MULTIPLE SCLEROSIS BACKGROUND
Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which 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 be seen with a magnetic resonance imaging (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 among 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 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 [DMTs]), and improve symptoms that occur, such as fatigue, pain, and depression.
The four major types of MS include:
- Clinical isolated syndrome (CIS) is the first episode of a neurologic event associated with inflammation and demyelination involving the CNS that lasts at least 24 hours. There is a high chance (60 percent–80 percent) of developing a secondary episode and a diagnosis of relapsing/remitting MS (RRMS) when CIS is accompanied by lesions on a brain MRI that are similar to those seen in MS. When not accompanied by MS-like lesions on a brain MRI, there is a lower chance (20 percent) of developing MS.
- Treatment of CIS may consist of the following medications:
- Ocrelizumab (Ocrevus) and
siponimod (Mayzent®) are US Food and Drug Administration (FDA)-approved for CIS; however, there is a paucity of published data for siponimod (Mayzent)
- Glatiramer acetate and interferon beta 1a (IFN-β-1a) are more effective than placebo in reducing the proportion of individuals progressing to MS (Rae-Grant et al., 2018)
- Per the authors of the systematic review, the following DMTs are probably more effective than placebo in reducing the proportion of individuals converting to MS: cladribine (safety concerns), immunoglobulins, IFN- β-1a (Avonex®, Rebif®), IFN- β-1b (Betaseron®), and teriflunomide (Aubagio®) (Rae-Grant et al., 2018).
- Relapsing-remitting MS (RRMS): RRMS is the most common form of MS, accounting for approximately 85 percent 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 (Filippini et al., 2013; Rae-Grant et al., 2018):
- MS DMTs (e.g., alemtuzumab [Lemtrada®], dimethyl fumarate [Tecfidera®], fingolimod [Gilenya®]), glatiramer acetate [Copaxone®], IFN- β-1a [Avonex, Rebif], IFN- β-1b [Betaseron], natalizumab [Tysabri®], ocrelizumab [Ocrevus], rituximab [Rituxan®], siponimod (Mayzent), teriflunomide [Aubagio].
- Azathioprine (Imuran®)
- Cladribine
- Intravenous immunoglobulin (IVIG)
- Mitoxantrone
- Stem cell transplantations
- The results of a Cochrane review and practice guideline suggested an unfavorable risk-benefit balance for the following drugs: IFN-β-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 et al., 2013; Rae-Grant et al., 2018).
- Primary progressive MS (PPMS): PPMS represents about 10 percent to 15 percent 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) was the first and only drug FDA-approved for the treatment of PPSM.
- 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, intravenous (IV) bimonthly glucocorticoid pulses, IV cyclophosphamide, MS DMTs (e.g., interferons, glatiramer acetate [Copaxone®], fingolimod [Gilenya®]), IVIG, methotrexate, mitoxantrone, rituximab (Rituxan®), stem cell transplantations. The results of a Cochrane review in 2013 showed a paucity of high-quality data for the following drugs, since they were ineffective in preventing disability progression over 2 to 3 years: IFN- β-1a [Avonex, Rebif], IFN- β-1b [Betaseron], glatiramer acetate [Copaxone®]), mitoxantrone, methotrexate, cyclophosphamide, IVIG, rituximab (Rituxan®), and long-term corticosteroids. (Filippini 2013, Rae-Grant 2018).
- 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 percent of all individuals with RRMS will develop this type of MS.
- Treatments for SPMS may consist of the following: MS DMTs (e.g., ocrelizumab [Ocrevus], siponimod [Mayzent®]), cladribine, mitoxantrone, IV bimonthly glucocorticoid pulses, or IV cyclophosphamide
- 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, IV cyclophosphamide, interferons, IVIG, methotrexate, mitoxantrone, stem cell transplantation (Rae-Grant et al., 2018)
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) AND OCRELIZUMAB AND HYALURONIDASE-OCSQ
(OCREVUS ZUNOVO)
Ocrelizumab (Ocrevus) was approved by the FDA on March 28, 2017, for the treatment of adults with relapsing or primary progressive forms of MS. Ocrelizumab (Ocrevus) was the first drug FDA-approved for the treatment of primary progressive multiple sclerosis (PPMS). On July 16, 2019, the FDA expanded the indication of relapsing forms of MS to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. Ocrelizumab (Ocrevus) is a recombinant humanized monoclonal antibody that selectively targets Cluster of Differentiation 20 (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, and so on, to cause cell destruction. The specificity for targeting only certain B cells allows the immune function to remain intact, because the levels of immunoglobulin G (IgG) and IgM are not diminished. Hyaluronidase is an endoglycosidase used to increase dispersion and absorption of coadministered drugs when administered as a subcutaneous (SC) injection.
Peer-reviewed Literature
Intravenous Administration
Primary Progressive Multiple Sclerosis
In 2017, Montalban et al. performed the ORATORIO (A Study of Ocrelizumab in Participants With Primary Progressive Multiple Sclerosis) 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. A total of 732 participants were diagnosed with PPMS per 2005 revised McDonald criteria and had a score on the Expanded Disability Status Scale (EDSS) of 3 to 6.5 at screening (range, 0–10; higher scores indicate greater disability). Approximately 88 percent of participants had not received a previous DMT 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 individuals with disability progression confirmed at 12 weeks in a time-to-event analysis in which disability progression was defined as an increase in EDSS of at least one 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 percent of those in the ocrelizumab (Ocrevus) group and 39.3 percent in the placebo group, which was statistically significant. The adverse event that was most frequently reported was infusion-related reactions: 39.9 percent in the ocrelizumab (Ocrevus) group and 25.5 percent in the placebo group. There was an increased incidence of neoplasms in the ocrelizumab (Ocrevus) group (2.3 percent) compared to those in the placebo group (0.8 percent). 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
Hauser et al. in 2017 investigated the safety and effectiveness of ocrelizumab (Ocrevus) in the treatment of RMS in the OPERA I (A Study of Ocrelizumab in Comparison With Interferon Beta-1a [Rebif] in Participants With Relapsing Multiple Sclerosis) (N=821) and OPERA II (N=835) studies, which are identical, Phase 3, randomized (1:1) trials. Eligibility included a diagnosis of RMS per 2010 revised McDonald criteria, a score on the Expanded Disability Status Scale (EDSS) of 0 to 5.5 at screening (range, 0–10, in which higher scores indicate greater disability), and at least two documented clinical relapses within the previous 2 years or one clinical relapse within the year before screening. Approximately 73 percent of participants had not received a previous DMT for MS. Participants received ocrelizumab (Ocrevus) 600 mg every 24 weeks and placebo subcutaneous injection three times weekly or subcutaneous IFN-β-1a 44 mcg three times weekly and placebo IV 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 percent lower rate in the ocrelizumab (Ocrevus) group and Trial 2 (0.16 vs 0.29; 47 percent lower rate in the ocrelizumab (Ocrevus) group. Infusion reactions occurred more frequently in the ocrelizumab (Ocrevus) group (34.3 percent) compared to the IFN- β-1a group that received placebo IV infusions (9.7 percent). There was an increase incidence of neoplasms in the ocrelizumab (Ocrevus) group (0.5 percent) compared to those in the placebo group (0.2 percent). During the open-label extension study where all participants received ocrelizumab (Ocrevus), five more cases of neoplasm occurred. No cases of PML have been reported during clinical studies. The authors reported that further evaluation of the occurrence of neoplasms and PML risk is warranted.
Subcutaneous AdministrationIn 2024, Newsome et al. investigated the noninferiority of ocrelizumab and hyaluronidase-ocsq (Ocrevus
Zunovo) administered as a SC injection to ocrelizumab (Ocrevus) administered as
an IV injection in the OCARINA II (A Phase III, Non-Inferiority, Randomized, Open-Label, Parallel Group, Multicenter Study To Investigate The Pharmacokinetics, Pharmacodynamics, Safety And Radiological And Clinical Effects Of Subcutaneous Ocrelizumab Versus Intravenous Ocrelizumab In Patients With Multiple Sclerosis) clinical trial (NCT05232825). This phase III,
randomized, open-label trial enrolled 213 individuals with RMS and 23
individuals with PPMS. Participants were randomly assigned 1:1 to receive either the
IV injection or the SC injection. The primary endpoint was serum ocrelizumab
area under the concentration-time curve at week 12 (AUCW 1–12). A key secondary
endpoint was the total number of new or enlarging T2 lesions as detected by
brain MRI. At week 12, the geometric mean ratio
for AUCW 1–12 for the SC injection versus the IV injection was 1.29 (1.23–1.35). The results of the MRI demonstrated near-complete suppression of new or
enlarging lesions for both cohorts. No new safety concerns were identified for
the SC injection.
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.
