Ocrelizumab

Identification

Summary

Ocrelizumab is a CD20 specific monoclonal antibody used to treat relapsing remitting multiple sclerosis.

Brand Names

Ocrevus

Generic Name

Ocrelizumab

DrugBank Accession Number

DB11988

Background

Ocrelizumab is a CD20-directed cytolytic antibody indicated for the treatment of patients with relapsing or primary progressive forms of multiple sclerosis. It is a second-generation recombinant humanized monoclonal IgG1 antibody that selectively targets the B lymphocytes that express the CD20 antigen. As a humanized molecule, ocrelizumab is expected to be less immunogenic with repeated infusions which improves the benefit-to-risk profile for patients with relapsing or progressive forms of MS.

Multiple sclerosis (MS) is a chronic, inflammatory, autoimmune disease of the central nervous system that leads to neurological disabilities and significantly reduced quality of life ⁵. Most patients with MS experience episodes of relapses with worsening function, followed by recovery periods, or remissions. Primary progressive multiple sclerosis (PPMS) accounts for 10-15% of the overall population of patients with MS, and involves gradual worsening of neurologic disability from symptom onset, often without early relapses or remissions ⁴.

Developed by Genentech/Roche, ocrelizumab was approved by the FDA in March 2017 under the market name Ocrevustm for intravenous injection. It was later approved by Health Canada (as Ocrevus) in August 2017, making the drug the first available treatment for PPMS in both U.S. and Canada. In clinical trials of patients with relapsing forms of MS, treatment with ocrelizumab resulted in reduced relapse rates and reduced worsening of disability compared to interferon beta-1a ⁵. In phase 3 clinical trials of patients with PPMS, treatment with ocrelizumab demonstrated lower rates of clinical and MRI progression than placebo ⁴.

Type

Biotech

Groups

Approved, Investigational

Biologic Classification

Protein Based Therapies
Monoclonal antibody (mAb)

Protein Chemical Formula

C₆₄₉₄H₉₉₇₈N₁₇₁₈O₂₀₁₄S₄₆

Protein Average Weight

145000.0 Da (Approximate, glycosylated)

Sequences

Not Available

Synonyms

Ocrelizumab
Ocrelizumab (genetical recombination)

External IDs

PR-070769
PR070769
R-1594
RG-1594

Pharmacology

Indication

Indicated for the treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis ^Label.

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Associated Conditions

Contraindications & Blackbox Warnings

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Pharmacodynamics

Since ocrelizumab interferes with the CD20 assay, CD19+B-cells were used to assess B-cell counts after ocrelizumab treatment. 14 days following infusion, a reduction in CD19+B-cell counts was observed. In clinical studies, B-cell counts rose to above the lower limit of normal (LLN) or above baseline counts between infusions of ocrelizumab at least one time in 0.3% to 4.1% of patients. In a clinical study involving 51 patients, the time for B-cell counts to return to baseline or LLN was ranged from 27 to 125 weeks, with the median time of 72 weeks, after the last infusion. Within 2.5 years after the last infusion, B-cell counts returned to either baseline or LNN in 90% of the patients ^Label.

Mechanism of action

B lymphocytes are known to contribute to the pathogenesis of MS through activation of pro-inflammatory T cells and secretion of proinflammatory cytokines. B cells may differentiate into plasma cells that can produce autoantibodies directed against myelin and cause complement-mediated attack on the myelin sheath ³. CD20 is a cell-surface antigen found on pre-B cells, naïve and mature B cells and memory B cells. However, this activated glycosylated phosphoprotein is not expressed on haematopoietic stem cells, pro-B cells (precursors), or differentiated plasma cells ^3,4.

While the exact mechanism of ocrelizumab leading to B-cell depletion is unknown, there are several different proposed mechanisms. Upon cell surface binding to CD20-expressing B lymphocytes, ocrelizumab promotes antibody-dependent cellular cytotoxicity and complement-mediated cell lysis. The capacity for B-cell reconstitution and preexisting humoral immunity is preserved ⁴, such as levels of IgG and IgM antibodies in the blood of cerebrospinal fluid. Ocrelizumab may induce antibody-dependant cellular cytotoxicity involving macrophages, natural killer cells, and cytotoxic T cells that act together to cause cell death ³. Another mechanism is apoptosis, which may result from cross-linking membrane CD20 on the target cell surface ³.

Target	Actions	Organism
AB-lymphocyte antigen CD20	antagonist antibody	Humans

Absorption

Ocrelizumab displays a two-compartment pharmacokinetic model with time-dependent clearance. The overall exposure at the steady-state (AUC over the 24 week dosing intervals) of ocrelizumab was 3,510 mcg/mL per day. Following intravenous infusion of maintenance doses of 600 mg every 6 months in relapsing MS patients, the mean peak plasma concentration (Cmax) was 212 mcg/mL. Following intravenous infusion of two 300 mg doses separated by 14 days every 6 months in patients with PPMS, Cmax was reported to be 141 mcg/mL. The pharmacokinetics of ocrelizumab was essentially linear and dose proportional between 400 mg and 2000 mg ^Label.

Volume of distribution

Central volume of distribution was 2.78 L ^Label.

Protein binding

Not Available

Metabolism

As with other antibodies, ocrelizumab is expected to undergo nonspecific catabolism and broken into smaller peptides and amino acids ^Label.

Route of elimination

Not Available

Half-life

The terminal elimination half-life was 26 days ^Label.

Clearance

Constant clearance was estimated at 0.17 L/day, and initial time-dependent clearance at 0.05 L/day. Peripheral volume and inter-compartment clearance were estimated at 2.68 L and 0.29 L/day, respectively ^Label.

Adverse Effects

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Toxicity

Studies assessing the carcinogenicity and mutagenicity of ocrelizumab have not been conducted ^Label.

Pathways

Not Available

Pharmacogenomic Effects/ADRs

Not Available

Interactions

Drug Interactions

This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.

Drug	Interaction
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Abatacept	Ocrelizumab may increase the immunosuppressive activities of Abatacept.
Abciximab	The risk or severity of adverse effects can be increased when Abciximab is combined with Ocrelizumab.
Adalimumab	The risk or severity of adverse effects can be increased when Adalimumab is combined with Ocrelizumab.
Adenovirus type 7 vaccine live	The risk or severity of infection can be increased when Adenovirus type 7 vaccine live is combined with Ocrelizumab.
Aducanumab	The risk or severity of adverse effects can be increased when Ocrelizumab is combined with Aducanumab.
Aldesleukin	Ocrelizumab may increase the immunosuppressive activities of Aldesleukin.
Alefacept	The risk or severity of adverse effects can be increased when Alefacept is combined with Ocrelizumab.
Alemtuzumab	Ocrelizumab may increase the immunosuppressive activities of Alemtuzumab.
Alirocumab	The risk or severity of adverse effects can be increased when Alirocumab is combined with Ocrelizumab.
Allogeneic processed thymus tissue	The therapeutic efficacy of Allogeneic processed thymus tissue can be decreased when used in combination with Ocrelizumab.

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Food Interactions

No interactions found.

Products

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Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End
Ocrevus	Injection, solution, concentrate	300 mg	Intravenous	Roche Registration Gmb H	2020-12-16	Not applicable
Ocrevus	Injection	300 mg/10mL	Intravenous	Genentech, Inc.	2017-03-28	Not applicable
Ocrevus	Injection, solution, concentrate	300 mg	Intravenous	Roche Registration Gmb H	2020-12-16	Not applicable
Ocrevus	Solution	30 mg / mL	Intravenous	Hoffmann La Roche	2017-09-21	Not applicable

Chemical Identifiers

UNII: A10SJL62JY
CAS number: 637334-45-3

References

General References

McGinley MP, Moss BP, Cohen JA: Safety of monoclonal antibodies for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017 Jan;16(1):89-100. Epub 2016 Oct 31. [Article]
Reddy V, Dahal LN, Cragg MS, Leandro M: Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? Drug Discov Today. 2016 Aug;21(8):1330-8. doi: 10.1016/j.drudis.2016.06.009. Epub 2016 Jun 22. [Article]
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. doi: 10.1177/1756285615601933. [Article]
Montalban X, Hauser SL, Kappos L, Arnold DL, Bar-Or A, Comi G, de Seze J, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Rammohan KW, Selmaj K, Traboulsee A, Sauter A, Masterman D, Fontoura P, Belachew S, Garren H, Mairon N, Chin P, Wolinsky JS: Ocrelizumab versus Placebo in Primary Progressive Multiple Sclerosis. N Engl J Med. 2017 Jan 19;376(3):209-220. doi: 10.1056/NEJMoa1606468. Epub 2016 Dec 21. [Article]
FDA Press Announcements: FDA approves new drug to treat multiple sclerosis [Link]

External Links

KEGG Drug: D05218
PubChem Substance: 347911266
RxNav: 1876366
Wikipedia: Ocrelizumab

FDA label

Download (249 KB)

Clinical Trials

Clinical Trials

Phase	Status	Purpose	Conditions	Count
4	Active Not Recruiting	Treatment	Multiple Sclerosis	1
4	Active Not Recruiting	Treatment	Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Completed	Treatment	Multiple Sclerosis	1
4	Not Yet Recruiting	Treatment	Multiple Sclerosis	1
4	Recruiting	Basic Science	Clinically Isolated Syndrome (CIS) / Relapsing Multiple Sclerosis (RMS)	1
4	Recruiting	Other	Clinically Isolated Syndrome (CIS) / Multiple Sclerosis	2
4	Recruiting	Prevention	Multiple Sclerosis / Radiologically Isolated Syndrome (RIS)	1
4	Recruiting	Treatment	Coronavirus Disease 2019 (COVID‑19) / Relapsing Remitting Multiple Sclerosis (RRMS)	1
4	Recruiting	Treatment	Multiple Sclerosis	2
4	Recruiting	Treatment	Relapsing Multiple Sclerosis (RMS)	2

Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection	Intravenous	300 mg/10mL
Injection, solution, concentrate	Intravenous	300 mg
Injection, solution, concentrate	Intravenous; Parenteral	300 MG
Solution	Intravenous	30 mg / mL
Injection	Parenteral
Solution, concentrate	Intravenous	30 mg

Prices

Not Available

Patents

Not Available

Properties

State: Solid
Experimental Properties: Not Available

Targets

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Details1. B-lymphocyte antigen CD20

Kind: Protein
Organism: Humans
Pharmacological action: Yes
Actions: Antagonist
Antibody

General Function: Mhc class ii protein complex binding
Specific Function: This protein may be involved in the regulation of B-cell activation and proliferation.
Gene Name: MS4A1
Uniprot ID: P11836
Uniprot Name: B-lymphocyte antigen CD20
Molecular Weight: 33076.99 Da

References

McGinley MP, Moss BP, Cohen JA: Safety of monoclonal antibodies for the treatment of multiple sclerosis. Expert Opin Drug Saf. 2017 Jan;16(1):89-100. Epub 2016 Oct 31. [Article]
Reddy V, Dahal LN, Cragg MS, Leandro M: Optimising B-cell depletion in autoimmune disease: is obinutuzumab the answer? Drug Discov Today. 2016 Aug;21(8):1330-8. doi: 10.1016/j.drudis.2016.06.009. Epub 2016 Jun 22. [Article]

Drug created at October 20, 2016 21:08 / Updated at May 21, 2022 00:27

Ocrelizumab

Identification

Pharmacology

Interactions

Products

Categories

Chemical Identifiers

References

Clinical Trials

Pharmacoeconomics

Properties

Targets

References