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Last updated: 5 May 2013

Rituximab

Summary
Trade name: 
Rituxan [[481]]
MabThera [[484]]
Mabtas (biosimilar version) [[5912]]
Class: 
Immunosuppressor [[481]] [[346]]
Target: 
B cells [[481]]
CD20 [[481]]
Status for MS: 
Results from Phase II trials for RRMS have been published (2009, 2010) [[359]] [[352]]
Used off-label to treat MS [[345]]
Administration: 
Intravenous infusion [[388]]
Example of frequency of intravenous infusions in clinical trials is two 1000 mg infusions every 24 weeks [[359]]
Results presented at a meeting indicate that subcutaneous administration is a non-inferior alternative to intravenous infusion, which would allow administration over 5 minutes rather than 2.5 hours (8 December 2012) [[4141]]
Commercial: 
Discovered by Biogen Idec [[484]]
Co-marketed by Genentech and Biogen Idec in the US [[484]]
Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan [[484]]
Marketed by Roche as MabThera elsewhere in the world [[484]]
Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) [[5912]]
Names
Name: 
Rituximab
Trade name: 
Rituxan [[481]]
MabThera [[484]]
Mabtas (biosimilar version) [[5912]]
Synonyms: 
HSDB 7455 [[465]]
IDEC-102 [[465]]
Immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer [[465]]
Mabtas [[5912]]
Mab Thera [[465]]
MabThera [[484]]
Rituxan [[465]]
Rituximab [[465]]
UNII-4F4X42SYQ6 [[465]]
Systematic name: 
Immunoglobulin G1, anti-(human CD20 (antigen)(human-mouse monoclonal IDEC-C2B8 gamma1-chain), disulfide with human-mouse monoclonal IDEC- C2B8 kappa-chain, dimer [[465]]
Physiology
Class: 
Immunosuppressor [[481]] [[346]]
Target: 
B cells [[481]]
CD20 [[481]]
Properties: 
Genetically engineered chimeric murine/human monoclonal antibody that binds to CD20, a B cell antigen [[346]] [[395]]
Contains murine anti-CD20 antibody complementarity-determining regions and human kappa and IgG1 heavy-chain constant regions [[388]]
Molecular weight: 145 kD [[388]]
Produced in Chinese hamster ovarian cells [[388]]
Binding affinity for CD20 is ~8 nM [[388]]
Mean half-life in serum in patients with B cell lymphoma receiving intravenous infusion is 59.8 hours, although range is wide [[388]]
Half life is 20 days in patients with rheumatoid arthritis (after receiving second dose) [[388]]
Serum levels generally increase as doses are repeated and levels of CD20 decrease [[395]]

Mechanisms/Effects

Human: 
Complete mechanism unknown [[351]]
Targets the antigen CD20, which is expressed on pre-B cells and mature B cells [[346]] [[373]]
Rapidly eliminates mature circulating B cells for up to 6 to 9 months [[481]] [[482]] [[388]]
Decreases or eliminates B cells in the cerebrospinal fluid of MS patients [[351]]
Affects chemokine levels in the cerebrospinal fluid of MS patients, such that levels of CXCL13 and CCL19 are reduced [[351]]
Reduces T cell levels in the cerebrospinal fluid of many MS patients, possibly because B cells (depleted by drug) influence T cell trafficking into the central nervous system by affecting chemokine production [[351]]
May induce cell death through apoptotic pathways involving caspase-3 activation, as shown by studies of chronic lymphocytic leukemia patients [[395]]
Can cause complement activation, resulting in cell lysis (complement-dependent cytotoxicity), but the strength of the effect varies depending on the B-cell lymphoma cell line studied and does not correlate with clinical responses to the drug [[395]]
May act through antibody-dependent cellular cytotoxicity (in which cells are killed by effector cells that have been activated by the Fc portion of rituximab bound to the lymphoma cell) [[395]]
Binding to CD20 induces intracellular signaling pathways, and if crosslinked, the degree of signaling increases, as shown with studies of malignant B cells [[395]]
Binding to CD20 induces intracellular signaling, and the result of such signaling (such as apoptosis or cell cycle arrest) appears to depend on the cell line studied [[395]]
Regulatory and Commercial Status
Status for MS: 
Results from Phase II trials for RRMS have been published (2009, 2010) [[359]] [[352]]
Used off-label to treat MS [[345]]
Highest status achieved (for any condition): 
Approved [[480]] [[481]]
Other uses: 
First monoclonal antibody approved for treating cancer [[395]]
Approved by FDA in Nov 1997 for treating CD20-positive, B-cell, non-Hodgkins lymphoma [[480]] [[481]]
Approved in June 1998 in European Union, under tradename MabThera, for treating non-Hodgkin's lymphoma [[484]]
Approved by FDA in Feb 2006 for treating rheumatoid arthritis [[481]] [[484]]
Approved by FDA for treating additional non-Hodgkins lymphomas in 2006 [[484]]
Prescribed off-label for treating certain other diseases, such as systemic lupus erythematosus [[481]]
Has been used to treat transplant patients, but results have not been tested in randomized trials (2006) [[483]]
Has shown some success for treating several autoimmune diseases, including Sjorgren's syndrome, vasculitis, thrombocytopenic purpura, and neuromyelitis optica [[373]]
Administration: 
Intravenous infusion [[388]]
Example of frequency of intravenous infusions in clinical trials is two 1000 mg infusions every 24 weeks [[359]]
Results presented at a meeting indicate that subcutaneous administration is a non-inferior alternative to intravenous infusion, which would allow administration over 5 minutes rather than 2.5 hours (8 December 2012) [[4141]]
Negative effects: 
Angina [[484]]
Anthralgia [[484]]
Bronchospasm [[482]]
Cardiac arrhythmias [[484]]
Hypertension [[484]]
Hypotension [[482]]
Hypoxia [[482]]
Infections [[484]]
Infusion-related reactions [[345]]
Nausea [[484]]
Pyrexia [[484]]
Progressive multifocal leukoencephalopathy [[481]]
Viral reactivation [[484]]
Commercial: 
Discovered by Biogen Idec [[484]]
Co-marketed by Genentech and Biogen Idec in the US [[484]]
Co-marketed by Chugai and Zenyaku Kogyo Co. Ltd in Japan [[484]]
Marketed by Roche as MabThera elsewhere in the world [[484]]
Biosimilar version has been launched by Intas Pharmaceuticals in India (May 2013) [[5912]]
Key Clinical Trials
Placebo-controlled Trials: 
Trial name: 
Naismith et al., Neurology, Jun 2010 trial [[352]]
Phase: 
Phase II trial [[352]]
Study Design: 
MRI-blinded, single-center study to evaluate the effects of rituximab (375 mg/m2 weekly for four weeks) on gadolinium-enhancing lesions (primary objective) in patients who had been treated with a standard injectable disease-modifying agent in the past 18 months but had shown an inadequate response and were then given rituximab as add-on therapy [[352]]
Disease Stage: 
RRMS [[352]]
Enrollment/Number of Patients: 
30 [[352]]
Duration: 
52 weeks, such that the drug was given for the first four weeks and MRI scans were performed monthly beginning 12 weeks after the first drug treatment [[352]]
Status/Outcome: 
Drug caused a reduction in the number of gadolinium-enhancing lesions, such that 74% of posttreatment MRI scans were free of gadolinium-enhancing activity versus 26% of baseline MRI scans [[352]]
Trial name: 
Hawker et al., Ann. Neurol., Oct 2009 trial [[359]]
Phase: 
Phase II/III trial [[359]]
Study Design: 
Randomized, double-blind, placebo-controlled, multicenter trial to evaluate the effects of rituximab (two 1000 mg infusions or placebo every 24 weeks) on time to confirmed disease progression (primary endpoint) and T2 lesion volume and total brain volume (secondary endpoints) [[359]]
Disease Stage: 
PPMS [[359]]
Enrollment/Number of Patients: 
439 [[359]]
Duration: 
96 weeks [[359]]
Status/Outcome: 
Drug was not associated with a decrease in time to confirmed disease progression (but there was a suggestion of a potential decrease in younger patients, especially those with inflammatory lesions) [[359]] [[484]]
Trial name: 
Hauser et al., N. Engl. Med., Feb 2008 trial [[376]]
Phase: 
Phase II trial [[376]]
Study Design: 
Double-blind, placebo-controlled trial to evaluate the effects of intravenous rituximab (1000 mg or placebo on weeks 1 and 15) on the total count of gadolinium-enhancing lesions (primary endpoint) and on the proportion of patients with relapses [[376]]
Disease Stage: 
RRMS [[376]]
Enrollment/Number of Patients: 
104 [[376]]
Duration: 
48 weeks [[376]]
Status/Outcome: 
Drug was associated with a reduced number of inflammatory brain lesions and a reduced number of relapses (14.5% vs 34.3% at week 24 and 20.3% vs 40% at week 48) [[376]]
Head-to-Head Trials: 
Other Trials: 
Trial name: 
Bar-Or et al., Ann. Neurol., Mar 2008 trial [[375]]
Phase: 
Phase I trial [[375]]
Study Design: 
Open-label trial to evaluate the safety, tolerability, pharmacodynamics, and activity of two courses of rituximab (total dose, 4000 mg), six months apart, in MS [[375]]
Disease Stage: 
RRMS [[375]]
Enrollment/Number of Patients: 
26, with 22 completing the trial [[375]]
Duration: 
72 weeks [[375]]
Status/Outcome: 
The drug was not associated with any serious adverse effects, although mild and moderate infusion-associated events were seen; furthermore, the drug was associated with fewer new gadolinium-enhancing or T2 lesions [[375]]
References
ChemIDplus Advanced
United States National Library of Medicine
Accessed on 4 Jan 2012 from http://chem.sis.nlm.nih.gov/chemidplus/chemidheavy.jsp.

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Intas launches biosimilar version of Rituximab
Unnithan C, The Times of India, 30 Apr 2013
Accessed on 5 May 2013 from http://timesofindia.indiatimes.com/business/india-business/Intas-launches-biosimilar-version-of-Rituximab/articleshow/19804674.cms.