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7Department: Pharmacy Management Original Approval: 12/24/2015 Policy #: PM118 Last Approval: 01/25/2021 Title: (Lemtrada®) Approved By: UM Pharmacy Subcommittee

Line(s) of Business WAH-IMC (HCA) BHSO Medicare Advantage (CMS) Medicare SNP (CMS) Cascade Select

REQUIRED CLINICAL DOCUMENTATION FOR REVIEW

Documentation required to determine medical necessity for Lemtrada (Alemtuzumab): History and/or physical examination notes and relevant specialty consultation notes that address the problem and need for the service: -Age -Diagnosis - Medication list (current and past) to include start and end dates of previous trials of disease-modifying agents used for MS -Prescribed by or in consultation with a neurologist or a physician that specializes in the treatment of MS -Dosing -Initial/Extended Approval - Duration of therapy.

OVERVIEW Lemtrada, a CD52-directed cytolytic monoclonal , is indicated for the treatment of patients with relapsing forms of (MS) to include relapsing remitting disease and active secondary progressive MS in adults.1 Lemtrada is not recommended for use in patients with clinically isolated syndrome because of its safety profile.

Due to its safety profile, use of Lemtrada should generally be reserved for patients who have had an inadequate response to two or more medications indicated for the treatment of MS.1 Lemtrada contains the same active ingredient found in Campath® (alemtuzumab injection for intravenous use). The safety and efficacy of Lemtrada have not been established in pediatric patients less than 17 years of age.

Disease Overview MS is a chronic, inflammatory, demyelinating, autoimmune disease of the that impacts almost 1,000,000 people in the US.2 The condition is marked by inflammation and demyelination, as well as degenerative alterations. Patients usually experience relapses and remissions in their neurological symptoms. For most patients, the onset of MS symptoms occurs when patients are 20 to 40 years of age; however, children can get MS and new onset disease can occur in older adults. The MS disease course is heterogeneous but has some patterns. Approximately 85% to 90% of patients have a relapsing pattern at onset. However, this transitions over time in patients who are untreated to a worsening with very few or no relapses or magnetic resonance imaging (MRI) activity (secondary progressive MS). Around 10% to 15% of patients have a steady progression of symptoms over time

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(primary progressive MS), marked by some clinical manifestations or by MRI activity. Primary progressive MS is generally diagnosed in patients on the upper level of the typical age range (e.g., almost 40 years of age) and the distribution is equivalent among the two genders. Advances in the understanding of the MS disease process, as well as in MRI technology, spurned updated disease course descriptions in 2013,3 as well as in 2017.4 The revised disease courses are clinically isolated syndrome, relapsing remitting MS, primary progressive MS, and secondary progressive MS.2-4 Clinically isolated syndrome is now more recognized among the course descriptions of MS. It is the first clinical presentation of MS that displays characteristics of inflammatory demyelination that may possibly be MS but has yet to fulfill diagnostic criteria.

Guidelines In September 2019, a consensus paper was updated by the MS Coalition that discusses the use of disease-modifying therapies in MS.2 Many options from various disease classes, involving different mechanisms of action and modes of administration, have shown benefits in patients with MS.

A practice guideline recommendation regarding disease-modifying agents for adults with MS from the American Academy of Neurology (2018) states to consider Lemtrada for patients with MS who have highly active disease.5

Safety Lemtrada is available only through a restricted Risk Evaluation Mitigation Strategy (REMS) program called the LEMTRADA REMS Program due to the risks of autoimmunity, infusion reactions, stroke, and malignancies.1 Use of Lemtrada is contraindicated in patients who has infection with human immunodeficiency virus and those with active infection. Progressive multifocal leukoencephalopathy has occurred in a patient with MS who received Lemtrada.

DEFINITIONS None.

INDICATIONS/CRITERIA

Medicaid Continue to criteria for approval below. Members Medicare Step-utilization of Part D drugs not required. Members

SPECIAL CONSIDERATIONS Coverage of Lemtrada is recommended in those who meet one of the following criteria:

FDA-Approved Indications

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1. Multiple Sclerosis (MS). Approve for the duration of therapy noted if the patient meets one of the following criteria (A or B): A) Initial Therapy (this includes patients who have started but not completed the first course of Lemtrada Therapy). Approve for 5 days in patients who meet all of the following criteria (i, ii, iii, and iv): i. The patient is ≥ 17 years of age; AND ii. The patient has a relapsing form of MS (include relapsing remitting disease and active secondary progressive disease.); AND iii. Lemtrada is prescribing by or in consultation with a neurologist or a physician that specializes in the treatment of multiple sclerosis; AND iv. The patient meets one of the following (a or b): a) According to the prescriber, the patient has experienced inadequate efficacy or significant intolerance two disease-modifying agents used for multiple sclerosis; OR Note: Examples include Avonex® ( beta-1a injection [intramuscular]), Rebif® (interferon beta-1a injection [subcutaneous]), Betaseron®/Extavia® (interferon beta-1b injection), injection (Copaxone®/Glatopa®, generic), Plegridy® (peginterferon beta-1a injection), Gilenya® ( capsules), Aubagio® ( tablets), Mavenclad® ( tablets), Mayzent® ( tablets), Vumerity® ( delayed-release capsules), Tysabri® ( injection for intravenous use), Bafiertam™ (monomethyl fumarate delayed-release capsules), delayed- release capsules (Tecfidera®, generic), Zeposia® ( capsules), Kesimpta® (ofatumumab injection for subcutaneous use), and Ocrevus® ( injection for intravenous use). b) According to the prescribing physician the patient has highly-active or aggressive multiple sclerosis by meeting one of the following (1, 2, 3, or 4): 1. The patient has demonstrated rapidly-advancing deterioration(s) in physical functioning (e.g., loss of mobility/or lower levels of ambulation, severe changes in strength or coordination) [documentation required]; OR 2. Disabling relapse(s) with suboptimal response to systemic corticosteroids [documentation required]; OR 3. Magnetic resonance imaging [MRI] findings suggest highly-active or aggressive multiple sclerosis (e.g., new, enlarging, or a high burden of T2 lesions or gadolinium-enhancing lesions) [documentation required]; OR 4. Manifestations of multiple sclerosis-related cognitive impairment [documentation required]; OR B) Patient Who Have Complete One Prior Course of Lemtrada therapy. Approve for 3 days in patients who meet all of the following criteria (i, ii, and iii): i. The patient is ≥ 17 years of age; AND ii. The patient has a relapsing form of MS (relapsing remitting disease and active secondary progressive disease); AND

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iii. Lemtrada is prescribed by or in consultation with a neurologist or a physician that specializes in the treatment of MS. iv. At least 12 months has elapsed from the last dose of any prior Lemtrada treatment course.

Dosing in Multiple Sclerosis (MS). Dosing must meet the following (A OR B): A) First treatment course of 12 mg/day by IV infusion on 5 consecutive days (60 mg total dose); OR B) Additional treatment course of 12 mg/day by IV infusion on 3 consecutive days (36 mg total dose) administered 12 months after the first Lemtrada treatment course.

Conditions Not Recommended for Approval Lemtrada has not been shown to be effective, or there are limited or preliminary data or potential safety concerns that are not supportive of general approval for the following conditions. Rationale for non-coverage for these specific conditions is provided below. (Note: This is not an exhaustive list of Conditions Not Recommended for Approval).

1. Concurrent Use with Other Disease-Modifying Agents Used for Multiple Sclerosis (MS).

Lemtrada should not be given in combination with other disease-modifying agents used for MS. Concomitant use of Lemtrada with immunosuppressive therapies could increase the risk of .1 Note: Examples include Avonex® (interferon beta-1a injection [intramuscular]), Rebif® (interferon beta-1a injection [subcutaneous]), Betaseron®/Extavia® (interferon beta-1b injection), glatiramer acetate injection (Copaxone®/Glatopa®, generic), Plegridy® (peginterferon beta-1a injection), Gilenya® (fingolimod capsules), Aubagio® (teriflunomide tablets), Mavenclad® (cladribine tablets), Mayzent® (siponimod tablets), Vumerity® (diroximel fumarate delayed-release capsules), Tysabri® (natalizumab injection for intravenous use), Bafiertam™ (monomethyl fumarate delayed-release capsules), dimethyl fumarate delayed-release capsules (Tecfidera®, generic), Zeposia® (ozanimod capsules), Kesimpta® (ofatumumab injection for subcutaneous use), and Ocrevus® (ocrelizumab injection for intravenous use).

2. Human Immunodeficiency Virus (HIV) Infection (Patients With). Use of Lemtrada is contraindicated in patients who are infected with HIV because Lemtrada causes prolonged reductions of CD4+ counts.1

3. Non-Relapsing Forms of Multiple Sclerosis. Note: An example of a non-relapsing form of MS is primary progressive MS. The efficacy of Lemtrada has not been established in patients with MS with non-relapsing forms of the disease.1

4. Clinically Isolated Syndrome. Lemtrada is not recommended for use in patients with clinically isolated syndrome due to its safety profile.1

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5. Coverage is not recommended for circumstances not listed in the Recommended Authorization Criteria. Criteria will be updated as new published data are available.

LIMITATIONS/EXCLUSIONS Please refer to a product line’s certificate of coverage for benefit limitations and exclusions for these services:

PRODUCT LINE LINK TO CERTIFICATE OF COVERAGE Medicare Advantage https://medicare.chpw.org/chpw-washington- state-medicare-advantage-plans/all-medicare- plans-2020/ Washington Apple Health (Medicaid) Integrated https://www.chpw.org/for-members/benefits-and- Managed Care coverage-imc/

Citations & References CFR 42 CFR § 438.210 WAC WAC 284-43-2050 RCW Contract WAH - IMC IMC section 17.3.2.1 General Citation Description of Contracted Services - Pharmacy Benefit and Services - Apple Health Preferred Drug List and Plan Formularies BHSO MA WAC 284-43-5642 - Essential health benefit Cascade Select categories Other Requirements NCQA Elements References 1. Lemtrada® injection for intravenous use [prescribing information]. Cambridge, MA: Genzyme Corporation; September 2020. 2. A Consensus Paper by the Multiple Sclerosis Coalition. The use of disease-modifying therapies in multiple sclerosis. Updated September 2019. Available at: https://www.nationalmssociety.org/NationalMSSociety/media/MSNationalFiles/Brochures/DMT_Con sensus_MS_Coalition.pdf. Accessed on November 6, 2020. 3. Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83:278-286. 4. Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.

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5. Rae-Grant A, Day GS, Marrie RA, et al. Practice guideline recommendations summary: disease- modifying therapies for adults with multiple sclerosis. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90:777-788.

Revision History Revision Date Revision Description Revision Made By 12/23/2015 New Kelly Force; Yusuf Rashid, RPh 12/24/2015 Approval MMLT 01/11/2017 No revisions Fran McGaugh 01/12/2017 Approval MMLT 07/24/2017 Criteria completely updated and revised Michael Sporck, Pharmacy Intern Sophia Yun, PharmD 07/25/2017 Approved MMLT 06/11/2018 Revised Jennifer Farley, PharmD 06/14/2018 Approval UM Committee 03/12/2019 Revised. Defined highly-active or aggressive Ivan Figueira, PharmD disease. Updated criteria such that patients with highly-active or aggressive MS need not try and fail two disease-modifying agents. 03/14/2019 Approval UM Pharmacy Subcommittee 01/24/2020 Annual review. Vumerity and glatiramer Jennifer Farley, PharmD acetate added to list of meds to trial. Clinically Isolated Syndrome was added as a Condition Not Recommended for Approval 01/31/2020 Approval UM Pharmacy Subcommittee 01/13/2021 Annual review. Bafiertam™ (monomethyl Jennifer Farley, PharmD fumarate delayed-release capsules), Zeposia® (ozanimod capsules), and Kesimpta® (ofatumumab injection for subcutaneous use) were added to list of meds to try and fail for MS and to not use concurrently with Lemtrada. 01/25/2021 Approval UM Pharmacy Subcommittee

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