Description
Ocrelizumab is an immune-suppressing humanized monoclonal antibody designed to target CD20 B-cell surface antigens. Ocrelizumab binds to CD20 which triggers cell lysis and has been used to treat individuals diagnosed with forms of multiple sclerosis (MS). Ocrelizumab's efficacy is thought to lie in its potential ability to preserve B-cell reconstitution and long-term immune memory.

Policy
Ocrelizumab is considered MEDICALLY NECESSARY for the treatment of primary progressive multiple sclerosis (PPMS) in individuals 18 years of age or older who have been diagnosed with PPMS in accordance with the McDonald Criteria.

Ocrelizumab is considered MEDICALLY NECESSARY for the treatment of relapsing multiple sclerosis (RMS) in individuals 18 years of age or older who have been diagnosed with RMS in accordance with the McDonald Criteria.

Continuation of Ocrelizumab is considered MEDICALLY NECESSARY when the member experienced disease improvement or slowing of disease progression (for example, decrease in number of relapses, improvement or no decline in Kurtzke Expanded Disability Status Scale (EDSS) or in MRI findings) since starting therapy.

Ocrelizumab is considered NOT MEDICALLY NECESSARY as a treatment for RMS or PPMS when either of the following contraindications is present:

1. Diagnosis of active hepatitis B virus infection
2. A history of life-threatening infusion reaction to ocrelizumab

Ocrelizumab is considered investigational/unproven therefore is NOT MEDICALLY NECESSARY as a treatment for RMS or PPMS when the criteria above are not met and for all other indications, including but not limited to treatment for secondary progressive multiple sclerosis.

Policy Guidelines/Dosing
Administer OCREVUS under the close supervision of an experienced healthcare professional with access to appropriate medical support to manage severe reactions such as serious infusion reactions.

• 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
• Observe the patient for at least one hour after the completion of the infusion

Recommended Dose, Infusion Rate, and Infusion Duration for RMS and PPMS

¹Solutions of OCREVUS for intravenous infusion are prepared by dilution of the drug product into an infusion bag containing 0.9 percent Sodium Chloride Injection, to a final drug concentration of approximately 1.2 mg/mL.
²Administer the first subsequent dose six months after infusion 1 of the initial dose.
³Infusion time may take longer if the infusion is interrupted or slowed.

If a planned infusion of OCREVUS is missed, administer OCREVUS as soon as possible; do not wait until the next scheduled dose. Reset the dose schedule to administer the next sequential dose 6 months after the missed dose is administered. Doses of OCREVUS must be separated by at least 5 months.

Dose modifications in response to infusion reactions depends on the severity.

Life-Threatening Infusion Reactions

Immediately stop and permanently discontinue OCREVUS if there are signs of a life-threatening or disabling infusion reaction. Provide appropriate supportive treatment.

Severe Infusion Reactions

Immediately interrupt the infusion and administer appropriate supportive treatment, as necessary. Restart the infusion only after all symptoms have resolved. When restarting, begin at half of the infusion rate at the time of onset of the infusion reaction. If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose.

Mild to Moderate Infusion Reactions

Reduce the infusion rate to half the rate at the onset of the infusion reaction and maintain the reduced rate for at least 30 minutes. If this rate is tolerated, increase the rate as described in Table 1. This change in rate will increase the total duration of the infusion but not the total dose.

Rationale
On March 28, 2017, ocrelizumab received Food and Drug Administration (FDA) approval as a therapy for individuals with primary progressive and relapsing forms of multiple sclerosis (FDA Product Information [PI] Label, 2017). The FDA approval of ocrelizumab for relapsing MS (RMS) was based on two identically designed Phase III double-blind, double-dummy randomized controlled trials, OPERA I and II. Approval for primary progressive MS (PPMS) was based on a randomized, double-blind, placebo-control Phase III clinical trial, ORATORIO.

In the OPERA I and II trials, 1,656 study participants (18 – 55 years of age) were randomized 1:1 to receive ocrelizumab or interferon Beta-1a (IFNβ-1a) via intravenous (IV) infusion every 6 months. Placebo injections matching subcutaneous IFN β-1a were given 3 times per week in the ocrelizumab arm and IV infusions matching ocrelizumab were administered every 6 months in the IFN β-1a arm. Notable inclusion criteria included diagnosis of MS according to the revised McDonald criteria (Polman, 2011), at least two documented clinical attacks within the last 2 years prior to screening or one clinical attack in the year prior to screening (but not within the most recent 30 days), neurologic stability for at least the past 30 days at baseline and expanded disability status scale (EDSS) score of 0 – 5.5. Exclusion criteria included diagnosed with PPMS, EDSS score of < 2.1 with a disease duration over 10 years, immunosuppression, and active infection. The primary endpoint in the studies was the annualized relapse rate at week 96 (2 years). Secondary endpoints included confirmed disability progression (CDP) at weeks 12 and 24 and the number of new or enhancing T1 and T2 lesions as seen on MRI at weeks 24, 48 and 96. Over 85% of those enrolled in the ocrelizumab arm completed the studies. Only 82.7% of interferon β-1a subjects in OPERA I and 76.6% of subjects in OPERA II completed their course of treatment. The superior efficacy of ocrelizumab in reducing the annualized relapse rate and disability progression was demonstrated and sustained compared to standard of care IFNβ-1a at week 96. In both OPERA I and II, the annualized relapse rate was 16% compared to 29% in the subjects treated with IFNβ-1a (absolute risk reduction 13%, number needed to treat 8, 46% relative risk reduction; p < 0.001). The secondary endpoint of a reduction in CDP was also met at week 24 (Hazard Ratio (HR) = 0.60, p = 0.003). Additionally, the secondary endpoints of a reduction in T1 Gd+ lesions and new/enlarging T2 lesions were also significantly reduced in ocrelizumab arms (p < 0.0001). There was no significant difference detected in the quality of life between the two arms. The most common adverse event (AE) associated with ocrelizumab was infusion-related reactions (0.01% were life-threatening and 1.3% withdrew during the first infusion). During the studies, 3 deaths occurred, 2 in the IFN β-1a arm (due to suicide and mechanical ileus) and 1 in the ocrelizumab arm (due to suicide). A total of 6 malignant neoplasms were reported (2 in the IFN β-1a arm (0.2%) and 4 [1.3%] in the ocrelizumab arm). Overall, in OPERA I and OPERA II, ocrelizumab had a similar safety profile compared with IFN β-1a over 96 weeks (Hauser, 2016). Caution is urged in the use of ocrelizumab due to higher than expected risks of herpes reactivation and cancers. Additional phase IV trials and community surveillance is warranted to further characterize risks associated with ocrelizumab administration as a treatment for MS.

ORATORIO evaluated the efficacy and safety of ocrelizumab (n = 488; 600 mg administered via IV infusion every 6 months) compared to placebo (n = 244) in 732 individuals (18 – 55 years of age) diagnosed with PPMS who were randomized 2:1. The primary outcome of interest was time to onset of sustained disability progression, defined as an increase in EDSS score that is sustained for at least 12 weeks. Secondary outcomes included interim analysis of the primary outcome at 24 weeks, change in 25-foot walk test from baseline to 120 weeks, and change in volume of T2 brain lesions on MRI. Inclusion criteria included a diagnosis of PPMS as defined by the McDonald Criteria (Polman, 2011) and EDSS score of 3 to 6.5. Those with a history of relapsing forms of MS or secondary progressive MS (SPMS) were excluded as were those with other neurologic disorders, active infection, previous treatment with B-cell targeted therapies (for example, rituximab, ocrelizumab or ofatumumab) or lymphocyte trafficking blockers (for example, alemtuzumab, methotrexate or cyclophosphamide) and comorbidities that may require chronic immunosuppressive therapy. The study's primary endpoint was met. A total of 32.9% of subjects in the ocrelizumab arm experienced disability progression lasting 12 weeks or longer compared to 39.3% of subjects in the placebo arm (absolute risk reduction, 6.4%; number needed to treat, 16; HR = 0.76, 95% Confidence Interval [CI], 0.59 – 0.98; p = 0.03). A total of 29.6% of ocrelizumab subjects experienced disability lasting 24 weeks or longer compared to 35.7% of the subjects receiving placebo injections (absolute risk reduction 6.1%, NNT = 17, HR = 0.75, 95% CI, 0.58 – 0.98; p = 0.04). At week 120, 402 individuals (82%) in the ocrelizumab group and 174 individuals (71%) in the placebo group were available for analysis. There was a statistically significant reduction in the progression rate of 25-foot walk time from baseline to week 120 (55.1% change from baseline in placebo and 38.9% change from baseline in the ocrelizumab arm, absolute risk reduction 16.2%, relative risk reduction = 29.3% [95% CI, -1.6 to 51.5), p = 0.04). The secondary endpoints of reduction in T2 brain lesion volume (mean percent change -3.4 vs +7.4; p < 0.0001) as well as the rate of whole brain volume loss (-0.90 vs. -1.09; p = 0.02) also favored ocrelizumab over placebo at week 120. The mean treatment duration was approximately 3 years, during which time the proportion of study participants experiencing AEs and serious AEs associated with ocrelizumab, was similar to placebo. The most serious events were mild-to-moderate infusion-related reactions. A notable potential safety concern was that 2.3% of the ocrelizumab arm (n = 11; 4 breast cancer, 3 basal cell carcinoma, and 1 each of endometrial adenocarcinoma, anaplastic large cell lymphoma, malignant fibrous histiocytoma, and pancreatic carcinoma) were diagnosed with a malignant neoplasm while only 0.8% (n = 2) of the placebo arm were diagnosed with a malignant neoplasm. The differential development of neoplasms is also continuing to be investigated in individuals with PPMS (Montalban, 2016).

Ocrelizumab has not been studied in individuals diagnosed with secondary progressive multiple sclerosis (SPMS).

According to the National Institute of Neurological Disorders and Stroke (NINDS, 2016), there are currently 250,000 to 350,000 people in the U.S. diagnosed with MS. This estimate includes approximately 200 new cases diagnosed every week. Studies of the prevalence of individuals with MS indicate that the rate of the disease has increased steadily during the twentieth century.

MS is an autoimmune disease of the central nervous system (CNS). During the MS disease process, inflammation of nervous tissue causes the loss of myelin, a fatty material that acts as a protective insulation for the nerve fibers in the brain and spinal cord. This demyelination leaves multiple areas of hard scarred tissue (plaques) along the covering of the nerve cells. Another characteristic of MS is the destruction of axons, which are the long filaments that carry electric impulses away from a nerve cell. The demyelination and axon destruction disrupts the ability of the nerves to conduct electrical impulses to and from the brain, and produces the various symptoms. Common symptoms of the disease include fatigue, numbness, coordination and balance problems, bowel and bladder dysfunction, emotional and cognitive changes, spasticity, vision problems, dizziness, sexual dysfunction, and pain. Classifications of MS are RRMS, PPMS, progressive relapsing (PRMS), and SPMS. Most individuals with MS have a relapsing course and their first attack may present as a clinically isolated syndrome (CIS). A CIS is a single demyelinating episode with consistent MRI findings (indicating inflammation/demyelination in one or more sites in the CNS). Individuals with this syndrome are at high risk for developing clinically definite MS.

Approximately 85% of individuals diagnosed with MS start with a relapsing course, which is known as RRMS. The majority of individuals whose disease first presents as RRMS, will eventually develop progressive symptoms without remissions, known as SPMS. The average length of time from initial diagnosis to development of a progressive disease course is 20 years. Approximately 15% of MS presents with a progressive disease course from the first onset of illness, this is known as PPMS.

Diagnostic criteria for MS have evolved in recent years. Although the diagnosis can be made on clinical grounds alone, MRI of the CNS can support, supplement, or even replace some clinical criteria (Polman, 2011). The McDonald Criteria, a tool for the diagnosis of MS, was updated in 2010 by the International Panel on Diagnosis of MS (The Panel). The Panel stressed that the McDonald Criteria should only be applied in those individuals who present with a typical CIS suggestive of MS or symptoms consistent with a CNS inflammatory demyelinating disease. This is because the development and validation of the criteria was limited to individuals with such a presentation. The 2010 McDonald Criteria include clinical presentations as well as additional data needed for MS diagnosis, such as MRI findings for demonstration of dissemination of CNS lesions in space and time. The 2010 revision of the MacDonald Criteria provides guidance to distinguish Acute Disseminated Encephalomyelitis (ADEM) from MS in children. It also recommends testing for AQP4 antibodies to distinguish Neuromyelitis Optica (NMO) from MS in Asian and Latin Americans.

The treatment of MS varies depending upon individual disease characteristics. RRMS is the most common type and is characterized by clearly defined exacerbations followed by periods of remission. There is no disease progression during the periods between disease relapses. RRMS is generally associated with a better prognosis than progressive disease courses. Certain immunomodulatory agents, including interferon beta preparations, glatiramer acetate, natalizumab, fingolimod, dimethyl fumarate, alemtuzumab, daclizumab and teriflunomide, have shown beneficial effects for individuals with RRMS, including a decreased relapse rate and a slower accumulation of brain lesions on MRI.

The progressive forms of MS (SPMS and PPMS) are more difficult to treat than RRMS. Many of the same agents used in RRMS provide temporary benefit for those with progressive disease, but their long-term use is often limited by serious and sometimes worsening side-effects. Many of these drugs have failed to show lasting benefit in clinical trials and there are few clinical trials that have observed outcomes beyond 2 or 3 years. Ocrelizumab is the first FDA-approved pharmacologic therapy for PPMS.

Summary of 2017 McDonald Criteria for the Diagnosis of MS

DIT = Dissemination in time       CNS = central nervous system    CSF = cerebrospinal fluid
DIS = Dissemination in space    T2 lesion = hyperintense lesion on T2-weighted MRI

References 

1. Harigai , Tanaka Y, Maisawa S; JA21963 Study Group. Safety and efficacy of various dosages of ocrelizumab in Japanese patients with rheumatoid arthritis with an inadequate response to methotrexate therapy: a placebo-controlled double-blind parallel-group study.J Rheumatol. 2012; 39(3):486-495.
2. Hauser SL, Bar-Or A, Comi G, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017; 376(3):221-234.
3. Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779-1787.
4. Montalban X, Hauser SL, Kappos L, et al. Ocrelizumab versus placebo in primary progressive multiple Sclerosis. N Engl J Med. 2017; 376(3):209-220.
5. Morschhauser F, Marlton P, Vitolo U, Results of a phase I/II study of ocrelizumab, a fully humanized anti-CD20 mAb, in patients with relapsed/refractory follicular lymphoma. Ann Oncol. 2010; 21(9):1870-1876.
6. Mysler EF, Spindler AJ, Guzman R, et al. Efficacy and safety of ocrelizumab in active proliferative lupus nephritis: results from a randomized, double-blind, phase III study. Arthritis Rheum. 2013; 65(9):2368-2379.
7. Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011; 69(2):292-302.
8. Rigby W, Tony HP, Oelke K, et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to methotrexate: results of a forty-eight-week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthritis Rheum. 2012; 64(2):350-359.
9. Stohl W, Gomez-Reino J, Olech E, Safety and efficacy of ocrelizumab in combination with methotrexate in MTX-naive subjects with rheumatoid arthritis: the phase III FILM trial. Ann Rheum Dis. 2012; 71(8):1289-1296.
10. Tak PP, Mease PJ, Genovese MC, et al. Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight–week randomized, double-blind, placebo-controlled, parallel-group phase III trial. Arthritis Rheum. 2012; 64(2):360-370. 
11. American Academy of Neurology. Multiple Sclerosis: Practice Guidelines. March 2014 Available at: https://www.aan.com/Guidelines/Home/ByTopic?topicId=18 . Accessed March 28, 2017.
12. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis: Hope Through Research. Last Updated November 19, 2015. Available at: http://www.ninds.nih.gov/disorders/multiple_sclerosis/detail_multiple_sclerosis.htm. Accessed on March 28, 2017.
13. National Institute of Neurological Disorders and Stroke (NINDS). Multiple Sclerosis Information Page. Last Updated on November 19, 2015. Available at: http://www.ninds.nih.gov/disorders/multiple_sclerosis/multiple_sclerosis.htm. Accessed on March 28, 2017.
14. National Multiple Sclerosis Society. What is MS? Available at: http://www.nationalmssociety.org/about-multiple-sclerosis/index.aspx. Accessed March 28, 2017.
15. Tarver, M. Kurtzke Expanded Disability Status Scale (EDSS). Department of Veterans Affairs: Multiple Sclerosis Centers for Excellence. Last Updated on July 2015. Available at: http://www.va.gov/MS/Professionals/Diagnosis/Kurtzke_Expanded_Disability_Status_Scale.asp. Accessed on March 28, 2017.  

Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

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