Identification

Name
Ocrelizumab
Accession Number
DB11988
Type
Biotech
Groups
Approved, Investigational
Biologic Classification
Protein Based Therapies
Monoclonal antibody (mAb)
Description

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].

Protein chemical formula
C6494H9978N1718O2014S46
Protein average weight
145000.0 Da (Approximate, glycosylated)
Sequences
Not Available
Synonyms
  • Ocrelizumab (genetical recombination)
External IDs
PR-070769 / PR070769 / R-1594 / RG-1594
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
OcrevusSolution30 mgIntravenousHoffmann La Roche2017-09-21Not applicableCanada
OcrevusInjection300 mg/10mLIntravenousGenentech, Inc.2017-03-28Not applicableUs
Categories
UNII
A10SJL62JY
CAS number
637334-45-3

Pharmacology

Indication

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

Associated Conditions
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].

TargetActionsOrganism
AB-lymphocyte antigen CD20
antagonist
antibody
Human
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].

Toxicity

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

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
2-MethoxyethanolThe risk or severity of adverse effects can be increased when 2-Methoxyethanol is combined with Ocrelizumab.
9-(N-methyl-L-isoleucine)-cyclosporin AThe risk or severity of adverse effects can be increased when Ocrelizumab is combined with 9-(N-methyl-L-isoleucine)-cyclosporin A.
AbataceptThe risk or severity of adverse effects can be increased when Abatacept is combined with Ocrelizumab.
AbciximabThe risk or severity of adverse effects can be increased when Abciximab is combined with Ocrelizumab.
AbetimusThe risk or severity of adverse effects can be increased when Abetimus is combined with Ocrelizumab.
AbituzumabThe risk or severity of adverse effects can be increased when Ocrelizumab is combined with Abituzumab.
ActeosideThe risk or severity of adverse effects can be increased when Ocrelizumab is combined with Acteoside.
AdalimumabThe risk or severity of adverse effects can be increased when Adalimumab is combined with Ocrelizumab.
AdecatumumabThe risk or severity of adverse effects can be increased when Adecatumumab is combined with Ocrelizumab.
Adenovirus type 7 vaccine liveThe therapeutic efficacy of Adenovirus type 7 vaccine live can be decreased when used in combination with Ocrelizumab.
Food Interactions
Not Available

References

General References
  1. 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. [PubMed:27756172]
  2. 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. [PubMed:27343722]
  3. 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. [PubMed:26788130]
  4. 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. [PubMed:28002688]
  5. FDA Press Announcements: FDA approves new drug to treat multiple sclerosis [Link]
External Links
KEGG Drug
D05218
PubChem Substance
347911266
Wikipedia
Ocrelizumab
AHFS Codes
  • 92:20.00 — Immunomodulatory Agents
FDA label
Download (249 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1, 2CompletedTreatmentNon-Hodgkin's Lymphoma (NHL)1
1, 2CompletedTreatmentRheumatoid Arthritis1
1, 2TerminatedTreatmentRheumatoid Arthritis1
2Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
2TerminatedTreatmentRheumatoid Arthritis2
3Active Not RecruitingTreatmentMultiple Sclerosis, Primary Progressive1
3Active Not RecruitingTreatmentRelapsing Multiple Sclerosis (RMS) / Relapsing Remitting Multiple Sclerosis (RRMS)2
3Active Not RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
3CompletedTreatmentNephritis, Lupus / Systemic Lupus Erythematosus (SLE)1
3CompletedTreatmentRheumatoid Arthritis1
3RecruitingTreatmentDisseminated Sclerosis2
3RecruitingTreatmentDisseminated Sclerosis / Multiple Sclerosis, Primary Progressive / Relapses / Relapsing or Primary Progressive Multiple Sclerosis1
3RecruitingTreatmentMultiple Sclerosis, Primary Progressive / Multiple Sclerosis, Relapsing Forms / Relapsing Multiple Sclerorsis / Relapsing Multiple Sclerosis (RMS)1
3RecruitingTreatmentProgressive Multiple Sclerosis (PMS)1
3RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)2
3TerminatedTreatmentRheumatoid Arthritis3
3TerminatedTreatmentSystemic Lupus Erythematosus (SLE)1
4Not Yet RecruitingTreatmentRelapsing Remitting Multiple Sclerosis (RRMS)1
4RecruitingTreatmentDisseminated Sclerosis1
Not AvailableEnrolling by InvitationNot AvailableDisseminated Sclerosis1
Not AvailableNo Longer AvailableNot AvailableDisseminated Sclerosis1
Not AvailableNot Yet RecruitingNot AvailableDisseminated Sclerosis1
Not AvailableRecruitingNot AvailableAutoimmune Diseases / Demyelinating Autoimmune Diseases / Demyelinating Diseases / Disseminated Sclerosis / Immune System Diseases / Multiple Sclerosis, Primary Progressive / Nervous System Diseases / Pathologic Processes / Relapsing Remitting Multiple Sclerosis (RRMS)1
Not AvailableRecruitingNot AvailableDisseminated Sclerosis / Immune System Diseases1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
InjectionIntravenous300 mg/10mL
SolutionIntravenous30 mg
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
Not Available

Taxonomy

Description
Not Available
Kingdom
Organic Compounds
Super Class
Organic Acids
Class
Carboxylic Acids and Derivatives
Sub Class
Amino Acids, Peptides, and Analogues
Direct Parent
Peptides
Alternative Parents
Not Available
Substituents
Not Available
Molecular Framework
Not Available
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
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
  1. 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. [PubMed:27756172]
  2. 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. [PubMed:27343722]

Drug created on October 20, 2016 15:08 / Updated on December 12, 2018 07:22