For Patients and Caregivers

MS DISEASE PROGRESSION

Progression in MS starts early1-5

Inflammatory activity is thought to be highest early in MS and is associated with2,6:

Disability progression can occur across many functional domains and recognizing it early can be challenging10-12

Visual
Sensory
Brain Stem
Bowel and Bladder
Pyramidal
Cerebral
Cerebellar
Ambulation

Some signs and symptoms may be difficult to detect on exam, such as changes in mood and cognition, fatigue, and sexual dysfunction.13,14

Understanding of the MS disease course is evolving15

4 distinct phenotypes 2 forms 1 disease continuum
Relapsing and progressive forms, with and without activity and progression16,17

Based on recent clinical and scientific findings, the idea that the MS disease course is 1 disease continuum, characterized by acute and chronic inflammation, is challenging the disease model.2,3,8,18-20

Progression independent of relapse activity (PIRA) may be measurable as early as clinically isolated syndrome (CIS). Progression may not be “silent” when investigated closely with sensitive measures.18,21-23

DISABILITY ACCUMULATION

Disability can accumulate in 2 ways21,22,24

Progression independent of relapse activity (PIRA)

Clinical disability that is not associated with a relapse

Relapse-associated worsening (RAW)

Incomplete recovery from a relapse

How “silent” is silent progression?

Multiple studies have demonstrated that, among patients who experience confirmed disability events, a substantial amount of disability is due to PIRA, even in patients with CIS.4,18,21-23

MECHANISM OF ACTION

Proposed mechanism of action for ocrelizumab

OCREVUS® [IV] and OCREVUS ZUNOVO® have the same mechanism of action24-27

*OCREVUS [IV] and OCREVUS ZUNOVO contain ocrelizumab, a recombinant humanized monoclonal antibody directed against CD20-expressing B cells. Lymphoid stem cells and plasma cells do not express CD20 and therefore are not directly targeted by OCREVUS [IV] or OCREVUS ZUNOVO.24-26

The precise mechanisms through which OCREVUS [IV] and OCREVUS ZUNOVO exert their therapeutic clinical effects in relapsing multiple sclerosis (RMS) and relapsing-remitting multiple sclerosis (RRMS) are not fully elucidated but are presumed to involve immunomodulation through selective binding to CD20-expressing B cells. Following cell surface binding to B lymphocytes, OCREVUS [IV] and OCREVUS ZUNOVO result in antibody-dependent cellular cytolysis and complement-mediated lysis.24,25

OCREVUS ZUNOVO also contains hyaluronidase, an active excipient that works in a transient and reversible way to increase the dispersion area and allow large fluid volumes to be administered subcutaneously.25,28,29


CIS=clinically isolated syndrome; IV=intravenous; MRI=magnetic resonance imaging; MS=multiple sclerosis; PIRA=progression independent of relapse activity; PPMS=primary progressive multiple sclerosis; RAW=relapse-associated worsening; RMS=relapsing multiple sclerosis; RRMS=relapsing-remitting multiple sclerosis; SPMS=secondary progressive multiple sclerosis.

NEXT: Why OCREVUS ZUNOVO?

 

Important Safety Information & Indications

Indications

OCREVUS and OCREVUS ZUNOVO are indicated for the treatment of:

  • Relapsing forms of multiple sclerosis (MS), to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults
  • Primary progressive MS, in adults.
Contraindications

Treatment with ocrelizumab is contraindicated in patients with active hepatitis B virus infection and in patients with a history of life-threatening administration reactions to ocrelizumab. OCREVUS ZUNOVO is also contraindicated in patients with a history of hypersensitivity to ocrelizumab, hyaluronidase, or any component of OCREVUS ZUNOVO.

Warnings and Precautions
Injection Reactions (OCREVUS ZUNOVO) OR Infusion Reactions (OCREVUS)

OCREVUS ZUNOVO can cause injection reactions, which can be local or systemic. Common symptoms of local injection reactions reported by patients treated with OCREVUS ZUNOVO in multiple sclerosis (MS) clinical trials included erythema, pain, swelling, and pruritus. Common symptoms of systemic injection reactions reported by patients included headache and nausea. In an open-label, active-controlled trial, injection reactions were more frequently reported with the first injection; 49% of patients experienced an injection reaction with the first injection.

In OCREVUS MS clinical trials, the incidence of infusion reactions in patients [who received methylprednisolone (or an equivalent steroid) and possibly other pre-medication to reduce the risk of infusion reactions prior to infusion] was 34% to 40%, with the highest incidence with the first infusion. There were no fatal infusion reactions, but 0.3% of intravenous ocrelizumab-treated MS patients experienced infusion reactions that were serious, some requiring hospitalization. Symptoms of infusion reactions can include pruritus, rash, urticaria, erythema, bronchospasm, throat irritation, oropharyngeal pain, dyspnea, pharyngeal or laryngeal edema, flushing, hypotension, pyrexia, fatigue, headache, dizziness, nausea, tachycardia, and anaphylaxis.

Monitor OCREVUS ZUNOVO patients during and after injections. Observe patients treated with OCREVUS for infusion reactions during the infusion and for at least one hour after completion of the infusion. Inform patients that administration reactions can occur during or within 24 hours of treatment.

Reducing the Risk and Managing Injection or Infusion Reactions

For OCREVUS ZUNOVO, administer oral pre-medication (e.g., dexamethasone or an equivalent corticosteroid, and an antihistamine) at least 30 minutes prior to each OCREVUS ZUNOVO injection to reduce the risk of injection reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.

For OCREVUS, administer pre-medication (e.g., methylprednisolone or an equivalent corticosteroid, and an antihistamine) to reduce the frequency and severity of infusion reactions. The addition of an antipyretic (e.g., acetaminophen) may also be considered.

Management recommendations depend on the type and severity of the reaction. For life-threatening reactions, immediately and permanently stop OCREVUS ZUNOVO or OCREVUS and administer appropriate supportive treatment. For less severe OCREVUS ZUNOVO injection reactions, the injection should be interrupted immediately, and the patient should receive symptomatic treatment. The injection should be completed at the healthcare provider’s discretion and only after all symptoms have resolved. For less severe OCREVUS infusion reactions, management may involve temporarily stopping the infusion, reducing the infusion rate, and/or administering symptomatic treatment.

Infections

Serious, including life-threatening or fatal, bacterial, viral, parasitic and fungal infections have been reported in patients receiving ocrelizumab. An increased risk of infections (including serious and fatal bacterial, fungal, and new or reactivated viral infections) has been observed in patients during and following completion of treatment with anti-CD20 B-cell depleting therapies.

A higher proportion of OCREVUS-treated patients experienced infections compared to patients taking REBIF or placebo. In RMS trials, 58% of OCREVUS-treated patients experienced one or more infections compared to 52% of REBIF-treated patients. In the PPMS trial, 70% of OCREVUS-treated patients experienced one or more infections compared to 68% of patients on placebo. OCREVUS was not associated with an increased risk of serious infections in MS patients in controlled trials.

Ocrelizumab increases the risk for upper respiratory tract infections, lower respiratory tract infections, skin infections, and herpes-related infections. Delay administration of ocrelizumab in patients with an active infection until the infection has resolved.

Respiratory Tract Infections

A higher proportion of OCREVUS-treated patients experienced respiratory tract infections compared to patients taking REBIF or placebo. In RMS trials, 40% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 33% of REBIF-treated patients, and 8% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 5% of REBIF-treated patients. In the PPMS trial, 49% of OCREVUS-treated patients experienced upper respiratory tract infections compared to 43% of patients on placebo, and 10% of OCREVUS-treated patients experienced lower respiratory tract infections compared to 9% of patients on placebo. The infections were predominantly mild to moderate and consisted mostly of upper respiratory tract infections and bronchitis.

Herpes

In active-controlled (RMS) clinical trials, herpes infections were reported more frequently in OCREVUS-treated patients than in REBIF-treated patients, including herpes zoster (2.1% vs. 1.0%), herpes simplex (0.7% vs. 0.1%), oral herpes (3.0% vs. 2.2%), genital herpes (0.1% vs. 0%), and herpes virus infection (0.1% vs. 0%). Infections were predominantly mild to moderate in severity. In the placebo-controlled (PPMS) clinical trial, oral herpes was reported more frequently in the OCREVUS-treated patients than in the patients on placebo (2.7% vs. 0.8%).

Serious cases of infections caused by herpes simplex virus and varicella zoster virus, including central nervous system infections (encephalitis and meningitis), intraocular infections, and disseminated skin and soft tissue infections, have been reported in the postmarketing setting in multiple sclerosis patients receiving ocrelizumab. Serious herpes virus infections may occur at any time during treatment with ocrelizumab. Some cases were life-threatening.

If serious herpes infections occur, treatment with ocrelizumab should be discontinued or withheld until the infection has resolved, and appropriate treatment should be administered.

Hepatitis B Virus Reactivation

Hepatitis B virus (HBV) reactivation has been reported in MS patients treated with ocrelizumab in the postmarketing setting. Fulminant hepatitis, hepatic failure, and death caused by HBV reactivation have occurred in patients treated with anti-CD20 antibodies. Perform HBV screening in all patients before initiation of treatment with ocrelizumab. Do not administer ocrelizumab to patients with active HBV confirmed by positive results for HBsAg and anti-HB tests. For patients who are negative for surface antigen [HBsAg] and positive for HB core antibody [HBcAb+] or are carriers of HBV [HBsAg+], consult liver disease experts before starting and during treatment.

Possible Increased Risk of Immunosuppressant Effects With Other Immunosuppressants

When initiating treatment with ocrelizumab after an immunosuppressive therapy or initiating an immunosuppressive therapy after ocrelizumab-containing products, consider the potential for increased immunosuppressive effect. Treatment with ocrelizumab has not been studied in combination with other MS therapies.

Vaccinations

Administer all immunizations according to immunization guidelines at least 4 weeks prior to initiation of ocrelizumab treatment for live or live-attenuated vaccines and, whenever possible, at least 2 weeks prior to initiation of ocrelizumab treatment for non-live vaccines. Ocrelizumab may interfere with the effectiveness of non-live vaccines. The safety of immunization with live or live-attenuated vaccines following treatment with ocrelizumab has not been studied, and vaccination with live-attenuated or live vaccines is not recommended during treatment and until B-cell repletion.

Vaccination of Infants Born to Mothers Treated With Ocrelizumab Products During Pregnancy

In infants of mothers exposed to ocrelizumab during pregnancy, do not administer live or live-attenuated vaccines before confirming the recovery of B-cell counts as measured by CD19+ B-cells. Depletion of B-cells in these infants may increase the risks from live or live-attenuated vaccines.

You may administer non-live vaccines, as indicated, prior to recovery from B-cell depletion, but you should consider assessing vaccine immune responses, including consultation with a qualified specialist, to assess whether a protective immune response was mounted.

Progressive Multifocal Leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients with MS treated with ocrelizumab in the postmarketing setting. PML is an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically occurs only in patients who are immunocompromised, and that usually leads to death or severe disability. PML has occurred in ocrelizumab-treated patients who had not been treated previously with natalizumab, (which has a known association with PML), were not taking any immunosuppressive or immunomodulatory medications associated with risk of PML prior to or concomitantly with ocrelizumab and did not have any known ongoing systemic medical conditions resulting in compromised immune system function.

JCV infection resulting in PML has also been observed in patients treated with other anti-CD20 antibodies and other MS therapies.

At the first sign or symptom suggestive of PML, withhold treatment with ocrelizumab-containing products and perform an appropriate diagnostic evaluation. Typical symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. 

Magnetic resonance imaging (MRI) findings may be apparent before clinical signs or symptoms of PML. Monitoring with MRI for signs consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. If PML is confirmed, treatment with ocrelizumab should be discontinued.

Reduction in Immunoglobulins

As expected with any B-cell depleting therapy, decreased immunoglobulin levels are observed with ocrelizumab treatment. The pooled data of OCREVUS clinical studies (RMS and PPMS) and their open-label extensions (up to approximately 7 years of exposure) have shown an association between decreased levels of immunoglobulin G (IgG<LLN) and increased rates of serious infections. Monitor the levels of quantitative serum immunoglobulins during treatment with ocrelizumab and after discontinuation of treatment, until B-cell repletion, and especially in the setting of recurrent serious infections. Consider discontinuing treatment with ocrelizumab in patients with serious opportunistic or recurrent serious infections, and if prolonged hypogammaglobulinemia requires treatment with intravenous immunoglobulins.

Malignancies

An increased risk of malignancy with ocrelizumab may exist. In controlled trials, malignancies, including breast cancer, occurred more frequently in OCREVUS-treated patients. Breast cancer occurred in 6 of 781 females treated with OCREVUS and none of 668 females treated with REBIF or placebo. Patients should follow standard breast cancer screening guidelines.

Immune-Mediated Colitis

Immune-mediated colitis, which can present as a severe and acute-onset form of colitis, has been reported in patients receiving ocrelizumab in the postmarketing setting. Some cases of colitis were serious, requiring hospitalization, with a few patients requiring surgical intervention. Systemic corticosteroids were required in many of these patients. The time from treatment initiation to onset of symptoms in these cases ranged from a few weeks to years. Monitor patients for immune-mediated colitis during ocrelizumab treatment and evaluate promptly if signs and symptoms that may indicate immune-mediated colitis, such as new or persistent diarrhea or other gastrointestinal signs and symptoms, occur.

Liver Injury

Clinically significant liver injury, without findings of viral hepatitis, has been reported in the postmarketing setting in patients treated with anti-CD20 B-cell depleting therapies approved for the treatment of MS, including ocrelizumab. Signs of liver injury, including markedly elevated serum hepatic enzymes with elevated total bilirubin, have occurred from weeks to months after administration.

Patients treated with ocrelizumab found to have an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) greater than 3x the upper limit of normal (ULN) with serum total bilirubin greater than 2x ULN are potentially at risk for severe drug-induced liver injury.

Obtain liver function tests prior to initiating treatment with ocrelizumab, and monitor for signs and symptoms of any hepatic injury during treatment. Measure serum aminotransferases, alkaline phosphatase, and bilirubin levels promptly in patients who report symptoms that may indicate liver injury, including new or worsening fatigue, anorexia, nausea, vomiting, right upper abdominal discomfort, dark urine, or jaundice. If liver injury is present and an alternative etiology is not identified, discontinue ocrelizumab.

Use in Specific Populations
Pregnancy

There are no adequate data on the developmental risk associated with use of ocrelizumab in pregnant women. There are no data on B-cell levels in human neonates following maternal exposure to ocrelizumab-containing products. However, transient peripheral B-cell depletion and lymphocytopenia have been reported in infants born to mothers exposed to other anti-CD20 antibodies during pregnancy. Ocrelizumab is a humanized monoclonal antibody of an immunoglobulin G1 subtype and immunoglobulins are known to cross the placental barrier.

Lactation

There are no data on the presence of ocrelizumab or hyaluronidase in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. Ocrelizumab was excreted in the milk of ocrelizumab-treated monkeys. Human IgG is excreted in human milk, and the potential for absorption of ocrelizumab to lead to B-cell depletion in the infant is unknown. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for ocrelizumab and any potential adverse effects on the breastfed infant from ocrelizumab or from the underlying maternal condition.

Females and Males of Reproductive Potential

Women of childbearing potential should use effective contraception while receiving ocrelizumab and for 6 months after the last dose of ocrelizumab. Instruct patients that if they are pregnant or plan to become pregnant while taking OCREVUS or OCREVUS ZUNOVO, they should inform their healthcare provider.

Most Common Adverse Reactions

In patients treated with OCREVUS:

  • RMS: The most common adverse reactions (≥10% and >REBIF): upper respiratory tract infections and infusion reactions
  • PPMS: The most common adverse reactions (≥10% and >placebo): upper respiratory tract infections, infusion reactions, skin infections, and lower respiratory tract infections

The most common adverse reaction observed with OCREVUS ZUNOVO in patients with RMS and PPMS was injection reactions (incidence of 49%).

You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555.

Please see additional Important Safety Information throughout and click here for full OCREVUS Prescribing Information and Medication Guide. For OCREVUS ZUNOVO, click here for full Prescribing Information and Medication Guide.

    • De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74(23):1868-1876. doi:10.1212/WNL.0b013e3181e24136

      De Stefano N, Giorgio A, Battaglini M, et al. Assessing brain atrophy rates in a large population of untreated multiple sclerosis subtypes. Neurology. 2010;74(23):1868-1876. doi:10.1212/WNL.0b013e3181e24136

    • Fox RJ, Cohen JA. Multiple sclerosis: the importance of early recognition and treatment. Cleve Clin J Med. 2001;68(2):157-171. doi:10.3949/ccjm.68.2.157

      Fox RJ, Cohen JA. Multiple sclerosis: the importance of early recognition and treatment. Cleve Clin J Med. 2001;68(2):157-171. doi:10.3949/ccjm.68.2.157

    • Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(3):606-616. doi:10.1093/brain/awl007

      Confavreux C, Vukusic S. Natural history of multiple sclerosis: a unifying concept. Brain. 2006;129(3):606-616. doi:10.1093/brain/awl007

    • University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666. doi:10.1002/ana.25463

      University of California, San Francisco MS-EPIC Team; Cree BAC, Hollenbach JA, et al. Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol. 2019;85(5):653-666. doi:10.1002/ana.25463

    • Kantarci OH, Lebrun C, Siva A, et al. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Ann Neurol. 2016;79(2):288-294. doi:10.1002/ana.24564

      Kantarci OH, Lebrun C, Siva A, et al. Primary progressive multiple sclerosis evolving from radiologically isolated syndrome. Ann Neurol. 2016;79(2):288-294. doi:10.1002/ana.24564

    • Singh S, Dallenga T, Winkler A, et al. Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis. J Neuroinflammation. 2017;14(1):57. doi:10.1186/s12974-017-0831-8

      Singh S, Dallenga T, Winkler A, et al. Relationship of acute axonal damage, Wallerian degeneration, and clinical disability in multiple sclerosis. J Neuroinflammation. 2017;14(1):57. doi:10.1186/s12974-017-0831-8

    • Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-1821. doi:10.1177/1352458520970841

      Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: insights from the Atlas of MS, third edition. Mult Scler. 2020;26(14):1816-1821. doi:10.1177/1352458520970841

    • Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93(1):1-12. doi:10.1016/j.pneurobio.2010.09.005

      Dutta R, Trapp BD. Mechanisms of neuronal dysfunction and degeneration in multiple sclerosis. Prog Neurobiol. 2011;93(1):1-12. doi:10.1016/j.pneurobio.2010.09.005

    • Kamel FO. Factors involved in relapse of multiple sclerosis. J Microsc Ultrastruct. 2019;7(3):103-108. doi:10.4103/JMAU.JMAU_59_18

      Kamel FO. Factors involved in relapse of multiple sclerosis. J Microsc Ultrastruct. 2019;7(3):103-108. doi:10.4103/JMAU.JMAU_59_18

    • Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-1452. doi:10.1212/wnl.33.11.1444

      Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983;33(11):1444-1452. doi:10.1212/wnl.33.11.1444

    • Strik M, Shanahan CJ, van der Walt A, et al. Functional correlates of motor control impairments in multiple sclerosis: a 7 Tesla task functional MRI study. Hum Brain Mapp. 2021;42(8):2569​​-2582.

      Strik M, Shanahan CJ, van der Walt A, et al. Functional correlates of motor control impairments in multiple sclerosis: a 7 Tesla task functional MRI study. Hum Brain Mapp. 2021;42(8):2569​​-2582.

    • Krieger S, Sumowski J. Subclinical burden of multiple sclerosis at EDSS 0. Mult Scler J. 2021;27(2S):3-133.

      Krieger S, Sumowski J. Subclinical burden of multiple sclerosis at EDSS 0. Mult Scler J. 2021;27(2S):3-133.

    • Watson TM, Ford E, Worthington E, Lincoln NB. Validation of mood measures for people with multiple sclerosis. Int J MS Care. 2014;16(2):105-109. doi:10.7224/1537-2073.2013-013

      Watson TM, Ford E, Worthington E, Lincoln NB. Validation of mood measures for people with multiple sclerosis. Int J MS Care. 2014;16(2):105-109. doi:10.7224/1537-2073.2013-013

    • Javůrková A, Zimová D, Tomašovičová K, Raudenská J. Cognitive deficits and neuropsychological assessment in multiple sclerosis. In: Gonzalez-Quevedo A, ed. Trending Topics in Multiple Sclerosis. IntechOpen; 2016:211-226.

      Javůrková A, Zimová D, Tomašovičová K, Raudenská J. Cognitive deficits and neuropsychological assessment in multiple sclerosis. In: Gonzalez-Quevedo A, ed. Trending Topics in Multiple Sclerosis. IntechOpen; 2016:211-226.

    • Krieger SC, Sumowski J. New insights into multiple sclerosis clinical course from the topographical model and functional reserve. Neurol Clin. 2018;36(1):13-25. doi:10.1016/j.ncl.2017.08.003

      Krieger SC, Sumowski J. New insights into multiple sclerosis clinical course from the topographical model and functional reserve. Neurol Clin. 2018;36(1):13-25. doi:10.1016/j.ncl.2017.08.003

    • Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. doi:10.1212/WNL.0000000000000560

      Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278-286. doi:10.1212/WNL.0000000000000560

    • Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911. doi:10.1212/wnl.46.4.907

      Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis. Neurology. 1996;46(4):907-911. doi:10.1212/wnl.46.4.907

    • Portaccio E, Bellinvia A, Fonderico M, et al. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain. 2022;145(8):2796-2805. doi:10.1093/brain/awac111

      Portaccio E, Bellinvia A, Fonderico M, et al. Progression is independent of relapse activity in early multiple sclerosis: a real-life cohort study. Brain. 2022;145(8):2796-2805. doi:10.1093/brain/awac111

    • 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;3(5):e279. doi:10.1212/NXI.0000000000000279

      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;3(5):e279. doi:10.1212/NXI.0000000000000279

    • Kuhlmann T, Moccia M, Coetzee T, et al; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023;22(1):78-88. doi:10.1016/S1474-4422(22)00289-7

      Kuhlmann T, Moccia M, Coetzee T, et al; International Advisory Committee on Clinical Trials in Multiple Sclerosis. Multiple sclerosis progression: time for a new mechanism-driven framework. Lancet Neurol. 2023;22(1):78-88. doi:10.1016/S1474-4422(22)00289-7

    • Kappos L, Wolinsky JS, Giovannoni G, et al. Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77(9):1132-1140. doi:10.1001/jamaneurol.2020.1568

      Kappos L, Wolinsky JS, Giovannoni G, et al. Contribution of relapse-independent progression vs relapse-associated worsening to overall confirmed disability accumulation in typical relapsing multiple sclerosis in a pooled analysis of 2 randomized clinical trials. JAMA Neurol. 2020;77(9):1132-1140. doi:10.1001/jamaneurol.2020.1568

    • Lublin FD, Häring DA, Ganjgahi H, et al. How patients with multiple sclerosis acquire disability. Brain. 2022;145(9):3147-3161. doi:10.1093/brain/awac016

      Lublin FD, Häring DA, Ganjgahi H, et al. How patients with multiple sclerosis acquire disability. Brain. 2022;145(9):3147-3161. doi:10.1093/brain/awac016

    • Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, et al. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80(2):151-160. doi:10.1001/jamaneurol.2022.4655

      Tur C, Carbonell-Mirabent P, Cobo-Calvo Á, et al. Association of early progression independent of relapse activity with long-term disability after a first demyelinating event in multiple sclerosis. JAMA Neurol. 2023;80(2):151-160. doi:10.1001/jamaneurol.2022.4655

    • OCREVUS [prescribing information]. South San Francisco, CA: Genentech, Inc. 2025.

      OCREVUS [prescribing information]. South San Francisco, CA: Genentech, Inc. 2025.

    • OCREVUS ZUNOVO [prescribing information]. South San Francisco, CA: Genentech, Inc. 2025.

      OCREVUS ZUNOVO [prescribing information]. South San Francisco, CA: Genentech, Inc. 2025.

    • 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;376(3):221-234. doi:10.1056/NEJMoa1601277

      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;376(3):221-234. doi:10.1056/NEJMoa1601277

    • Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine. 2017;16:41-50. doi:10.1016/j.ebiom.2017.01.042

      Baker D, Marta M, Pryce G, Giovannoni G, Schmierer K. Memory B cells are major targets for effective immunotherapy in relapsing multiple sclerosis. EBioMedicine. 2017;16:41-50. doi:10.1016/j.ebiom.2017.01.042

    • Connor RJ, Taverna DM, Thrall K, LaBarre MJ, Kang DW. Use of computed tomography to assess subcutaneous drug dispersion with recombinant human hyaluronidase PH20 in a swine model. J Pharmacol Toxicol Methods. 2020;106:106936. doi:10.1016/j.vascn.2020.106936

      Connor RJ, Taverna DM, Thrall K, LaBarre MJ, Kang DW. Use of computed tomography to assess subcutaneous drug dispersion with recombinant human hyaluronidase PH20 in a swine model. J Pharmacol Toxicol Methods. 2020;106:106936. doi:10.1016/j.vascn.2020.106936

    • Bookbinder LH, Hofer A, Haller MF, et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release. 2006;114(2):230-241. doi:10.1016/j.jconrel.2006.05.027

      Bookbinder LH, Hofer A, Haller MF, et al. A recombinant human enzyme for enhanced interstitial transport of therapeutics. J Control Release. 2006;114(2):230-241. doi:10.1016/j.jconrel.2006.05.027