Rituximab - Rituxan; IDEC-C2B8; MabThera; CD20 monoclonal antibody, recombinant
Status - approved; marketed
Organizations involved:
Genentech, Inc. – Manuf.; R&D; Tech.; USA mark.
Biogen Idec – R&D; Tech.; Former
IDEC Pharmaceuticals Corp. – R&D; Tech.; Former
Lonza Biologics plc - Manuf.
Emcure Pharmaceuticals Ltd. – Manuf.
Hoffmann-La Roche Ltd. – Intl. Mark.; R&D; Parent
Hoffmann-La Roche Inc. – R&D
Xoma Corp. – Tech.
Royalty Pharma, AG – Tech.
Trubion Pharmaceuticals, Inc. – Patent dispute
Genentech/Roche – Patent dispute
MedImmune Inc. – Patent dispute
AstraZeneca plc – Patent dispute
Genmab A/S – Patent dispute
Centocor Inc./J&J – Patent dispute
GlaxoSmithKline (GSK) – Patent dispute
Merck Serono S.A. – Patent dispute
Wyeth – Patent dispute
Pfizer Inc. – Patent dispute
Pharmaceutical Partners LLC – Form inv.
Zenyaku Kogyo Co., Ltd. – R&D; Japan mark.
Nippon Roche Ltd. – Japan mark.
GlaxoSmithKline Inc. – Patent dispute
Columbia University – Tech.; Patent dispute
Amgen Inc. – Tech.
Trubion Pharmaceutical, Inc. – Patent dispute
Cross ref.: See the Monoclonal Antibodies entry (#300). See the entry below for Rituximab Formulated Bulk (For Further Manufacturing Use), which is the source/intermediate used for manufacture of this product. See also radioimmune conjugate products involving recombinant CD20 monoclonal antibodies – ibritumomab tiuxetan (Zevalin) and Iodine-131 tositumomab (Bexxar).
Description: Rituxan is an aqueous formulation of a recombinant chimeric murine/human monoclonal antibody glycoprotein (rituximab) targeted to the CD20 receptor on B-cells produced by a transformed Chinese hamster ovary (CHO) cell line. Rituximab is an IgG1 kappa immunoglobulin (antibody) containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis). The molecular weight of rituximab is 144,544 Daltons (144.544 kDa), based on the primary sequence for the reduced, non-glycosylated form, as reported in the product insert; approximately 144.187 kDa according the the USP monograph.. Three oligosaccharide structures (G0, G1 and G2 glycoforms) have been identified by capillary zone electrophoresis (CE) and MALDI-TOF, with no evidence for a terminal sialic acid containing oligosaccharides.
Rituximab is an IgG1 kappa immunoglobulin containing murine (mouse) light- and heavy-chain variable regions (epitope-specific Fab domain) and human kappa and gamma-1 constant regions (framework Fc domain). The monoclonal antibody is targeted to the CD20 receptor antigen expressed on the surface of mature B-lymphocytes (B-cells) and B-cell-derived tumor cells. Rituximab is based on the 2H7 murine monoclonal antibody (gamma 2b, kappa), originally reported by Clark, E. A., et al., in Proc. Natl. Acad. Sci., U.S.A. 82:1766 (1985). Rituximab recognizes a human B-cell surface antigen, Bp35 (CD20), and does not react with stem cells (which are progenitors of B-cells), epithelial, mesenchymal, or fibroblastic cells. Recombinant murine-human chimeric 2H7 monoclonal antibody (rituximab) binds to Bp35 (CD20) antigen positive human B cells, but not precursor B-cells, to approximately the same extent as the source murine 2H7 monoclonal antibody. Rituximab is more resistant to clearance and less immunogenic in vivo than the murine 2H7 monoclonal antibody; and because it has a human constant region (framework), rituximab exhibits complement dependent and antibody dependent cytotoxicity, which the mouse 2H7 does not. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM (reported as 5.2 nM in EMEA, European Union, documents).
Rituxan is packaged in 10 and 50 mL single-use vials containing 100 mg and 500 mg of rituximab, respectively, in a sterile, clear, colorless, liquid concentrate (concentration of 10 mg/mL) for intravenous administration. The dissolving liquid contains 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, and 0.7 mg/mL polysorbate 80 (Tween 80) in Sterile Water for Injection. The pH is adjusted to 6.5. The product contains no preservatives. Rituxan vials are stored at 2-8˚C (36-46˚C; refrigerated), with a shelf life of 24 months.
Ritixumab heavy chain has the sequence: QVQLQQPGAE LVKPGASVKM SCKASGYTFT SYNMHWVKQT PGRGLEWIGA IYPGNGDTSY NQKFKGKATL TADKSSSTAY MQLSSLTSED SAVYYCARST YYGGDWYFNV WGAGTTVTVS AASTKGPSVF PLAPSSKSTS GGTAALGCLV KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ TYICNVNHKP SNTKVDKKAE PKSCDKTHTC PPCPAPELLG GPSVFLFPPK PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPAPIEKTI SKAKGQPREP QVYTLPPSRD ELTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG K [from the USP monograph]
The rituximab light chain has the sequence: QIVLSQSPAI LSASPGEKVT MTCRASSSVS YIHWFQQKPG SSPKPWIYAT SNLASGVPVR FSGSGSGTSY SLTISRVEAE DAATYYCQQW TSNPPTFGGG TKLEIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEKHKV YACEVTHQGL SSPVTKSFNR GEC [from the USP monograph]
The molecular formula is 6416H9874N1688O1987S44
Nomenclature: CD20 Mab, rDNA [BIO]; Rituxan [TR]; MabThera [TR used by Roche outside U.S. and Japan]; Rituximab [FDA USAN INN]; immunoglobulin G 1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 kappa-chain, dimer [CAS]; anti-(human CD20 antigen) immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain) disulfide with human-mouse monoclonal IDEC-C2B8 gamma-chain, dimer [CAS]; 174722-31-7 [CAS RN]; anti-CD20 monoclonal antibody [SY]; IDEC-C2B8 [SY]; pan-B antibodies [SY]; CD20 monoclonal antibody, recombinant [SY]
Biological.: The rituximab monoclonal antibody (Mab) is targeted to the CD20 receptor antigen, a transmembrane phosphorylated protein, expressed on the surface of pre-B and mature B lymphocytes (B-cells) and B-cell-derived tumor cells (except for myelomas and most precursor B-cell acute lymphocytic leukemias). The CD20 antigen is a suitable target for rituximab – CD20 is not shed from the surface of B-cells after binding of rituximab (which happens with murine CD20 Mabs) and CD20 does not internalize upon antibody binding.
Rituximab binds specifically to CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic cellular transmembrane protein with a molecular weight of approximately 35 kDa located on the surface of pre-B and mature B lymphocytes (i.e., on formative and mature antibody-producing B-cells). The antigen is also expressed on over 90% of B-cell non-Hodgkin’s lymphoma (NHL) cells, but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. Binding of ritixumab to CD20 can induce apoptosis (programmed cell death) in CD20+ B-cells in vitro. CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface, i.e., free/soluble CD20 antigen is not found in the circulation.
The Fab domain (murine antibody-derived, epitope-specific portion) of Rituximab binds to the CD20 antigen on B-lymphocytes and the Fc domain (constant or non-varying human framework) recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include cellular immune responses – complement-dependent cytotoxicity (CDC) and antibody-dependent cell mediated cytotoxicity (ADCC). Rituximab has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.
Companies.: Rituxan was commercially developed by a collaboration of IDEC (now Biogen Idec), Genentech, Hoffmann-La Roche, Ltd. (Roche; majority owner of Genentech) and Zenyaku Kogyo Co., Ltd. Operating profits for Rituxan are split 60–40 between Roche and Biogen Idec, respectively.
Genentech is the primary manufacturer of bulk rituximab concentrate, and the only manufacturer of the finished product. IDEC Pharmaceuticals Corp., now Biogen Idec, was the original manufacturer of bulk rituxmab, and continues to manufacture bulk product for finishing by Genentech, Inc. However, mid-2005 press coverage of Genentech’s manufacturing activities and capacity no longer mention Biogen Idec as a manufacturer of rixuximab bulk.
Lonza Biologics plc at its facility in Portsmouth, NH, also manufactures bulk rituximab for Genentech. See the CD20 Mab, concentrate entry below for further information about bulk manufacturers. Genentech reports that it hopes to further expand Rituxan (and also Avastin) manufacture by about 50% using its currently-licensed cell line. FDA sBLA approval for related process changes for Rituxan is expected by late 2006. Although Genentech does not report the distribution of manufacturing capacity between itself and contract manufacturers, it has reported that it expects Lonza to manufacture about one-half of rituximab bulk by late 2005 (after expected FDA approval).
Biogen Idec (originally, IDEC) and Genentech both co-promote Rituxan in the U.S. Roche holds exclusive marketing rights outside the U.S., and markets its as MabThera in Europe. Zenyaku Kogyo Co. Ltd. and Nippon Roche co-market Rituxan in Japan. Based on prior reports from IDEC, Biogen Idec receives royalties on the order of 50% from foreign sales of Rituxan to Hoffmann-La Roche and Zenyaku Kogyo Co.
Genentech books all U.S. sales, and profits are split between the Biogen Idec and Genentech based on a formula providing Genentech with the majority share (largely due to Genentech having supported Phase III trials). Biogen Idec apparently receives 30-40% of combined profits from U.S. sales. Biogen Idec’s share of co-promotion profits with Genentech is received in two tiers, a lower tier, that resets annually at the beginning of each year and a higher tier which applies once a certain co-promotion profit level is met.
As part of Hoffmann-La Roche’s broad licensing agreement with Genentech (amended in 1999 and extended to 2015; probably now irrelevant with Roche having fully acquired Genentech), Genentech provides finished product to Roche for international marketing at cost plus 20%. Roche pays Genentech a royalty of 12.5% on the first $100 million total sales and 15% after that, until either the expiration of Genentech’s patents in that country or 25 years from the first launch of the product.
The original marketing agreement between Genentech and IDEC included Genentech paying $9 million upfront in equity and licensing fees, $17.5 million funding before approval, and $30.5 million in milestone and option payments. Genentech sublicensed Japanese marketing rights to Zenyaku Kogyo Co. (with IDEC receiving $1.5 million from this action). Roche subsequently exercised its standing option to market certain Genentech products, including Rituximab, in Europe, and became IDEC’s (now Biogen Idec’s) marketing partner in Europe and the rest of the world, excluding Japan. Biogen Idec’s royalty revenue on sales outside the U.S. is based on Roche’s end-user sales and is recorded with a one-quarter lag.
In Jan. 1998, Xoma sold its interest in certain CD20 antibody-related patent licensing royalties on sales of Rituxan to Pharmaceutical Partners LLC (PPL; now Royalty Pharma, AG) for $17 million. Royalty Pharma now receives the royalties on sales previously due to Xoma.
In June 2009, an arbitration proceeding ruled that Genentech must halt several trials with Rituxan follow-on products until Biogen Idec says they can move forward. In 2006, the two companies filed for arbitration to settle whether Genentech could develop follow-on drugs to Rituxan without Biogen's approval. The arbitrator ruled that three Genentech trials must be stopped. In order for trials to proceed in the future, a Joint Development Committee comprised of three members from each company must unanimously approve a development plan for each specific indication.
In late 2010, Biogen Idec initiated transfer of U.S. marketing of Rituxan to Genentech/Roche.
In March 2012, Roche concluded an agreement with Emcure Pharmaceuticals (India) for manufacture of MabThera in India for the Indian market. This is likely an effort by Roche to deflect Indian concerns about it having a monopoly and MabThera prices being high (relatively) in India.
Manufacture: See the Rituximab concentrate entry below for manufacturing information. During its development, rituximab was manufactured at different facilities with slight modifications in the manufacturing processes.
Rituxan is manufactured from Rituximab Formulated Bulk (For Further Manufacturing Use) (see entry below), i.e., formulated recombinant bulk rituximab manufactured by Genentech, Biogen Idec, and Lonza Biologics, with Genentech being the primary manufacturer. The bulk product is provided exclusively to Genentech for further manufacture of Rituxan. Rituximab is produced by Chinese Hamster ovary (CHO) cell suspension culture in a culture medium containing the antibiotic gentamicin, with purification including affinity and ion exchange chromatography. Gentamicin is not detectable in the final product. The purification processes include specific but unspecified viral inactivation and removal steps.
FDA class: Biologic BLA
CBER class: Blood And Blood Derivatives
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19971126; first approval, BLA, granted to Genentech, Inc.; orphan designation (granted 06/13/94); for Rituxan from bulk rituximab manufactured by IDEC
Date = 19980200 (est; reported as 1st quarter); BLA supplement granted to Genentech; Indication = approval for large-scale (12,000 liter) manufacture of rituximab, supplementing rituximab manufactured by IDEC
Date = 19980900; BLA supplement; Indication = insert/label change to include warning about potential severe adverse effects during initial infusion of patients with a high tumor burden (high numbers of circulating tumor cells which lyse in the bloodstream, leading to a cascade of cytokine release)
Date = 20010419; BLA supplement; new dosing regimen for retreatment of patients and administration of eight weekly doses, and various changes to package insert/labeling
Date = 20010500 (est.); BLA supplement; Indication = for treatment of low-grade non-Hodgkin’s leukemia (NHL)
Date = 20060210; BLA supplement; Indication = use in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy for diffuse large B-Cell, CD20+, non-Hodgkin’s lymphoma (DLBCL)
Date = 20020219; BLA supplement; Indication = use of Rituxan as a component of the Zevalin (Ibritumomab Tiuxetan) therapeutic regimen [see Zevalin entry]
Date = 20060228; BLA supplement; Indication = in combination with methotrexate in adult patients with moderately-to-severely active rheumatoid arthritis with inadequate response to one or more tumor necrosis factor (TNF) antagonists
Date = 20060900; BLA supplement; Indication = first-line treatment of follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma in combination with CVP (cyclophosphamide, vincristine and prednisolone) chemotherapy; for the treatment of low-grade, CD20-positive, B-cell non-Hodgkin’s lymphoma in patients with stable disease or who achieve a partial or complete response following first-line treatment with CVP chemotherapy
Date = 20091017; BLA supplement; Indication = include on labeling guidance on how later-stage patients, those who have inadequately responded to tumor necrosis factor (TNF)-antagonist therapies, can be retreated with Rituxan.
Date = 20100419; BLA supplement; Indication =
Date = 20110419; BLA supplement; Indication = in combination with glucocorticoids (steroids), to treat patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA), two rare disorders that cause blood vessel inflammation (vasculitis). Note, . both WG and MPA are considered orphan diseases with an estimated prevalence in the U.S. of approximately three cases per 100,000 people.
Indications: [full text of "INDICATIONS AND USAGE” section from product insert/labeling; 6/2012]:
RITUXAN is a CD20-directed cytolytic antibody indicated for the
treatment of patients with:
Status: The BLA for Rituxan was filed on Feb. 28, 1997, received priority review, and was approved on Nov. 28, 1997, with FDA reporting a review time of 8.9 months (~.92 years). Rituxan is exempt from CBER/FDA lot release requirements (i.e., the original approval included exemption for Rituxan manufactured by Genentech). Rituxan was the first monoclonal antibody approved for the treatment of cancer in the U.S.
In the first quarter of 1998, Genentech received FDA approval for large-scale (12,000 liter) manufacture of Rituximab at its South San Francisco manufacturing facility. This supplements/supplants the rituximab manufactured by Biogen Idec.
Hoffmann-La Roche Ltd. filed for European Union (EU) approval of MabThera on Feb. 29, 1997 and received approval on June 3, 1998. The EU-approved indication was more restrictive than that in the U.S. – treatment of stage III-IV follicular B-cell non-Hodgkin’s lymphoma (NHL) patients resistant to chemotherapy or in second or subsequent relapse after chemotherapy. Roche received European Union approval in March 2002 for treatment of aggressive non-Hodgkin’s lymphoma (NHL) in combination with CHOP chemotherapy. Roche markets the product under the trade name MabThera in Europe and many of its other territories. In Jan. 2004, Roche filed for EU approval of MabThera as a first line treatment for indolent non-Hodgkin’s lymphoma in combination with conventional chemotherapy.
IDEC sent a “Dear Doctor” letter in September 1998 to all U.S. physicians warning about adverse effects associated with initial infusion of Rituxan, and the U.S. product insert/labeling was modified. The warnings concerned severe adverse effects – tumor lysis syndrome or cytokine release syndrome, after initial (first-time) use in patients with a high tumor burden (high number of circulating tumor cells). Tumor cells in the bloodstream are rapidly lysed, releasing and initiating a cascade of further release of cytokines. This is only associated with initial use, which presumably clears most of the offending circulating CD20+ tumor cells. No treatment-related deaths were reported in clinical trials and the two U.S. deaths reported at the time as associated with Rituxan occurred in patients receiving it off-label (e.g., for prolymphocytic leukemia). A similar “Dear Doctor” letter was distributed to European physicians by EMEA, European Union. The ~1% fatality rate associated with Rituxan treatment compares favorably with the 4% fatality rate associated with chemotherapy drug treatments.
In Aug. 2004, MabThera received European Union approval for first-line use in treatment of indolent non-Hodgkin‘s lymphoma in combination with conventional chemotherapy.
In Dec. 2005, Roche submitted an application in the European Union to expand the labeling for MabThera to include use as maintenance therapy for indolent lymphoma.
On Feb. 10, 2005, FDA approved a supplemental BLA for Rituxan use in the first-line treatment of patients with diffuse large B-cell CD20-positive, non-Hodgkin’s lymphoma (DLBCL), in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens. With this approval, Rituxan in combination with chemotherapy became the first FDA-approved treatment to improve survival for patients with this type of Non-Hodgkin’s Lymphoma since the introduction of the CHOP regimen more than 25 years earlier. The sBLA had received priority review.
On Feb. 28, 2006, FDA approved a supplemental BLA for use of Rituxan in combination with methotrexate to reduce signs and symptoms in adult patients with moderately-to-severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies. Biogen Idec and Genentech had submitted the sBLA on August 29, 2005.
On March 30, 2006, Biogen Idec and Genentech submitted a BLA supplement seeking approval of Rituxan for first-line treatment of previously-untreated patients with low-grade or follicular, CD20-positive, B cell non-Hodgkin’s lymphoma (NHL) in combination with CVP (cyclophosphamide, vincristine and prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone), or following CVP chemotherapy in those patients who achieved a response of stable disease or better.
On July 17, 2006, MabThera received European Union approval for treatment of rheumatoid arthritis in combination with methotrexate for patients having failed tumor necrosis factor (TNF) antibody (see related entries) therapy. Approval was largely based on the REFLEX trial.
In Dec. 2006, FDA requested additional information from Genentech, and Genentech and Biogen Idec sent out a warning letter to health care professionals regarding the safety of Rituxan after reports of two deaths of non-Hodgkins lymphoma patients from progressive multifocal leuklencephalopathy (PML) attributed to reactivation of latent JC virus infection (for which there was already a warning on the product’s labeling/insert). FDA also announced its intensions to add more warnings to the product label. At its Web site, FDA advised physicians to “maintain a high index of suspicion for the development” of this brain virus infection in patients taking Rituxan. With about 80% of the population latently infected with JC virus, reactivation in a significant concern. The two patients were taking Rituxan for systemic lupus erythematosus, an off-label indication, and had longstanding SLE with multiple courses of immunosuppressant therapy prior to receiving Rituxan, a factor known to be associated with induction of PML. [Note, Tysabri (see related entry) was voluntarily pulled from the market in 2005 after three cases of the brain infection, two of which were fatal, were found in patients taking this multiple sclerosis therapeutic. Tysabri is now back on the market but its marketing is heavily restricted].
In Jun 2009, an arbitrator has ruled that Genentech must halt several trials until Biogen Idec says they can move forward. Genentech and Biogen Idec were then partners in Rituxan. In 2006, the two companies filed for arbitration to settle whether Genentech could develop follow-on drugs to Rituxan without Biogen's approval. The arbitrator ruled that three trials must be stopped, though Phase III trials for the arthritis biologic ocrelizumab (later abandoned) will continue. In order for trials to proceed in the future, a Joint Development Committee comprised of three members from each company must unanimously approve a development plan for each specific indication.
On Feb. 26, 2009, the European Union granted supplemental approval to MabThera in combination with chemotherapy for use in patients with previously-untreated chronic lymphocytic leukaemia (CLL).
In June 2009, Roche filed a supplemental MAA in the European Union (EU) seeking approval of MabThera for for rheumatoid arthritis in patients have been treated with methotrexate, the current standard treatment option; for those who have had an inadequate response to methotrexate; and to prevent joint damage across all RA patients. MabThera was then only approved for use in RA patients who do not respond to tumor necrosis factor inhibitors, and Roche hoped to expand its use further in autoimmune diseases.
On May 19, 2009, Genentech and Biogen Idec submitted two supplemental BLAs to FDA for Rituxan plus standard chemotherapy for use in patients with previously untreated and treated chronic lymphocytic leukemia (CLL). The applications are based on positive results from two of the largest global Phase III clinical trials conducted in patients with ClL.
On Oct. 17, 2009, Genentech and Biogen Idec received a Complete Response from FDA for a supplemental BLA for Rituxan plus methotrexate (MTX) in patients with moderately-to-severely active rheumatoid arthritis (RA) who no longer respond to treatment with a disease modifying antirheumatic drug (DMARD), including MTX. FDA indicated that they did not believe an approval for Rituxan (in people with RA who have not previously received MTX or those who were MTX inadequate responders) could be supported at this time due to the rare risk of progessive multifocal leukeoencephalopathy (PML) in light of the number of effective RA treatments currently available to patients in earlier stages of the disease. PML is a usually fatal brain disease caused by the reactivation of a common virus called the JC virus. Although the incidence of PML in RA patients treated with Rituxan is rare (then three reports out of approximately 100,000 patients), there are no known reliable PML treatments.
In Feb. 2010, FDA granted supplemental approval to Rituximab for treatment of CLL in combination with chemotherapy drugs, fludarabine and cyclophosphamide.
On Oct. 17, 2010 FDA approved an additional sBLA submission to include updated safety and efficacy data in the label that provides guidance on how later-stage patients, those who have inadequately responded to tumor necrosis factor (TNF)-antagonist therapies, can be retreated with Rituxan. The prescribing information includes language that subsequent courses of the standard Rituxan regimen (two doses at 1000 mg each) can be administered every 24 weeks or based on clinical evaluation. Subsequent courses should not be administered sooner than 16 weeks. Rituxan's ability to improve physical function and slow joint damage for up to two years as demonstrated in clinical studies was also added.
On Oct. 23, 2010, Genentech and FDA notified U.S. healthcare professionals about a third case of progressive multifocal leukoencephalopathy (PML), the first case of PML in a patient with rheumatoid arthritis treated with Rituxan who has not previously received treatment with a TNF antagonist. Information to date suggested that patients with RA who receive Rituxan have an increased risk of PML. Physicians should consider PML in any patient being treated with Rituxan who presents with new onset of neurologic manifestations.
In Feb. 2010, FDA granted supplemental approval to Rituximab for treatment of CLL in combination with chemotherapy drugs, fludarabine and cyclophosphamide.
On Feb. 27, 2010, EMEA/European Union approved MabThera (rituximab) in combination with chemotherapy for use in patients with previously-untreated chronic lymphocytic leukaemia (CLL), the most common type of leukaemia to affect adults. The approval is based on compelling results from the pivotal Phase III study CLL8.
On Sept. 24, 2010, the Committee for Medicinal Products for Human Use (CHMP), EMEA, European Union (EU), has issued a positive recommendation for the use of MabThera as maintenance treatment for people suffering from follicular lymphoma who have responded to induction therapy.
In Nov. 2010, the European Commission approved the use of MabThera as a maintenance treatment for people suffering from follicular lymphoma who have responded to initial induction therapy. Maintenance treatment is an important approach to blood cancer management as it reduces the risk of relapse and the use of repeated chemotherapy, ultimately improving the lives of follicular lymphoma patients. The approval of MabThera maintenance expanded effective treatment options for people with this common type of incurable blood cancer, doubling the likelihood of them living longer without their disease worsening.
In Jan. 2011, Genentech has agreed to pay $20 million to the U.S. government to settle a qui tam suit alleging kickbacks for off-label promotion of Rituxan.
In April 2011, the new indications for Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) were the first U.S. approvals for these orphan indications.
In May 2012, the European Medicines Agency (EMA) OKed MabThera after concluding that contamination of its bioreactors pose little threat. This came about a year after Roche first found Leptospira licerasiae, a potentially deadly bacterium, in bioreactors at its MabThera (rituximab) plant in California. An EMA investigation began in Dec. 2011 and concluded patients are safe to continue using product. No bacteria were detected in the active substance or in the finished product,” the Committee for Medicinal Products for Human Use wrote in its conclusion. Roche detected the contaminant, which causes leptospirosis, in bioreactors used in the pre-harvest steps of rituximab production in May 2011 and again in August. This prompted the EMA to look into the problem and a Danish team visited the plant to assess its infrastructure and quality management. The EMA concluded the benefits of MabThera outweigh the risks and recommended maintaining its marketing authorization with certain caveats. These conditions include the development of a more sensitive test for detection of the contaminant and further data on corrective steps Roche took. Investigators believe the contamination stemmed from cell culture media used in the bioreactors. The media preparation process or employees acting as carriers are two possible routes for contamination of the production cultures. The lack of L. licerasiae in the later stages of production suggested the manufacturing process removes the bacteria and any proteins which it releases. Roche discarded all material in which the bacterium was detected.
In May 2013, the USP issued a monograph concerning the identity and analytical criterial for rituximab.
On March 28, 2014, the European Commission (EC) has approved a new subcutaneous (SC) formulation of MabThera (rituximab) for the treatment of patients with follicular lymphoma and diffuse large B-cell lymphoma. The new formulation, which was approved to treat some patients with non-Hodgkin lymphoma, cuts the treatment time from two-and-a-half hours for the original intravenous version to 5 minutes.
Tech. transfer: Genentech in May 1996 exclusively licensed CD20 antibody technology from Xoma Corp. (see paragraph below). Genentech subsequently sublicensed this technology to IDEC (now Biogen Idec). Biogen Idec has claimed that U.S. patent coverage for Rituxan will expire between 2015 and 2018.
U.S. patent 5,721,108 (also 5,677,180 and 5,500,362), “Chimeric antibody with specificity to human B cell surface antigen,” Robinson, R.R. and Liu, A.Y., Feb. 24, 1998, assigned to Xoma Corp., describes aspects of rituximab. The invention “relates to a chimeric antibody molecule comprising two heavy chains and two light chains, each of the chains comprising a variable region and a human constant region, said antibody having specificity for the antigen bound by the 2H7 murine monoclonal antibody” A transfected hybridoma cell line secreting recombinant chimeric murine-human 2H7 was deposited as ATCC HB 9303. See also U.S. 5,763,137 and WO 9411026.
U.S. 6,399,061, “Chimeric and radiolabelled antibodies specific to human CD20 antigen and use thereof for treatment of B-cell lymphoma,” assigned to IDEC, describes the murine antibody 2B8 deposited as ATCC HB11388 used to derive the recombinant chimeric CD20 monoclonal antibody secreted by transfectoma TCAE8, deposited as ATCC No. 69119. U.S. 6,455,043, “Combination Therapies for B-cell lymphomas comprising administration of anti-CD20 antibody,” assigned to IDEC, describes methods of using rituximab for reducing residual CD20+ tumor cells in bone marrow or stem cell tissue after myeloablative therapy,
Genentech currently holds very broad patent protection for recombinant chimeric/humanized monoclonal antibody design/construction and pression technology (particularly involving co-expression of heavy and light chains). This includes the “New Cabilly” U.S. patent (6,113,415), which includes the claims from the revoked “Boss” Celltech Group patent, and Genentech having cross-licensed its patents with Celltech. See the Tech. transfer section of the Monoclonal Antibodies entry (#300) for further information about the complex patent, licensing, cross-licensing and patent disputes concerning recombinant chimeric/humanized monoclonal antibodies.
In Sept. 2000, GlaxoSmithKline Inc. (GSK) filed suit against Genentech alleging that Rituxan (and also Herceptin) infringed its U.S. patents 5,633,162 and 5,545,405 concerning methods for culturing Chinese hamster ovary (CHO) cells. Genentech prevailed in this suit.
Genentech was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002, and the university again demanded royalties, which Genentech and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
In Jan. 2006, Genentech and Amgen cross-licensed their respective enabling recombinant monoclonal antibody technologies. Amgen received nonexclusive licenses to Genentech’s Cabilly II and other patents. Neither company will discuss what Genentech received in exchange. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
U.S. patent protection for Rituxan is projected by Decision Resources to expire in 2015, and in European countries in 2013. However, with diverse entity/active agent, use, manufacturing process, formulation and other patents, this may well be an oversimplification of the patents that may be expected to be asserted against competitors.
In mid-2008, it was reported that Rituxan-relevant CD20 antibody U.S.patents will expire by 2014. This patent broadly covers the use of CD20 antibodies for the treatment of rheumatoid arthritis (RA).
On Sept. 11, 2008, in a case filed by Trubion Pharmaceutical ,the European Patent Office (EPO) revoked Genentech and Biogen Idec's European Patent 1176981, in its entirety, with the patent not meeting standards for patenability. This patent was generally directed to the use of an anti-CD20 antibody for the treatment of rheumatoid arthritis (RA). The revocation was the result of an opposition proceeding brought by Trubion and several other parties. Genentech and Biogen Idec will likely appeal this ruling. Trubion is developing TRU-015 and other CD20 antibody-based therapeutics, including collaborating with Wyeth, which manufactures and markets Enbrel.
In June 2010, the Board of Appeal for the European Patent Office (EPO) has upheld the Opposition Division's original decision (announced Sept. 11, 2008) to revoke Genentech and Biogen Idec's European Patent 1176981, generally directed to the use of an anti-CD20 antibody for the treatment of rheumatoid arthritis (RA). The revocation of the patent claims as originally granted is now final. Subsequent to the original submission of Trubion's opposition, other parties filed oppositions to the Genentech patent, including MedImmune Inc., Genmab A/S, Centocor Inc./J&J, GlaxoSmithKline (GSK)., Merck Serono S.A, and Wyeth (now Pfizer). No further appeals can be made with regard to the revoked claims, but Genentech and Biogen Idec were allowed to pursue a claim limited to the use of rituximab in combination with methotrexate to treat RA. The Board of Appeal sent this claim to the Opposition Division to assess patentability.
Trials: In its pivotal Phase III trial, Rituxan at a dose of 375 mg/m2 was administered to 166 patients as an intravenous infusion at weekly intervals for four doses. Results were published in the August 1998 issue of the Journal of Clinical Oncology. The peak and trough serum levels of Rituximab were inversely correlated with baseline values for the number of circulating CD20+ B-cells and measures of disease burden. Median steady-state serum levels were higher for responders compared to nonresponders; however, no difference was found in the rate of elimination as measured by serum half-life. Serum levels of rituximab were higher in patients with International Working Formulation (IWF) subtypes B, C, and D tumors, as compared to those with subtype A. Rituximab was detectable in the serum of patients 3-6 months after completion of treatment. Also, the pharmacokinetic profile of Rituximab when administered as six infusions of 375 mg/m2 in combination with six cycles of CHOP (a combination chemotherapy regimen) was similar to that of Rituximab alone.
Administration of Rituxan resulted in a rapid and sustained depletion of circulating and tissue-based B-cells. Among the 166 patients, circulating B-cells (measured as CD19+ cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. B-cell recovery began at approximately six months following completion of treatment. Median B-cell levels returned to normal by twelve months following completion of treatment. There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following Rituximab administration. However, only 14% of patients had reductions in IgG and/or IgM serum levels resulting in values below the normal range (i.e., patients still retained circulating antibodies).
In Dec. 1998, Genentech and IDEC announced the results from the long-term follow-up of its pivotal trial. The data indicated that 48% (80/166) of patients with relapsed or refractory low-grade or follicular, CD20-positive, B-cell non-Hodgkin’s lymphoma responded to treatment with Rituxan – 6% were complete responses and 42% were partial responses. The median time to onset of response was 50 days, and the median duration of response was 11.6 months. Twenty-two of the 80 responders (28%) were experiencing ongoing remissions lasting from 1.5-3 years. Responses, as measured by CT scans, were confirmed in a blinded audit by independent lymphoma experts using the rigorous complete response criteria of ≤1.0 x 1.0 cm for normal lymph node size. This study confirmed that patients treated with Rituxan after their first chemotherapy relapse had a higher response rate (57%) than those treated after second or third relapses from chemotherapy (38%). In refractory patients, the overall response rate was 29% or 6 out of 21. Disease-related signs and symptoms were present in 23% (39/166) of patients at study entry and resolved in 64% (25/39) of these patients. Rituxan provided durable remissions in patients who typically experience multiple relapses with shorter disease-free intervals after each treatment.
In a second multicenter, multiple-dose study, 37 patients with relapsed or refractory B-cell NHL received 375 mg/m2 of Rituxan as an i.v. infusion once weekly for four doses. The overall response rate was 46% with a median duration of response of 8.6 months (range 2.6 to 26.2+). Single doses of up to 500 mg/m2 were well-tolerated.
In Dec. 2003, initial positive results were reported from the first randomized Phase III trial with Rituxan in previously untreated (first-line) patients with repeated indolent non-Hodgkin’s lymphoma (NHL). The addition of Rituxan to a chemotherapy regimen of cyclophosphamide, vincristine, and prednisone (R-CVP) prolonged time to treatment failure, the primary endpoint of the study, to 26 months compared to seven months for patients treated with R-CVP alone. This study met its primary endpoint two years earlier than expected. Rituxan was already approved for this indication.
As of early 2004, Rituxan was in advanced trials for repeated use (maintenance therapy), particularly for indolent or slow-growth NHL. Rituxan is also in trials for rheumatoid arthritis and multiple sclerosis. In June 2004, results were published in the New England Journal of Medicine from a Phase IIa study showing that Rituxan (2 doses, 2 weeks apart) improved symptoms in patients with moderate-to-severe rheumatoid arthritis (RA) for up to 48 weeks when combined with methotrexate (MTX), compared to MTX alone at 24 and 48 weeks.
In Nov. 2004, Biogen Idec, results were reported from DANCER, a Phase IIb clinical study of Rituxan in patients with moderate-to-severe rheumatoid arthritis who were also treated with methotrexate. The trial met its primary endpoint, with a significantly greate proportion of Rituxan plus methotrexate-treated patients achieved an American College of Rheumatology (ACR) 20 response at week 24, compared to placebo.
In April 2004, Genentech reported that the REFLEX (Randomized Evaluation of Long-term Efficacy of Rituximab in RA) Phase III trial of Rituxan in rheumatoid arthritis patients who inadequately responded with one or more anti-TNF therapies and received one course of two infusions of Rituxan with a stable dose of methotrexate met its primary endpoint, achieving an American College of Rheumatology (ACR) 20 response at week 24, compared to placebo. These were the first Phase III Rituxan data to demonstrate clinical improvement in this difficult-to-treat RA patient population. REFLEX was a multi-center, randomized, double-blind, placebo-controlled Phase III study. Patients who received an initial course of only two infusions of 1000 mg two weeks apart with a stable dose of methotrexate displayed a statistically significant improvement in ACR 20 measured at 24 weeks, compared to those receiving placebo and methotrexate, with no unexpected safety issues.
The Feb. 2006 approval for first-line treatment of patients with diffuse large B-cell, CD20-positive, non-Hodgkin’s lymphoma (DLBCL), in combination with CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or other anthracycline-based chemotherapy regimens was supported by three randomized, controlled, multicenter studies of Rituxan in combination with CHOP (R-CHOP) or other anthracycline-based chemotherapy induction regimens in 1,854 previously untreated (first-line) patients with DLBCL. In each study, hazard ratios for the time-to-event comparison, as well as the overall survival benefit, favored the Rituxan-containing arms. Results were generally consistent across subgroups, including age, gender and disease prognostic variables. With two years of follow-up, more patients survived in the Rituxan-containing vs. control arms for each study. In one of the studies with five years of follow-up, the GELA trial, R-CHOP improved overall survival by 47% compared to CHOP alone (a hazard ratio of 0.68, a 32% decrease in the risk of death).
The Feb. 2006 approval was based on three randomized, double-blind, placebo-controlled studies of patients with active RA. In Nov. 2005, Roche reported results from the Phase III REFLEX (Randomised Evaluation oF Long-term Efficacy of RituXimab) study, evaluating the efficacy and safety of MabThera in patients with rheumatoid arthritis (RA) with prior inadequate response to tumor necrosis factor (TNF) antibody therapy. The study included patients with active RA who had an inadequate response or were intolerant to prior treatment with one or more TNF antagonist therapies, e.g., Enbrel, and current methotrexate therapy. MabThera significantly improved all efficacy measures of RA for six months following a single course of two administrations two weeks apart, providing a highly convenient regimen. MabThera provided relief to almost three times as many patients compared to placebo. Currently, such difficult-to-treat RA patients, who represent at least 30% of all those treated with existing biologic therapy, have few treatment alternatives. MabThera in combination with methotrexate (MTX), a standard RA treatment, was highly effective, producing statistically significantly higher response rates compared to MTX plus placebo: 51% of patients achieved 20% improvement in signs and symptoms (ACR20%), compared to 18% with MTX alone. The difference in the two groups was apparent after 8 weeks and sustained for the duration of the study. Over the six-month period, more than five-times as many patients in the MabThera group achieved a 50% improvement (ACR50%) in signs and symptoms compared to MTX alone, and twelve-times more MabThera patients achieved a 70% improvement (ACR70%). Overall the MabThera was well tolerated. This study confirmed earlier findings from the DANCER study.
In Aug. 2006, Genentech and Biogen Idec reported encouraging results from a Phase II trial of Rituxan for relapsing-remitting multiple sclerosis (RRMS). The study of 104 patients who received Rituxan (1,000 mg on day 1 and 15) or placebo showed a statistically significant reduction in the total number of gadolinium-enhancing T1 lesions observed on serial MRI scans of the brain at weeks 12, 16, 20 and 24 in the Rituxan-treated group compared to placebo. Rates of overall adverse events and serious adverse events were comparable between the two treatment groups. Patients will continue to be followed for 48 weeks. These initial results exceeded the companies’ expectations, indicating Rituxan will likely move into a Phase III program for RRMS. Assuming Genentech initiates a Phase III study and two-year data are needed for approval, sales in RRMS are at least 3-4 years away.
In Nov. 2006, Roche reported long-term data from a Phase III study in 321 patients showing that Rituxan (MabThera) as a first-line therapy prolonged survival for patients with advanced follicular non-Hodgkin’s lymphoma when used in combination with cyclophosphamide, vincristine and prednisolone (CVP). Rituxan combination regimen increased overall survival at four years, with 81% patients treated with Rituxan and chemotherapy still alive compared with only 71% on chemotherapy alone. Patients in the combination arm had a significantly extended time to disease progression or death of 34 months compared with 15 months for patients receiving CVP alone. The estimated disease-free survival at four years was 54% for patients given the four drug regimen, versus 17% for those on CVP.
In Jan 2008, it was reported that the SERENE Phase III study of Rituxan in biologic-naïve patients met its primary endpoint of a significantly greater proportion of Rituxan-treated patients achieving an American College of Rheumatology (ACR) 20 response at week 24, compared to placebo. The study enrolled patients with moderately-to-severely active rheumatoid arthritis (RA) who had an inadequate response to prior treatment with methotrexate (MTX). Patients who received a single treatment course of two infusions of either 500 mg or 1000 mg of Rituxan in combination with a stable dose of MTX displayed a statistically significant improvement in ACR20 scores compared to patients who received placebo in combination with MTX. Although the study was not designed to compare the Rituxan doses, treatment efficacy appeared to be similar between both Rituxan doses. These findings support the potential use of Rituxan earlier in the course of treatment for RA.
In Jan 2008, it was reported that a Phase III trial of Rituxan for of adult leukaemia, chronic lymphocytic leukaemia (CLL) had reached its primary endpoint of progression-free survival. These results were obtained almost a year ahead of expectations. Roche expects to file for approval for adult CLL in the EU based on these results.
In April 2008, it was reported that the Phase II/III study of Rituxan for systemic lupus erythematosus (SLE) in 439 patients with moderate-to-severe SLE on a background immunosuppressant had not meet its primary endpoint defined as the proportion of Rituxan treated patients who achieved a major clinical response (MCR) or partial clinical response (PCR) measured by BILAG, a lupus activity response index, compared to placebo at 52 weeks. The study also did not meet any of the six secondary endpoints. Genentech and Biogen Idec will continue to analyze the study results and will submit the data for presentation at an upcoming medical meeting. Another ongoing Phase III trial in lupus nephritis (LUNAR) is testing Rituxan in a different patient population, those with active lupus nephritis.
In April 2008, it was reported that the OLYMPIC Phase II/III study of Rituxan for primary-progressive multiple sclerosis (PPMS) had not met its primary endpoint as measured by the time to confirmed disease progression during the 96-week treatment period. This study was designed to evaluate the efficacy, safety and tolerability of four courses of Rituxan in patients with PPMS. The incidence of overall adverse events was comparable between Rituxan and placebo treatment groups. PPMS is widely considered a difficult form of MS to treat and historically no therapy has proven efficacy in this disease state.
In Dec. 2008, results were reported from two global Phase III studies in chronic lymphocytic leukemia (CLL), CLL8 and REACH, showing that Rituxan plus chemotherapy significantly increased the time patients lived without their disease advancing, as defined by the primary endpoint of progression-free survival (PFS), when compared to chemotherapy alone. No new safety signals were observed in either of these studies and the safety profile was consistent with previous experience with Rituxan, These are among the largest studies ever conducted in chronic lymphocytic leukemia and are significant for patients with newly diagnosed or relapsed disease.
Also in Dec. 2008, results were reported from the IMAGE trial Phase III study of Rituxan in 755 MTX-naïve patients with early rheumatoid arthritis (RA) who had not previously been treated with methotrexate (MTX). I MAGE was a multi-year, Phase III, randomized, double-blind, placebo-controlled, parallel group, multicenter international study designed to evaluate the safety and efficacy profile of Rituxan in combination with a stable dose of MTX compared to MTX alone, in methotrexate-naive patients with active RA. The trial met its primary endpoint. At week 52, only patients in the 1000 mg treatment group met the primary endpoint and showed significantly less progression of joint damage compared to patients who received placebo in combination with MTX. Joint damage was assessed by changes in X-ray images using the Genant-modified total Sharp score. In both Rituxan treatment groups, secondary endpoints showed a significantly higher proportion of patients with a substantial improvement in RA signs and symptoms (including ACR scores and DAS remission) compared to patients receiving MTX alone.
In the May 14, 2009 issue of Blood, results were reported from the RADAR (Research on Adverse Drug Events and Reports) project linking rituximab to progressive multifocal leukoencephalitis (PML). The study reportd 57 cases from 1997 to 2008 in which patients with anemia, rheumatoid arthritis or lymphoma developed the fatal brain disease after taking rituximab, and died an average of two months after being diagnosed. It was not yet known how rituximab is connected to the brain virus and who may be at risk. Concerns about Rituxan's association with PML first surfaced in 2006 when two patients with lupus developed the illness after taking rituximab and other immunosuppressive treatments.
The Feb. 2010 FDA approval for CLL was based on data from two Phase III studies, CLL8 and REACH. Sponsored by Roche and conducted by the German CLL Study Group, CLL8 was a global, multi-center, randomized, open-label, Phase III study that enrolled 817 patients with previously untreated CD20-positive CLL. REACH was a global, multi-center, randomized, open-label, Phase III study sponsored by Genentech, Biogen Idec and Roche that enrolled 552 patients with previously treated CD20-positive CLL who had not previously received Rituxan (Rituxan-naïve). Both studies evaluated Rituxan plus ludarabine and cyclophosphamide (FC) compared with FC alone. The primary endpoint for both studies was PFS and secondary endpoints included overall survival, event-free survival, duration of response, response rate, complete response and toxicity..
The Sept. 2010 EU approval for the use of MabThera as maintenance treatment for people suffering from follicular lymphoma who have responded to induction therapy as based on the results of the PRIMA study. This showed that continuing MabThera for two years (maintenance treatment) in patients who responded to initial treatment with MabThera plus chemotherapy doubled the likelihood of progression-free survival (PFS), compared to those who did not receive maintenance treatment. After two years of follow-up, 82% of patients who received MabThera maintenance were in remission compared to 66% of patients who did not. The benefit of maintenance treatment was seen across all major patient groups analysed within the trial regardless of their tumour burden, age, gender or their response to initial treatment. Sponsored by the Groupe d'Etude des Lymphomes de l'Adulte (GELA), PRIMA was an international, multicenter, randomized, Phase III clinical study that enrolled 1217 patients with previously untreated advanced follicular lymphoma. The study evaluated the efficacy and safety profile of maintenance MabThera in patients who responded to initial treatment with MabThera plus chemotherapy (induction treatment).
Medical: The recommended dosage of Rituxan is 375 mg/m2 given as an intravenous infusion once weekly for four doses (days 1, 8, 15, and 22). Rituxan may be administered in an outpatient setting. The loss of antibody-forming B-cells increases patient susceptibility to infections. Normal, fully functional B-cells and normal humoral antibody induction are replenished by CD20-negative progenitor cells within six to nine months following therapy.
Disease: Non-Hodgkin’s lymphoma (NHL) currently is the 6th leading cause of death among cancers in the U.S. and has the second fastest growing mortality rate. Approximately 55,000 people in the U.S. are diagnosed with NHL each year, and about 65% of this group are of the low-grade or follicular subgroup of NHL, which is largely incurable using conventional chemotherapy (which is more effective against faster-growing cancers). According to the Lymphoma Research Institute, 332,000 persons in the U.S. are living with NHL, with 24,300 deaths annually, and a 55% five-year survival rate. According to the National Cancer Institute (NCI), approximately 300,000 people are living with NHL in the U.S., with approximately 140,000 people having low-grade or transformed low-grade disease (the type most treatable by Rituxan), and 120,000 people having intermediate-grade disease.
Market: Biogen Idec has reported that Ritixan “is the #1 seller of cancer therapeutics in the United States,” basing this on revenue, not number of treated patients.
Total 2006 sales of Rituxan/MabThera by Roche and Genentech were CHF 4,839 million (~$3.973 billion on 7/6/2007), up 15% from 2005 (est. $3.455 million, using 7/07 exchanges rates). MabThera is now the Roche Group’s single largest-selling product. Total sales were $2.989 billion in 2004; $2.243 billion in 2003; $1,163 billion in 2002; $818.7 million in 2001; $444.1 million in 2000; $279.4 million in 1999; and $162.6 million in 1998.
Total U.S. Rituxan sales reported by Genentech were $2.6 billion in 2009; $2.6 billion in 2007, $2.3 billion in 2006, $1.831.4 billion in 2005, $1.5740 billion in 2004, $1.3602 billion in 2003, $1.0802 billion in 2002, $779.0 million in 2001; $424.2 million in 2000; $262.7 million in 1999; $152.1 million in 1998; and $5.5 million in 1997. Total sales reported by Genentech to collaborators were $157.9 million in 2005; $137.2 million in 2004, $128.9 million in 2003; $82.7 million in 2002; $39.6 million in 2001; 19.9 million in 2000; $16.7 million in 1999; and $10.4 million in 1998. U.S. net sales include Biogen Idec’s/IDEC’s royalty income from F. Hoffmann-La Roche Ltd. on sales of Rituximab outside the U.S.
Total 2012 revenue reported by Roche was CHF 6.7 billion ($7.3 billion).
Total 2012 revenue reported by Biogen-Idec was about $1.1 billion.
Worldwide 2009 sales for RA indications: were estimated to be $845.9 million or ~15% of all sales.
In Sept. 2005, Friedman Billings and Ramsey (FBR) analysts had projected total Genentech’s revenue from worldwide sales of Rituxan, including ex-U.S. sales to collaborators, would be $2.002 billion in 2005, $2.196 billion in 2006, $2.475 billion in 2007, $2.598 billion in 2008, and $2.725 billion in 2009.
Biogen Idec/Biogen reported Rituxan-related revenue of $709 million in 2004, $615 million in 2004, $493 million in 2003, and $386 million for 2002 from its joint business (co-promotion) arrangement with Genentech. Biogen received royalties on sales of Rituxan outside of the U.S. of $67.9 million in 2003, and $45.4 million in 2002.
In the 1st quarter 2005, Genentech reported that the current adoption rate (market penetration) for Rituxan in combined NHL and CLL was 77%; 86% for front-line indolent NHL; 77% for relapsed indolent NHL; 86% for front-line agressive NHL; 61% for relapsed aggressive NHL; 64% for front-line CLL; 61% for relapsed CCL; with 69% of physicians using maintenance treatment; and 18% of treated patients receiving Rituxan maintenance.
The 2007 Average Wholesale Price (AWP) is $593.84/10 ml vial and $2,969.063/50 mL vial (Red Book, 2007), For comparison the 2005 AWP was $548.61/10 ml vial ($527.50 in 2004) and $2743.03/50 mL vial ($2,637.52 in 2004).
In April 2009, with its European Union approval for chronic lymphocytic leukemia (CLL) and recommendation for approval by National Institute for Clinical Excellence (NICE), U.K. (see below), NICE noted that the total cost in the U.K. for CLL treatment is 10,129 Pounds (about $15,700).
For cancer, Rituxan is commonly reported to cost about $20,000 for a six-treatment course; and for rheumatoid arthritis, about $9,088 for a six to nine month treatment. The price for a standard 22-day course of therapy upon original approval was reported as $8,904. In late 2005, the cost for a 22-day course (which includes four doses) of Rituxan treatment for NHL was reported by one source to cost $13,000. A full course of treatment involves a total of 2.8-3 grams of the monoclonal antibody (a substantial amount of recombinant protein, which helps explain Rituxan’s relatively expensive costs). Patients generally receive Rituxan intravenous infusions directly from their oncologist (generally covered by Medicare).
Biogen Idec has stated that about 2.8 million people in the U.S. have rheumatoid arthritis (RA), and that about 20% were receiving TNF antagonsts in 2004. The company estimated that about 25% of RA patients have an inadequate response to anti-TNF inhibitors, which would make the potential market for Rituxan about 140,000 patients.
In early 2004, it was reported that over 300,000 patients worldwide had received Rituxan, with Rituxan being “the number one anti-tumor product in the United States and the number two anti-tumor product in the world (in terms of sales).” Rituxan is also Genentech’s top-selling product. First year sales revenues from Rituxan exceeded that of any previously launched anticancer therapeutic. The majority of non-Hodgkin’s lymphoma and CLL patients now have received Rituxan. At the end of 2002, Rituxan was being administered to 62% of potential non-Hodgkin’s lymphoma and CLL patients, up from 47% in 2001.
At the start of 2003, with the implementation of the outpatient prospective payment system (OPPS), a new Medicare reimbursement system covering hospital outpatient treatment costs, some hospitals began to refuse to treat patients with Rituxan and some patients were unable to find a physician willing to provide treatment with Rituxan. Medicare simply was paying (reimbursing) less than the actual acquisition cost of Rituxan, and some party, whether hospital/clinic, patient, insurance, etc. had to cover the unreimbursed cost of Rituxan. OPPS primarily bases reimbursement presuming that regional labor costs are the primary cost for a medical procedure. This tends to short-change coverage for expensive therapeutics. With its increased sales, this problem presumably has been resolved.
A major benefit of Rituxan compared to conventional combination chemotherapy drug regimens is its relative lack of chronic toxicity and lack of chemotherapy-associated adverse effects. In late 1999, it was estimated that perhaps 50% of Rituxan sales came from off-label use, i.e., then unapproved use for treatment of B-cell cancers other than non-Hodgkin’s lymphoma. This is not unusual for cancer therapeutics.
The National Institute for Clinical Excellence (NICE), the U.K. agency that reviews the cost-effectiveness of therapeutics (and decides how products will be covered by national health insurance), in May 2003 issued a report recommending use of Rituxan in combination with CHOP (a standard chemotherapy combination regimen) for first-line treatment of all patients with CD20+ diffuse large B-cell NHL at stages II, III and IV. However, NICE reported that Rituxan alone is not cost-effective for patients with localized disease (stage I), and rejected its widespread use for this indication. Previously, in 2002, NICE recommended Rituxan use for treatment of stage III and IV follicular NHL, but not for patients considered candidates for conventional chemotherapy.
In Sept. 2006, NICE announced it would review MabThera use for rheumatoid arthritis (RA) under its new single technology appraisals (STA) process designed to reduce review time. In Aug. 2007, NICE ruled in favor of use of MabThera for treatment of severe RA.
In April 2009, NICE issued draft guidance and recommended use of MabThera in combination with fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia (CLL).
Rituxan may eventually compete for NHL indications: with Bexxar and Zevalin, both CD20-targeted radioimmune conjugates (radioisotope-monoclonal antibody conjugates). Currently, both Bexxar and Zevalin are approved only for NHL patients not responding to or having failed Rituxan therapy. Bexxar is not associated with infusion-related toxicity and can be administered in an hour or less, unlike Rituximab which can cause toxicity requiring halt or slowing of administration. Most lymphoma patients receiving Bexxar are treated by nuclear medicine specialists, while most patients receive Rituxan i.v. infusions from their oncologist. Biogen Idec is conducting a Phase III trial combining use of Rituxan and Bexxar.
In June 2011, National Institute for Health and Clinical Excellence (NICE), U.K., published final guidance recommending the use of MabThera (rituximab) as a maintenance therapy for non-Hodgkin’s lymphoma. The guidance states that the drug can be used as a first-line maintenance treatment in people with follicular non-Hodgkin’s lymphoma that has responded to first-line induction therapy with MabThera in combination with chemotherapy, in order to help prevent the spread of the disease.
In July 2010, NICE published its final recommendations for the use of MabThera as a treatment for leukaemia on the National Health Service. The Institute’s Final Appraisal Determination backed the use of MabThera as a cost-effective treatment for patients with relapsed/refractory forms chronic lymphocytic leukemia (CLL). NICE recommended use of Rituxan in combination with chemotherapy drugs fludarabine and cyclophosphamide, for the treatment of relapsed or refractory CLL (except when the condition has not previously responded to fludarabine or has relapsed within 6 months of treatment, or has previously been treated with rituximab). The Institute’s appraisal committee ruled that, at an incremental cost of £15,600 per QALY (quality-adjusted life year), MabThera is cost-effective for the NHS.
In Dec. 2010, National Institute for Health and Clinical Excellence (NICE), U.K., favored recommending Roche’s MabThera as a National Health Service funded maintenance option for patients with follicular non-Hodgkin’s lymphoma (NHL). A preliminary draft guidance endorsed MabThera as a first-line maintenance treatment for certain patients with the disease, based on evidence that the drug “could significantly help to delay the growth and spread of the cancer”
In Sept. 2011, NICE published draft recommendations for MabThera in combination with a wide range of chemotherapy treatments for symptomatic stage III and IV follicular lymphoma. An independent appraisal committee at NICE found that MabThera - used in combination with cyclophosphamide, vincristine and prednisolone (CVP), cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP), mitoxantrone, chlorambucil and prednisolone (MCP) and cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon-a (CHVPi) chemotherapy - is both clinically and cost-effective as a first-line treatment. NICE had previously recommended MabThera in combination with CVP for this indication, and this review of that appraisal now provisionally added three other chemotherapy plus MabThera options. This technology appraisal was a review of NICE technology appraisal 110, issued in September 2006. The previous guidance recommended the use of MabThera plus CVP as an option for first-line induction therapy for symptomatic stage III-IV follicular lymphoma. However, in 2008 the marketing authorization was revised to allow the use of a wider range of chemotherapy regimens, which is the subject of this newer guidance review.
In Jan. 2012, NICE adopted final recommendations for MabThera in combination chemotherapy treatments for symptomatic stage III and IV follicular lymphoma.
Ongoing: Based on positive preliminary results from studies of Rituxan in rheumatoid arthritis, as well as several other small investigator-sponsored studies in various autoimmune mediated diseases, Genentech has advanced Rituxan into trials for indications: including multiple sclerosis, systemic lupus erythematosis and ANCA-associated vasculitis. Biogen Idec is conducting a Phase III trial for non-Hodgin’s lymphoma combining use of Rituxan and Bexxar.
Hoffmann La-Roche/Genentech is developing RO5072759 (GA101), "the first humanized and glycoengineered type II monoclonal anti-CD20 antibody in clinical trials." This could be a potential follow-on or second-generation replacement in the company's product line for Rituxan/MabThera.
Competition: In May 2007, Reditux, a generic (biogeneric, biosimilar, follow-on protein, etc.) version of MabThera (Rituxan) from Dr. Reddy’s Laboratories Ltd. (DRL) received approval in India for treatment of non-Hodgkin’s lymphoma. The product costs about one-half of that of MabThera from Roche, about Rs10,000 ($243) for a 100 mg/10 mL vial. Dr. Reddy’s Labs. reports that Reditux was " explicitly designed to be a version of rituximab," and that, "The Indian market is a branded generics market and substitutability in the U.S. sense is not relevant." So, it was approved as being the same as Rituxan, but is marketed with its own trade name, not a generic name. Clinical trials involved 67 patients (a trivial amount by US/EU standards). DRL's post-market surveillance in more than 1000 patients (as of November 2010) has shown no difference in immunogenicity (no reported events). Sales of Reditux remain trivial by biopharmaceutical standards -- just $26 million at most in 2011 (CAGR of 39% from fiscal 2007-08).
Companies involvement:
Full monograph
115 CD20 Mab, rDNA
Non-Hodgkin’s Lymphoma (NHL)
Chronic Lymphocytic Leukemia (CLL)
Rheumatoid Arthritis (RA) in combination with methotrexate in adult
patients with moderately-to severely-active RA who have inadequate
response to one or more TNF antagonist therapies
Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)
in adult patients in combination with glucocorticoids
Limitations of Use: RITUXAN is not recommended for use in patients with
severe, active infections
Nomenclature:
CD20 Mab, rDNA [BIO]
Rituxan [TR]
Rituximab [FDA USAN INN]
anti-(human CD20 antigen) immunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain) disulfide with human-mouse mono-clonal IDEC-C2B8 gamma-chain, dimer [CAS]
immunoglobulin G 1 (human-mouse monoclonal IDEC-C2B8 gamma1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 kappa-chain, dimer [CAS]
174722-31-7 [CAS RN]
anti-CD20 monoclonal antibody [SY]
CD20 monoclonal antibody, recombinant [SY]
IDEC-C2B8 [SY]
pan-B antibodies [SY]
MabThera [TR used by Roche outside of U.S. and Japan]
molecular weight (kDa) = 144.6
FDA Class: Biologic BLA
Year of approval (FDA) = 1997
Date of 1st FDA approval = 19971126
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2015 (baesd on use patent 5,736,137, cited by Genentech)
2018 is commonly reported (but could be referring to Cabilly III, which applies; and Roche is presumed unlikely to grant licenses to competing products) Celltrion has reported it expects global patent expiration in 2014
Roche's marketing chief, David Loew, has reported that Roche does not expect any competition before 2015. |
U.S. Patent Expiration Year: | 2015 |
U.S. Biosimilars Data Exclusivity Expiration: | 2009 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2004 |
U.S. Biosimilars Launchability Year: | 2018 |
U.S. Biobetters Launchability Year: | 2018 |
Biosimilars/biobetters-related EU Patents: | 2013 based on EP 2000149; EP 0669836; EP 1005870; and EP 0752248. |
EU Patent Expiration Year: | 2013 |
EU Biosimilars Data Exclusivity Expiration: | 2008 |
EU Biosimilars Orphan Exclusivity Expiration: | 2008 |
EU Biosimilars Launchability Year: | 2013 |
EU Biobetters Launchability Year: | 2013 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
apheresis (hemapheresis)
biopharmaceutical products
blepharospasm
bovine lymph
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies, recombinant, chimeric
rattlesnakes
recombinant DNA
rodent cells <!-- rodentcells -->
albumin, bovine
Chinese hamster ovary (CHO) cells
fermenters, 1,000 liter
gentamicin (gentamycin)
glutamine synthetase (GS) expression system
leeches, medicinal
lymphocytes, human
mammalian cell culture
media, serum-based
rodent cells <!-- rodentcells -->
suspension cell culture
tranexamic acid
gentamicin (gentamycin)
polysorbate 80 (Tween 80)
Protein A affinity chromatography
sodium chloride
sodium citrate
Sterile Water for Injection
viral inactivation, unspecified
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
orphan status
priority review status
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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