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DRUG RECORD

 

OCRELIZUMAB

OVERVIEW
Ocrelizumab

 

Introduction

Ocrelizumab is a humanized monoclonal antibody to CD20 which is used as therapy of multiple sclerosis.  Ocrelizumab has not been associated with serum enzyme elevations during therapy nor with instances of clinically apparent liver injury, but is likely to cause reactivation of hepatitis B in susceptible patients.

 

Background

Ocrelizumab (ok" re liz' ue mab) is a humanized IgG1 monoclonal antibody to CD20, a cell surface antigen found on pre-B cells, mature B cells and memory B cells.  Engagement of CD20 causes cell lysis resulting in B cell depletion which may be beneficial in autoimmune conditions mediated by autoantibodies.  Ocrelizumab like rituximab is directed against CD20 but has a broader reactivity and is a humanized monoclonal, unlike rituximab that is a mouse-human chimeric molecule for which reason ocrelizumab may be less likely than rituximab to cause hypersensitivity reactions.  Ocrelizumab was found to be beneficial in multiple sclerosis, decreasing rates of relapse as well as slowing progression.  Ocrelizumab was approved for use in the United States in 2017 for both progressive and relapsing multiple sclerosis.  Ocrelizumab is under evaluation in other autoimmune and malignant conditions but is not approved for these uses.  Ocrelizumab is available in liquid solution in single use vials of 300 mg (30 mg/mL) under the brand name Ocrevus.  The recommended dose is 600 mg intravenously every 6 months, the initial dose being given as two separate infusions of 300 mg 2 weeks apart.  Treatment results in a rapid decline in circulating B cells and decrease in immunoglobulin levels, effects that persist for 6 to 18 months.  Common adverse events include infusion reactions, cough, diarrhea, skin rash and infections, particularly herpes simplex.  Rare but potentially serious adverse events include reactivation of hepatitis B, increased risk of malignancy and progressive multifocal leukoencephalopathy (PMLE).

 

Hepatotoxicity

Mild-to-moderate serum aminotransferase elevations were reported to occur in 1% to 2% of patients during ocrelizumab therapy.  The elevations, however, were self-limited and resolved even with continuing cyclic therapy and were no more frequent than occurred with placebo.  Neither during premarketing evaluation nor subsequently have there been case reports of clinically apparent, acute liver injury with symptoms or jaundice linked to ocrelizumab therapy, but experience with its use has been limited.

Monoclonal antibodies against CD20 similar to ocrelizumab such as rituximab and ofatumumab have been implicated in cases of reactivation of hepatitis B some of which have been severe and even fatal.  HBV reactivation typically occurs in patients with preexisting HBsAg and relatively inactive disease, but in some instances, it occurs in patients with anti-HBc without HBsAg.  Reactivation causes acute hepatocellular injury that can be severe and lead to acute liver failure and death or need for emergency liver transplantation.  No cases of reactivation of hepatitis B have been reported in patients receiving ocrelizumab, but the large clinical trials of this agent in multiple sclerosis excluded patients with HBsAg or anti-HBc (with HBV DNA) in serum.  Thus, while not reported, reactivation of hepatitis B should be considered likely to occur in patients at risk who are not given prophylaxis against reactivation (using oral antiviral agents with activity against HBV).

Likelihood score: E* (unproven but suspected cause of clinically apparent liver injury, particularly reactivation of hepatitis B).

 

Mechanism of Liver Injury

The mechanism of liver injury in reactivation of hepatitis B appears to be a brisk immunological response to newly expressed viral antigens following profound immune suppression and gradual recovery.  Injury generally arises between courses of monoclonal anti-CD20 therapy and may be delayed.

 

Outcome and Management

Guidelines for management of patients who are to receive ocrelizumab recommend routine screening for hepatitis B before starting treatment.  Screening should include tests for HBsAg and anti-HBc (and perhaps also anti-HBs as this may help in management).  Prophylaxis with a potent oral, antiviral agent effective against hepatitis B is recommended for persons who have HBsAg in serum and is suggested for those with anti-HBc without HBsAg.  An alternative approach which is perhaps more appropriate for ocrelizumab is careful monitoring for HBV DNA during therapy and early institution of antiviral therapy if levels rise.  At present, hepatitis B is considered a contraindication to the use of ocrelizumab in multiple sclerosis.

 

Drug Class:  Multiple Sclerosis Agents; Monoclonal Antibodies

 

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PRODUCT INFORMATION
Ocrelizumab

 

REPRESENTATIVE TRADE NAMES
Ocrelizumab – Ocrevus®

 

DRUG CLASS
Multiple Sclerosis Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Ocrelizumab 637334-45-3 Monoclonal Antibody Not Available

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References updated: 15 July 2018

  1. Reuben A. Hepatotoxicity of immunosuppressive drugs. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2011, pp. 569-91.  (Review of hepatotoxicity of immunosuppressive agents; does not mention ocrelizumab specifically but discussed the problems of reactivation of hepatitis B and states that "the biological immunosuppressants are largely free from hepatotoxicity, with the exception of the TNF alpha antagonists").

  2. https://www.accessdata.fda.gov/scripts/cder/daf/  (FDA Drug Approvals website that has product labels [package inserts], letters of approval and full FDA scientific review of the new drug application for safety and efficacy).

  3. Stohl W, Gomez-Reino J, Olech E, Dudler J, Fleischmann RM, Zerbini CA, Ashrafzadeh A, et al. 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: 1289-96. PubMed Citation  (Among 613 patients with rheumatoid arthritis treated with methotrexate with or without ocrelizumab [200 or 500 mg] for 52 weeks, clinical improvement was greater in the high dose group while adverse event rates were similar except for a high rate of serious infections that led to early discontinuation of the study; no mention of ALT elevations or hepatotoxicity, while none of 67 patients with anti-HBc developed evidence of HBV reactivation).

  4. Mysler EF, Spindler AJ, Guzman R, Bijl M, Jayne D, Furie RA, Houssiau FA, 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: 2368-79. PubMed Citation  (Among 378 patients with lupus nephritis treated with ocrelizumab [400 and 1000 mg doses] vs placebo for 48 weeks, overall renal response rates were minimally higher with ocrelizumab; no mention of ALT elevations or hepatotoxicity).

  5. Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, et al.; ORATORIO Clinical Investigators. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017; 376: 209-20. PubMed Citation  (Among 732 patients with progressive multiple sclerosis treated with ocrelizumab vs placebo, progression in disability over 12 weeks was less with ocrelizumab [33% vs 39%] while side effects that were more common with ocrelizumab were infusion reactions [40% vs 26%], upper respiratory infections [11% vs 6%], oral herpes [2.3% vs 0.9%] and neoplasms [2.3% vs 0.8%]; no mention of ALT elevations or hepatotoxicity).

  6. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, et al.; OPERA I and OPERA II Clinical Investigators. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017; 376: 221-34. PubMed Citation  (Among 1646 patients with relapsing multiple sclerosis treated with ocrelizumab vs interferon beta for 96 weeks in two clinical trials, relapse rates were 46-47% lower in ocrelizumab treated groups while overall and serious adverse event rates were similar including serious infections and herpes simplex; no mention of ALT elevations or hepatotoxicity).

  7. Hauser SL, Belachew S, Kappos L. Ocrelizumab in primary progressive and relapsing multiple sclerosis. N Engl J Med 2017; 376: 1694. PubMed Citation  (In a reply to a letter to the editor concerning Montalan [2017] and Hauser [2017], the authors explain that patients with HBsAg or anti-HBc with HBV DNA in serum were excluded from enrollment and those with anti-HBc alone were screened for HBV DNA at 12 week intervals, but do not mention whether instances of reactivation occurred).

  8. Frampton JE. Ocrelizumab: first global approval. Drugs 2017; 77: 1035-41. PubMed Citation  (Review of the development, mechanism of action, pharmacology, clinical efficacy and safety of ocrelizumab as therapy of multiple sclerosis, including a discussion of common adverse events such as infusion reactions and laboratory abnormalities of IgG, IgA and IgM and immunogenicity and serious adverse events such as infections and possibility of increased risk of malignancies, but does not mention ALT elevations, hepatotoxicity or reactivation of hepatitis B).

  9. Ocrelizumab (Ocrevus) for MS. Med Lett Drugs Ther 2017; 59 (1523): 98-101. PubMed Citation  (Concise review of the standard therapy of multiple sclerosis and the mechanism of action, clinical efficacy, safety and costs of ocrelizumab shortly after its approval in the US mentions that agents with similar mechanism of action can cause reactivation of HBV).

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OTHER REFERENCE LINKS
Ocrelizumab
  1. PubMed logoRecent References on Ocrelizumab

  2. Clinical Trials logoTrials on Ocrelizumab

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