (Lemtrada) is approved at the dose of 12 mg/day infused intravenously for 2 treatment courses 12 months apart. The first treatment course is 5 consecutive days (60 mg total dose) and the second treatment course is 3 consecutive days (36 mg total dose), administered 12 months after the first treatment course. The safety and efficacy of alemtuzumab at doses higher than 12 mg/day, and beyond 2 treatment courses have not been adequately evaluated in the treatment of MS. [1] Clinical Efficacy MULTIPLE SCLEROSIS - Two, randomized, open-label, rater-blinded, 2-year, studies compared alemtuzumab with interferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS). [2,3] * The CARE-MS I trial included previously untreated patients while CARE-MS II trial included patients who had at least one relapse while on an interferon beta product or glatiramer acetate. * Patients randomized to the alemtuzumab arm received 2 treatment courses, 12 months apart. * The co-primary endpoints of both studies were relapse rate at 2 years and time to confirmed disease progression, both standard, clinically relevant outcomes. * In each trial, there was a statistically significantly lower annualized relapse rate for patients treated with alemtuzumab (22%-35%) compared to interferon beta-1a (40%-51%). * Treatment-experienced patients treated with alemtuzumab experienced a statistically significant reduction in the rate of disease progression compared to those treated with interferon beta 1a (13% vs 20%, p=0.008). The difference in rates of disease progression was not statistically significant among treatmentnaïve patients. - Alemtuzumab has not been directly compared to disease-modifying MS therapies other than interferon beta-1a, nor has it been studied concomitantly with other disease modifying therapies. - Alemtuzumab has not been incorporated into national MS treatment guidelines. [4] dru381.0 Page 4 of 9

- Alemtuzumab was originally reviewed by the FDA for the treatment of MS in 2013. The FDA rejected the application citing a lack of adequate and well-controlled studies. While no new clinical trials were conducted, the manufacturer submitted a re-analyses geared to address issues noted in the original review to gain the most recent FDA approval. - A high dose formulation of alemtuzumab (Campath) was approved for the treatment of B-cell chronic lymphocytic leukemia (CLL) but was removed from the market in 2012 to prevent off-label use of Campath in MS. Since 2012, Campath has been available for very limited use in CLL through patient access programs. [5] Background on Multiple Sclerosis (MS) - There are four clinical courses of multiple sclerosis (characterized in Table 1 below). - Relapsing-remitting multiple sclerosis accounts for up to 85% of cases. Table 1: Multiple Sclerosis Forms/Clinical Course Definitions [4] Relapsing-remitting Characterized by acute relapses that are followed by some degree of (RRMS) recovery; patients do not develop worsening of disability between relapses. The American Academy of Neurology (AAN) defines RRMS as the first clinical course of MS and is characterized by selflimited attacks of neurologic dysfunction. These attacks develop acutely, evolving over days to weeks. Over the next several weeks to months, most patients experience a recovery of function that is often (but not always) complete. Between attacks the patient is Secondary progressive (SPMS) Primary progressive (PPMS) Progressive relapsing (PRMS) neurologically and symptomatically stable. Defined as sustained progression of physical disability occurring separately from relapses, in patients who previously had RRMS. The AAN defines SPMS as the second clinical course which begins as RRMS, but at some point the attack rate is reduced and the course becomes characterized by a steady deterioration in function unrelated to acute attacks. Defined as progression of disability from onset without superimposed relapses. The AAN defines PPMS as the third clinical type characterized by a steady decline in function from the beginning without acute attacks. Defined as primary progressive patients who develop acute relapses well after disease onset. The AAN defines PRMS as the fourth clinical type which also begins with a progressive course although these patients also experience occasional attacks. dru381.0 Page 5 of 9

Safety Treatment with alemtuzumab (Lemtrada) can result in the formation of autoantibodies and increase the risk of serious autoimmune mediated conditions, such as immune mediated thyroid disorders (34%), immune thrombocytopenia (2%), and glomerular nephritis (0.3%). [1] - Alemtuzumab (Lemtrada) has boxed warnings for the following: Sometimes fatal autoimmune conditions, such as immune thrombocytopenia and anti-glomerular basement membrane diseases Serious and life-threatening infusion reactions An increased risk of malignancies including thyroid cancer, melanoma and lymphoproliferative disorders - Due to its significant safety concerns a FDA Risk Evaluation and Mitigation Strategy (REMS) program limits the availability of alemtuzumab (Lemtrada) to certified prescribers, healthcare facilities, and specialty pharmacies. [1] - The most common (incidence > 10% and > interferon beta-1a) adverse effects associated with alemtuzumab: rash, headache, pyrexia, nasopharyngitis, nausea, urinary tract infection, fatigue, insomnia, upper respiratory tract infection, herpes viral infection, urticarial, pruritus, thyroid gland disorders, fungal infection, arthralgia, pain in extremity, back pain, diarrhea, sinusitis, oropharyngeal pain, paresthesia, dizziness, abdominal pain, flushing, and vomiting. [1] - Patients should complete any necessary immunizations at least 6 weeks prior to treatment with alemtuzumab (Lemtrada). Prior to alemtuzumab treatment, clinicians should determine whether patients have a history of varicella or have been vaccinated for varicella zoster virus (VZV). If not, test the patient for antibodies to VZV and consider vaccination for those who are anti-body negative. Postpone treatment with Lemtrada until 6 weeks after VZV vaccination. [1] - Although this drug is administered every 12 months for two years, regular monitoring is required. Complete blood count, serum creatinine levels, urinalysis should be collected prior to treatment and at monthly intervals. Thyroid function tests should be conducted prior to treatment and every three months thereafter. Baseline and annual skin exams should be conducted to monitor for melanoma. [1] dru381.0 Page 6 of 9

Dosing and Administration - Alemtuzumab (Lemtrada) is administered as an intravenous infusion (12 mg) over two treatment courses. The first treatment course is 5 consecutive days (60 mg total dose) and the second treatment course is 3 consecutive days (36 mg total dose), administered 12 months after the first treatment course. The safety and efficacy of alemtuzumab (Lemtrada) at doses higher than 12 mg/day have not been adequately evaluated in the treatment of MS. [1] - Safety data for patients receiving more than two treatment courses is limited. One observational cohort study in 87 patients evaluated the safety of alemtuzumab over seven years. Most patients (52%) received two cycles of alemtuzumab. Three, four, and five cycles were completed in 36%, 8%, and 1% of patients who relapsed, respectively. [6] A long-term extension study of patients enrolled in a phase 2 trial evaluated the safety of alemtuzumab in 151 patients after five years, and nine patients received retreatment with alemtuzumab during that time. [7] - Patients should be premedicated with high dose corticosteroids (1,000 mg methylprednisolone or equivalent) immediately prior to alemtuzumab (Lemtrada) infusion and for the first three days of each treatment course. - Administer anti-viral prophylaxis for herpectic viral infections starting on the first day of each treatment course and continue for a minimum of two months following treatment or until the CD4+ lymphocyte count is 200 cells per microliter, whichever occurs later. [1] Alemtuzumab Use in Other Conditions The Lemtrada REMS program mitigates off-label use of Alemtuzumab (Lemtrada), however it has been studied in other conditions. Due to a lack of published data, lack of high quality data, or lack of positive data, these conditions are considered investigational. Details of select investigational uses are reported below. - B-cell chronic lymphocytic leukemia There have been no controlled clinical trials evaluating the use of low-dose (12 mg) alemtuzumab (Lemtrada) in B-cell chronic lymphocytic leukemia. [8-10] High-dose alemtuzumab (Campath) is available for patients with leukemia directly from the manufacturer, free of charge through patient access programs. - Post-transplant antibody induction therapy There are no controlled clinical trials evaluating the use of low-dose (12 mg) alemtuzumab (Lemtrada) in the post-transplant setting. [11,12] dru381.0 Page 7 of 9

Appendix A: Disease-Modifying Agents Used in the Treatment of Multiple Sclerosis (MS) dimethyl fumarate (Tecfidera ) fingolimod (Gilenya ) glatiramer acetate (Copaxone ) interferon beta-1a (Avonex, Rebif, Plegridy TM ) interferon beta-1b (Betaseron, Extavia ) mitoxantrone (Novantrone ) natalizumab (Tysabri ) teriflunomide (Aubagio ) References Aubagio, teriflunomide, RegenceRx Medication Policy Manual, Policy No. 283 Betaseron /Extavia, interferon beta-1b, RegenceRx Medication Manual, Policy No. 108 Gilenya, fingolimod, RegenceRx Medication Manual, Policy No. 229 Plegridy TM, interferon beta-1a, RegenceRx Medication Policy Manual, Policy No. 376 Tysabri, natalizumab, RegenceRx Medication Manual, Policy No. 111 Codes Number Description HCPCS J2323 Injection, natalizumab, 1 mg HCPCS J3590 Unclassified Biologics dru381.0 Page 8 of 9

References 1. Lemtrada TM [package insert]. Genzyme; November 2014 2. Cohen, JA, Coles, AJ, Arnold, DL, et al. Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1819-28. PMID: 23122652 3. Coles, AJ, Twyman, CL, Arnold, DL, et al. Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy: a randomised controlled phase 3 trial. Lancet. 2012 Nov 24;380(9856):1829-39. PMID: 23122650 4. Goodin, DS, Frohman, EM, Garmany, GP, Jr., et al. Disease modifying therapies in multiple sclerosis: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology and the MS Council for Clinical Practice Guidelines. Neurology. 2002 Jan 22;58(2):169-78. PMID: 11805241 5. Sanofi withdraws Campath from US, European markets in anticipation of Lemtrada launch. [cited 11/25/2014]; Available from: http://www.firstwordpharma.com/node/1012051#axzz3k1r6zdde 6. Tuohy, O, Costelloe, L, Hill-Cawthorne, G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. Journal of neurology, neurosurgery, and psychiatry. 2014 May 21. PMID: 24849515 7. Deisenhammer, F, Hegen, H. Alemtuzumab more effective than interferon beta-1a at 5-year follow-up of CAMMS223 clinical trial. Neurology. 2012 Sep 4;79(10):1071-2. PMID: 22946117 8. Geisler, CH, van T' Veer, MB, Jurlander, J, et al. Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood. 2014 May 22;123(21):3255-62. PMID: 24735962 9. Hillmen, P, Skotnicki, AB, Robak, T, et al. Alemtuzumab compared with chlorambucil as firstline therapy for chronic lymphocytic leukemia. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2007 Dec 10;25(35):5616-23. PMID: 17984186 10. Wendtner, CM, Ritgen, M, Schweighofer, CD, et al. Consolidation with alemtuzumab in patients with chronic lymphocytic leukemia (CLL) in first remission--experience on safety and efficacy within a randomized multicenter phase III trial of the German CLL Study Group (GCLLSG). Leukemia. 2004 Jun;18(6):1093-101. PMID: 15071604 11. Farney, AC, Doares, W, Rogers, J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009 Sep 27;88(6):810-9. PMID: 19920781 12. Hanaway, MJ, Woodle, ES, Mulgaonkar, S, et al. Alemtuzumab induction in renal transplantation. The New England journal of medicine. 2011 May 19;364(20):1909-19. PMID: 21591943 dru381.0 Page 9 of 9