Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Ocrelizumab (Ocrevus™)

Policy #:08.01.38b

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's contract.

MEDICALLY NECESSARY

Ocrelizumab (Ocrevus) is considered medically necessary and, therefore, covered for the treatment of either relapsing forms of multiple sclerosis (RMS) or primary progressive forms of multiple sclerosis (PPMS) when the individual has negative results for hepatitis B surface antigen (HBsAG) and anti-hepatitis B virus tests.

EXPERIMENTAL/INVESTIGATIONAL

All other uses for ocrelizumab (Ocrevus) are considered experimental/investigational and, therefore, not covered unless the indication is supported as an accepted off-label use, as defined in the Company medical policy on off-label coverage for prescription drugs and biologics.

REQUIRED DOCUMENTATION

The individual's medical record must reflect the medical necessity for the care provided. These medical records may include, but are not limited to: records from the professional provider's office, hospital, nursing home, home health agencies, therapies, and test reports.

The Company may conduct reviews and audits of services to our members, regardless of the participation status of the provider. All documentation is to be available to the Company upon request. Failure to produce the requested information may result in a denial for the drug.

BILLING REQUIREMENTS

If there is no specific HCPCS code available for the drug administered, then the drug must be reported with the most appropriate unlisted code along with the corresponding National Drug Code (NDC).
Guidelines

The dosing of ocrelizumab (Ocrevus) for relapsing or primary progressive forms of multiple sclerosis is as follows:
  • Initial dose: 300 mg intravenous infusion, followed two weeks later by a second 300 mg intravenous infusion.
  • Subsequent doses: single 600 mg intravenous infusion every 6 months.

HEPATITIS B SEROLOGIC MARKER DEFINITIONS

According to the CDC:
  • Hepatitis B surface antigen (HBsAg): The presence of HBsAg, a protein on the surface of HBV, indicates that the person is infectious. It can be detected in high levels in serum during acute or chronic HBV infection. The body normally produces antibodies to HBsAg as part of the normal immune response to infection. HBsAg is the antigen used to make hepatitis B vaccine.
  • Hepatitis B surface antibody (anti-HBs): The presence of anti-HBs is generally interpreted as indicating recovery and immunity from HBV infection. Anti-HBs also develops in a person who has been successfully vaccinated against hepatitis B.

MCDONALD CRITERIA

The 2005 and 2010 revisions of the Diagnostic Criteria for Multiple Sclerosis (MS) are used by professional providers to determine a definitive diagnosis of MS. In order to exclude alternative diagnoses, these criteria utilize factors, such as the number of clinical attacks and the dissemination of lesions in space (DIS) and time (DIT) through magnetic resonance imaging (MRI).

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, ocrelizumab (Ocrevus) is covered under the medical benefits of the Company’s products when the medical necessity criteria listed in this medical policy are met.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

Ocrelizumab (Ocrevus) was approved by the FDA on March 28, 2017 for the treatment of adults with relapsing or primary progressive forms of multiple sclerosis.

PEDIATRIC USE

The safety and effectiveness of ocrelizumab (Ocrevus) in the pediatric population have not been established.

Description

MULTIPLE SCLEROSIS (MS) BACKGROUND

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) where the immune system attacks nerve fibers (called axons) and the protective coating that surrounds them (called myelin sheath). Myelin that has been damaged forms scar tissue called sclerosis or plaques that can been seen with an MRI scan of the brain in individuals with MS. The myelin sheath sends nerve impulses throughout the CNS; once damaged, communication between the nerve impulses and the targeted area of the body are distorted or interrupted, producing a variety of symptoms. Symptoms of MS vary between individuals; even in those who relapse, symptoms may differ with each episode. Examples of common symptoms include: motor weakness, limb ataxia, gait or balance problems, vertigo, bladder/bowel dysfunction, sensory loss, heat intolerance, fatigue, visual and cognitive impairment, depression, and pain. There are many hypotheses as to the causes of MS, including those with a basis of infection, genetics, immunological, and environmental, however, the causes of MS have not been established. It is estimated that 250,000 to 400,000 individuals in the United States and 2.5 million individuals worldwide are affected by MS.

TYPES OF MULTIPLE SCLEROSIS (MS) AND THEIR TREATMENTS

There is currently no cure for MS. Medications can be used to treat acute relapses (e.g., corticosteroids), slow the progression of the disease and reduce the number and severity of relapses (e.g., MS disease-modifying therapies), and improve symptoms that occur, such as fatigue, pain, depression.

The three major types of MS include:
  • Relapsing-remitting MS (RRMS): RRMS is the most common form of MS, accounting for approximately 85% of all MS cases. It is characterized by recurrent attacks to the nervous system, followed by complete recovery or partial recovery where some symptoms become permanent. There is no or minimal disease progression during remission.
    • Treatment of RRMS progression may consist of the following medications: MS disease-modifying therapies (e.g., ocrelizumab [Ocrevus], alemtuzumab [Lemtrada™], daclizumab [Zinbryta], natalizumab [Tysabri®], interferon beta-1a [Avonex®, Rebif®], interferon beta-1b [Betaseron®], glatiramer acetate [Copaxone®], dimethyl fumarate [Tecfidera®], teriflunomide [Aubagio®], or fingolimod [Gilenya®]), intravenous immunoglobulin (IVIG), or mitoxantrone.
    • Some individuals may respond to the following treatments, however randomized controlled trials have failed to show consistent benefit for the treatment of RRMS: azathioprine, mitoxantrone, stem cell transplantations. The results of a Cochrane review in 2013 suggested an unfavorable risk-benefit balance for the following drugs: interferon beta-1a [Avonex®], IVIG, cyclophosphamide, and long-term steroids. The Cochrane review also noted the paucity of high-quality data regarding the use of azathioprine. (Filippini 2013).
  • Primary progressive MS (PPMS): PPMS represents about 10-15% of all MS cases. It is characterized by gradual disease progression from symptom onset. There are periods of active disease, occasional plateaus, and temporary minor improvement of symptoms, but there are no distinct relapses or remissions.
    • Ocrelizumab (Ocrevus) is the first and only drug that is US Food and Drug Administration (FDA)-approved for the treatment of PPSM. Prior to ocrelizumab's (Ocrevus) approval, other treatments of PPMS progression have consisted of I.V. monthly glucocorticoid pulses, methotrexate, cladribine, intravenous immunoglobulin (IVIG), or mitoxantrone.
    • Some individuals may respond to the following treatments, however randomized controlled trials have failed to show consistent benefit for the treatment of PPMS: azathioprine, cladribine, I.V. monthly glucocorticoid pulses, I.V. cyclophosphamide, cyclosporine, MS disease-modifying therapies (e.g., glatiramer acetate [Copaxone®], fingolimod [Gilenya®]), IVIG, methotrexate, mitoxantrone, rituximab (Rituxan®), stem cell transplantations. The results of a Cochrane review in 2013 showed paucity of high-quality data for the following drugs, since they were ineffective in preventing disability progression over two to three years: interferon beta-1a [Avonex®, Rebif®], interferon beta-1b [Betaseron®], glatiramer acetate [Copaxone®]), mitoxantrone, methotrexate, cyclophosphamide, IVIG, and long-term corticosteroids. (Filippini 2013).
  • Secondary progressive MS (SPMS): SPMS initially presents as RRMS, but later transitions to a condition similar to PPMS. It is a progressive disease that may or may not have relapses. It is estimated that 80% of all individuals with RRMS will develop this type of MS.
    • Treatments for SPSM may consist of the following: MS disease-modifying therapies (e.g., interferons), mitoxantrone, intravenous monthly glucocorticoid pulses, intravenous cyclophosphamide, or methotrexate.
    • Ocrelizumab [Ocrevus] was studied in individuals with relapsing disease who were later diagnosed retrospectively as having SPMS.
    • Some individual may respond to the following treatments, however randomized controlled trials have failed to show consistent benefit for the treatment of PPMS: azathioprine, cladribine, intravenous monthly glucocorticoid pulses, intravenous cyclophosphamide, cyclosporine, interferons, intravenous immunoglobulin, methotrexate, mitoxantrone, stem cell transplantation.

In addition to the major types of MS listed above, all types of MS can further be characterized into the following stages of disease:
  • active disease: i.e., whether there are relapses or MRI changes
  • not active disease: i.e., showing no evidence of disease activity
  • disease worsening, or with progression: e.g., increased disability over a specific time period, with or without relapses; or objective measure of disease worsening over a specific time period, with or without relapses
  • non-worsening or stable or without progression: e.g., no evidence of disease worsening or increased disability over a specific time period

OCRELIZUMAB (OCREVUS)
Ocrelizumab (Ocrevus) was approved by the US Food and Drug Administration (FDA) on March 28, 2017 for the treatment of adults with relapsing or primary progressive forms of multiple sclerosis. Ocrelizumab (Ocrevus) is the first drug that was FDA-approved for the treatment of primary progressive multiple sclerosis (PPMS).Ocrelizumab (Ocrevus™) is a recombinant humanized monoclonal antibody that selectively targets CD20, a cell surface antigen expressed on only certain B-cells (pre-B, mature B, and memory B-cells, but not lymphoid stem cells and plasma cells). Following cell surface binding to B lymphocytes, ocrelizumab (Ocrevus™) is thought to cause apoptosis, antibody-dependent cellular cytolysis (cell membrane destruction), and complement-mediated lysis involving macrophages, natural killer cells, etc. to cause cell destruction. The specificity for targeting only certain B-cells allows the immune function to remain intact, since the levels of IgG and IgM are not diminished.

Peer-reviewed Literature
Summary

Primary Progressive Multiple Sclerosis (PPMS)
Montalban et al 2017 performed the ORATORIO trial, a Phase 3, randomized (2:1), double-blind, placebo-controlled trial that investigated the safety and effectiveness of ocrelizumab (Ocrevus) in the treatment of PPMS. Seven hundred thirty-two participants were diagnosed with PPMS per 2005 revised McDonald criteria and had a score on the Expanded Disability Status Scale (EDSS) of 3-6.5 at screening (range 0-10, where higher scores indicate greater disability). Approximately 88% of participants had not received a previous disease-modifying therapy for MS. Participants received ocrelizumab (Ocrevus) 600 mg (N=488) or placebo (N=244) every 24 weeks for at least 120 weeks. The primary endpoint of the study was the percentage of patients with disability progression confirmed at 12 weeks in a time-to-event analysis where disability progression was defined as an increase in EDSS of at least 1 point from baseline if baseline was 5.5 or less, or an increase of 0.5 if baseline was more than 5.5. Disability progression at 12-weeks was confirmed in 32.9% of those in the ocrelizumab (Ocrevus) group and 39.3% in the placebo group, which was statistically significant. The adverse event that was most frequently reported was infusion-related reactions: 39.9% in the ocrelizumab (Ocrevus) group and 25.5% in the placebo group. There was an increase incidence of neoplasms in the ocrelizumab (Ocrevus) group 2.3% compared to those in the placebo group 0.8%. No cases of progressive multifocal leukoencephalopathy (PML) have been reported during clinical studies. The authors reported that further evaluation of the occurrence of neoplasms and PML risk is warranted.

Relapsing Multiple Sclerosis (RMS)
Hauser et al 2017 investigated the safety and effectiveness of ocrelizumab (Ocrevus) in the treatment of relapsing multiple sclerosis (RMS) in the OPERA I (N=821) and OPERA II (N=835) studies, which are identical, Phase 3, randomized (1:1) trials. Eligibility included a diagnosed of RMS per 2010 revised McDonald criteria, a score on the Expanded Disability Status Scale (EDSS) of 0-5.5 at screening (range 0-10, where higher scores indicate greater disability), and at least two documented clinical relapses within the previous two years or one clinical relapse within the year before screening. Approximately 73% of participants had not received a previous disease-modifying therapy for MS. Participants received ocrelizumab (Ocrevus) 600 mg every 24 weeks and placebo subcutaneous injection three times weekly or subcutaneous interferon beta-1a 44mcg three times weekly and placebo intravenous infusion every 24 weeks for 96 weeks. The primary endpoint was the annualized relapse rate by 96 weeks. Ocrelizumab (Ocrevus) significantly decreased the annualized relapse rate at week 96 as follows: Trial 1 (0.16 vs 0.29; 46% lower rate in the ocrelizumab (Ocrevus) group and Trial 2 (0.16 vs 0.29; 47% lower rate in the ocrelizumab (Ocrevus) group. Infusions reactions occurred more frequently in the ocrelizumab (Ocrevus) group (34.3%) compared to the interferon beta-1a group who received placebo IV infusions (9.7%). There was an increase incidence of neoplasms in the ocrelizumab (Ocrevus) group 0.5% compared to those in the placebo group 0.2%; during the open-label extension study where all participants received ocrelizumab (Ocrevus), 5 more cases of neoplasm occurred. No cases of progressive multifocal leukoencephalopathy (PML) have been reported during clinical studies. The authors reported that further evaluation of the occurrence of neoplasms and PML risk is warranted.

OFF-LABEL INDICATIONS

There may be additional indications contained in the Policy section of this document due to evaluation of criteria highlighted in the Company’s off-label policy, and/or review of clinical guidelines issued by leading professional organizations and government entities.
References


American Hospital Formulary Service (AHFS). Drug Information 2018. ocrelizumab. [Lexicomp Online Web site]. 12/04/2017. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed June 1, 2018.

Centers for Disease Control and Prevention (CDC). Hepatitis B FAQs for Health Professionals. 05/07/18. Available at: https://www.cdc.gov/hepatitis/hbv/hbvfaq.htm . Accessed June 1, 2018.

Elsevier’s Clinical Pharmacology Compendium. ocrelizumab (Ocrevus™). 03/31/2017. [Clinical Key Web site]. Available at: https://www.clinicalkey.com/pharmacology/ [via subscription only]. Accessed June 1, 2018.

Filippini G, Del Giovane C, Vacchi L, D'Amico R, Di Pietrantonj C, Beecher D, Salanti G. Immunomodulators and immunosuppressants for multiple sclerosis: a network meta-analysis. Cochrane Database Syst Rev. 2013 Jun 6;(6):CD008933.

Hauser SL, Bar-Or A, Comi G, et al; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):221-234.

Krieger SC, Cook K, De Nino S, Fletcher M. The topographical model of multiple sclerosis: A dynamic visualization of disease course. Neurol Neuroimmunol Neuroinflamm. 2016 Sep 7;3(5):e279.

Lexi-Drugs Compendium. ocrelizumab (Ocrevus). 04/28/2018. [Lexicomp Online Web site]. Available at: http://online.lexi.com/lco/action/home [via subscription only]. Accessed June 1, 2018.

Luzzio C. Multiple sclerosis: Overview. 03/28/2018. [Medscape Web Site]. Available at: http://emedicine.medscape.com/article/1146199-overview . Accessed June 1, 2018.

Montalban X, Hauser SL, Kappos L, et al; ORATORIO Clinical Investigators. Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220.

National Institute of Neurological Disorders and Stroke. Multiple sclerosis: Hope through research. Published 06/2012. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research#3215_23 . Accessed June 1, 2018.

National Multiple Sclerosis Society. Definition of MS; What causes MS; Types of MS. Available at: http://www.nationalmssociety.org/What-is-MS/Definition-of-MS and http://www.nationalmssociety.org/What-is-MS/What-Causes-MS and http://www.nationalmssociety.org/What-is-MS/Types-of-MS . Accessed June 1, 2018.

National Organization for Rare Disorders (NORD). Multiple Sclerosis. 2017. Available at: https://rarediseases.org/rare-diseases/multiple-sclerosis/ . Accessed June 1, 2018.

Ocrevus. package insert. 03/2017. Genentech USA; South San Francisco, CA. Available at: https://www.ocrevus.com/hcp.html . Accessed June 1, 2018.

Olek MJ. Disease-modifying treatment of relapsing-remitting multiple sclerosis in adults. [UpToDate Web Site]. last updated: 04/12/1. Available at: https://www.uptodate.com/contents/disease-modifying-treatment-of-relapsing-remitting-multiple-sclerosis-in-adults?source=search_result&search=ocrelizumab&selectedTitle=1~5 [via subscription only]. Accessed June 1, 2018.

Olek MJ. Treatment of progressive multiple sclerosis in adults. [UpToDate Web Site]. last updated: 05/16/18. Available at: https://www.uptodate.com/contents/treatment-of-progressive-multiple-sclerosis-in-adults/print?source=search_result&search=ocrelizumab&selectedTitle=2~5 [via subscription only]. Accessed June 1, 2018.

Olek MJ, Narayan RN, Frohman EM, Frohman TC. Clinical features of multiple sclerosis in adults. [UpToDate Web Site]. last updated: 04/23/18. Available at: https://www.uptodate.com/contents/clinical-features-of-multiple-sclerosis-in-adults?source=search_result&search=multiple%20sclerosis&selectedTitle=3~150 [via subscription only]. Accessed June 1, 2018.

Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol. 2005 Dec;58(6):840-6.

Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011 Feb;69(2):292-302.

Riley CS, Tullman MJ. Multiple sclerosis. In: Rowland LP, Pedley TA. Merritt's Neurology. 12th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2010: 903-915.

Sorensen PS, Blinkenberg M. The potential role for ocrelizumab in the treatment of multiple sclerosis: current evidence and future prospects. Ther Adv Neurol Disord. 2016 Jan;9(1):44-52.

Truven Health Analytics. Micromedex® DrugDex® Compendium. ocrelizumab (Ocrevus). 01/12/2018. Greenwood Village, CO. [Micromedex® Solutions Web site]. Available at: http://www.micromedexsolutions.com/micromedex2/librarian [via subscription only]. Accessed June 1, 2018.

US Food and Drug Administration (FDA). Center for Drug Evaluation and Research. Ocrelizumab (Ocrevus) prescribing information and approval letter [FDA Web site]. updated 03/2017. Available at: https://www.accessdata.fda.gov/scripts/cder/daf/ or
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/761053lbl.pdf . Accessed June 1, 2018.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

G35 Multiple sclerosis


HCPCS Level II Code Number(s)

J2350 Injection, ocrelizumab, 1 mg


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

08.01.38b
07/03/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Ocrelizumab (Ocrevus™).

Definitions of two hepatitis B serologic markers have been added to the Guidelines Section.
01/01/2018This policy has been identified for the HCPCS code update, effective 01/01/2018.

The following HCPCS code has been added to this policy:
J2350 Injection, ocrelizumab, 1 mg

The following HCPCS codes have been removed from this policy:
C9494 Injection, ocrelizumab, 1 mg
J3590 Unclassified biologics


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 01/01/2018
Version Issued Date: 12/29/2017
Version Reissued Date: 07/03/2018

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