Tositumomab and Iodine I 131 Tositumomab - Bexxar therapeutic regimen; CD20 monoclonal antibody–Iodine I 131 radioimmune conjugate
Status: approved and marketed in U.S., not EU
Organizations involved:
Corixa Corp. – Manuf.; Tech.
Coulter Pharmaceutical, Inc. – R&D; Tech.; Former
GlaxoSmithKline Inc. – R&D; Tech.; World mark.
GlaxoSmithKline plc – Parent
Amersham plc – Former
GE Healthcare – Parent; Former
Australian Nuclear Sci. & Tech. Org. – Australia and Asia mark.
IDEC Pharm. Corp. – Tech.; Patent dispute; Former
Biogen Idec, Inc. – Tech.; Patent dispute
MDS Nordion – Manuf. other
SmithKline Beecham plc (SKB) – Former
University of Michigan – R&D; Tech.
Cross ref: See the entry for rituximab (Rituxan), a recombinant CD20 monoclonal antibody approved with much the same indications: as Bexxar. See the entry for ibritumomab tiuxetan (Zevalin), a similar recombinant CD20 monoclonal antibody conjugated with Yttrium-90 and Indium-111 radioisotopes. See the entry for Monoclonal Antibodies (#300).
Description: Bexxar refers to aqueous formulations of tositumomab, a murine hybridoma cell cultured monoclonal antibody, and Iodine I-131 Tositumomab, a radio-immune conjugate composed of tositumomab conjugated to radioactive iodine, with both having specificity for CD20 on the surface of B-cells, including non-Hodgkin’s lymphoma B-cells. The monoclonal antibody and the monoclonal antibody-radioisotope conjugate are used in the two-stage Bexxar therapeutic regimen (tositumomab plus Iodine I 131 tositumomab to determine optimal dosing, followed a week or two later by a larger therapeutic dose of tositumomab plus Iodine I 131 tositumomab). Tositumomab is composed of two murine gamma 2a heavy chains of 451 amino acids each and two lambda light chains of 220 amino acids each, with a molecular weight ~150 kDa. The I-131 component is directly linked to amino acid residues of the monoclonal antibody without the use of a linker chelating agent (e.g., as with Zevalin).
Bexxar combines the targeting ability of a monoclonal antibody and the therapeutic potential of radiation, with patient-specific dosing. The radiolabeled monoclonal antibody portion of Iodine I 131 tositumomab attaches to the target molecule CD20 on non-Hodgkin’s lymphoma (NHL) tumor cells, both mediating an immune response against the cells and delivering a dose of Iodine-131 radiation to the cells. Bexxar therapy is the only NHL therapy that is precisely dosed based on individual drug clearance rates, related to factors including tumor size. Patient-specific dosing allows for the delivery of a predictable amount of radiation to each patient. Bexxar apparently has multiple mechanisms of action resulting from activity of the CD20 monoclonal antibody component and the cytotoxic effects of the I-131 radioisotope.
The Bexxar therapeutic regimen is administered in two discrete steps: dosimetric and therapeutic. See the Medical section below for further information. Each step consists of a sequential infusion of the monoclonal antibody, tositumomab, followed by the radioconjugate, Iodine I 131 tositumomab. The dosimetric step is used to derive information about optimal dosage for the therapeutic step, which is administered 7-14 days after the dosimetric step. Bexxar dosimetric packaging involves a carton containing two single-use 225 mg vials and one single-use 35 mg vial of tositumomab (supplied by McKesson Biosciences); and a package containing a single-use vial of Iodine I 131 tositumomab (0.61mCi/mL at calibration; supplied by MDS Nordion). Bexxar therapeutic packaging involves a carton containing two single-use 225 mg vials and one single-use 35 mg vial of tositumomab (supplied by McKesson Biosciences); and a package containing one or two single-use vials of Iodine I 131 tositumomab (5.6 mCi/mL at calibration; supplied by MDS Nordion). The dosimetric dosage form is supplied at nominal protein and activity concentrations of 0.1 mg/mL and 0.61 mCi/mL (at date of calibration), respectively. The therapeutic dosage form is supplied at nominal protein and activity concentrations of 1.1 mg/mL and 5.6 mCi/mL (at date of calibration), respectively. The tositumomab formulation for the dosimetric and the therapeutic dosage forms also contains 5.0%–6.0% (w/v) povidone, 1–2 mg/mL maltose (dosimetric dose) or 9–15 mg/mL maltose (therapeutic dose), 0.85–0.95 mg/mL sodium chloride, and 0.9–1.3 mg/mL ascorbic acid. The pH is approximately 7.0.
The dating period for tositumomab is 36 months from the date of manufacture when stored at 2-8 °C. The dating period for dosimetric Iodine I 131 tositumomab is 14 days when stored at -20°C. The dating period for therapeutic Iodine I 131 Tositumomab is 5 days when stored at -20°C. The date of manufacture is the date of final sterile filtration of the formulated drug product. The expiration date for the packaged product containing one 35 mg vial of tositumomab and 1-2 225 mg vials of tositumomab is based on the shortest expiration date of either component.
Upon approval, Bexxar became the second radioimmune therapy in the U.S. market (Zevalin being the first), with the other radioimmune conjugates in the U.S. market used for radio-diagnostic imaging, not radiotreatment. Bexxar is used for the treatment of patients with relapsed or refractory low-grade and transformed low-grade B-cell non-Hodgkin’s lymphoma (NHL).
Nomenclature: CD20 Mab–I 131 radioconj. [BIO]; Bexxar [TR]; Iodine I-131-radiolabeled tositumomab [FDA USAN for conjugate]; tositumomab [FDA USAN for Mab]; anti-(human CD20 antigen) immunoglobulin G2a (mouse monoclonal clone B1R1 chain) disulfide with mouse monoclonal clone B1R1 x-chain, dimer [CAS for Mab]; immunoglobulin G2a, anti-(human CD20 (antigen)) (mouse monoclonal clone B1R1 gamma2a-chain), disulfide with mouse monoclonal clone B1R1 lambdax-chain, dimer, iodine-131I salt [CAS for conjugate]; 208921-02-2 [CAS RN for Mab]; 192391-48-3 [CAS RN for conjugate]; tositumomab Iodine-131 [SY]; I-131 Anti-B1 Antibody [SY]; CD20 antibody I-131 radioimmune conjugate [SY]; B1 therapy [SY]; SB-393229 [SY]; Bexxar therapeutic regimen [SY]; NDC 67800-101-31; NDC 67800-101-32; NDC 67800-111-10; NDC 67800-121-10 [NDC]
Biological.: Tositumomab binds specifically to the CD20 (human B-lymphocyte–restricted differentiation antigen, Bp 35, or B1) antigen, a transmembrane phosphoprotein expressed on pre-B lymphocytes (B-cells) and at higher density on mature B lymphocytes. The antigen is expressed on >90% of B-cell non-Hodgkin’s lymphoma (NHL) tumor cells. The recognition epitope for tositumomab is found within the extracellular domain of the CD20 antigen. CD20 is not shed from the cell surface, and does not internalize following antibody binding.
Possible mechanisms of action of the Bexxar therapeutic regimen include induction of apoptosis (programmed cell death), complement-dependent cytotoxicity (CDC), and antibody-dependent cellular cytotoxicity (ADCC), with these effects mediated by the antibody. Additionally, cell death is caused by ionizing radiation from the radioisotope. Besides its desired effect on CD20+ tumors, the Bexxar therapeutic regimen results in sustained depletion of circulating CD20+ B-cells (which can result in serious adverse effects).
The Iodine-131 decays with beta and gamma emissions with a physical half-life of 8.04 days. The principal beta emission has a mean energy of 191.6 keV and the principal gamma emission has an energy of 3,64.5 keV.
Companies.: Bexxar was commercially developed by Coulter Pharmaceutical, Inc. in collaboration with SmithKline Beecham Corp. (SKB), now GlaxoSmithKline Inc. (GSK). Coulter was acquired in Dec. 2000 by Corixa Corp., which was acquired by GSK in April 2005. Approval was granted to Corixa, CBER/FDA est. no. 1614, for manufacture of tositumomab and Iodine I 131 tositumomab. The original conception and early development of Bexxar is generally attributed to Drs. M. Kaminski and R. Wahl, University of Michigan Comprehensive Cancer Center, and collaborators. GSK currently has exclusive worldwide market rights. The timeline for corporate relationships involving Bexxar is further discussed below.
Coulter (now Corixa) concluded a strategic alliance with SKB (now GSK) on Dec. 4, 1998, for joint development and commercialization of Iodine-131 tositumomab. Corixa and GSK were to co-market Bexxar in the U.S., with profits shared equally. SKB/GSK received exclusive marketing rights outside of the U.S. and Japan.
For Coulter, the original agreement with SKB (GSK) was reported to have a potential value of $132 million, plus shared royalties and profits. SKB made an up-front payment of $41.5 million and provided a $15 million line of credit. Coulter could receive $76 million in milestone payments, based on development and approvals in specific areas of the world. Further development expenses would generally be shared by the companies, and both companies would jointly study the product for other indications:. SKB/GSK also obtained access to second generation anti-CD20 agents.
In April 2000, Coulter announced amendment of its original agreement with SKB (now GSK), with Coulter reacquiring all rights outside of the U.S. The amendment did not change Coulter’s (now Corixa) and SKB’s (now GSK) co-marketing of Bexxar in the U.S. The collaboration for U.S. marketing was further extended to include a co-promotion agreement, with Coulter’s sales force assisting the SKB oncology sales and marketing teams with marketing of several of SKB’s cancer drugs until the launch of Bexxar (to allow Coulter to develop its own sales force), with SKB compensating Coulter for use of its sales force. Corixa transferred Canadian marketing rights to GSK in May 2003.
Corixa acquired Coulter in Dec. 2000 for about $570 million in stock and subsequently granted certain European co-marketing rights to Amersham plc, now a subsidiary of GE Medical Systems. Corixa retained other international rights for Bexxar, including Europe and Japan.
In Oct. 2001, Corixa concluded a commercialization agreement with Amersham, granting the company exclusive European marketing rights, with Corixa responsible for regulatory approvals. This agreement was terminated in Dec. 2004 (with the acquisition of worldwide rights by GSK).
In June 2003, Corixa concluded a 7-year manufacturing contract with MDS Nordion for the company to perform iodine-133 radiolabeling of tositumomab. This replaced prior agreements concluded in 1995 and 1998. MDS Nordion manufactures the I-131 radioisotope used with Bexxar, and performs conjugation of the monoclonal antibody and radioisotope.
In May 2004, the Australian Nuclear Science and Technology Organization exclusively licensed development and marketing rights to Bexxar for NHL in Australia, New Zealand, Singapore, India, Indonesia and China; and co-exclusive rights in Japan, S. Korea, and Taiwan.
In Dec. 2004, GSK acquired from Corixa exclusive worldwide market rights for Bexxar. Corixa will continue to receive milestones and royalties on sales of Bexxar in the U.S., Canada and Australia and parts of Asia. GSK assumed Corixa’s relationship with the Australian Nuclear Science and Technology Organization for the commercialization of BEXXAR in Australasia; and European Union marketing rights held by Amersham were formally transferred to GSK. Amersham Health (now GE Healthcare) had previously returned these to Corixa. GSK and Corixa will continue to equally share royalties on Zevalin sales from Biogen Idec according to the terms of a prior patent litigation settlement.
In April 2005, GSK acquired Corixa for ~$300 million. GSK no longer has to pay royalties to Corixa.
Manufacture: Tositumomab is produced in an antibiotic-free culture of murine hybridoma cells. See the entries for other non-recombinant antibody-based radioimmune diagnostics in this section for further information, particularly examples, of the manufacture of murine antibodies. Unlabeled vials of tositumomab drug product are shipped to McKesson BioServices for labeling, packaging and distribution.
FDA class: Biologic BLA
Approvals: Date = 20030627; BLA (103906/0), original approval, with orphan designation; Indication = for the treatment of relapsed or refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma, and use in low-grade non-Hodgkin’s lymphoma patients who do not respond or progress following rituximab (Rituxan) therapy
Date = 20040104; supplemental BLA (sBLA), accelerated approval; Indication = use in patients with relapsed or refractory low grade, follicular or transformed CD20 positive non-Hodgkin’s lymphoma (NHL), whose disease has relapsed following chemotherapy (i.e., second-line therapy without patients needing to be refractory to Rituximab).
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling. 4/2005]:
The BEXXAR therapeutic regimen is not indicated for the initial treatment of patients with CD20 positive non-Hodgkin’s lymphoma. (see ADVERSE REACTIONS, Immunogenicity) The BEXXAR therapeutic regimen is intended as a single course of treatment. The safety of multiple courses of the BEXXAR therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated. The BEXXAR therapeutic regimen is not indicated for the initial treatment of patients with CD20 positive non-Hodgkin’s lymphoma. (see ADVERSE REACTIONS, Immunogenicity) The BEXXAR therapeutic regimen is intended as a single course of treatment. The safety of multiple courses of the BEXXAR therapeutic regimen, or combination of this regimen with other forms of irradiation or chemotherapy, has not been evaluated.
Status: The BLA (STN 103906/0) was originally submitted by Coulter on June 29, 1999 and granted priority review status (decision in six months). Data from a single pivotal trial were provided. The BLA sought approval of Bexxar for the treatment of relapsed or refractory low-grade or transformed low-grade non-Hodgkin’s lymphoma, and use in low-grade non-Hodgkin’s lymphoma patients who do not respond or progress following rituximab (Rituxan) therapy. The BLA had Fast Track Product designation, allowing submission of portions as completed. This initial BLA was rejected in August 1999 (refusal-to-file letter). The BLA was resubmitted in Sept. 2000, and was transferred to Corixa in Jan. 2001. In March 2001, FDA issued a complete response letter citing insufficient/inadequate manufacturing, efficacy, and safety data, with no requests for additional clinical trials. Many of the problems involved clinical trials using product manufactured at three different facilities, and FDA cited inadequate hematologic toxicity and immune rejection (HAMA) data.
Corixa and GSK received a complete review (but not approvable) letter from FDA on March 12, 2002. This questioned Bexxar in light of the availability of other approved therapies and cited insufficient data to evaluate Bexxar’s safety profile (essentially requiring new trials). On May 31, 2002, Corixa filed a formal appeal of Bexxar’s approval status (under guidelines in the Food and Drug Modernization Act). On June 26, 2002, FDA granted this appeal (overturning its prior ruling), allowing the company to file additional requested data and continue its application. On Dec. 2, 2002, FDA ruled that additional safety data and other responses to its March letter constituted a complete response, and Bexxar was returned to active review status with a new PDUFA date (target approval date) of May 2, 2003. In Dec. 2002, the Oncologic Drugs Advisory Committee, FDA, voted to recommend approval of Bexxar for treatment of relapsed or refractory low-grade follicular, or transformed low-grade non-Hodgkin’s lymphoma (by 13-0 vote), including patients with follicular lymphoma refractory to rituximab (Rituxan). Corixa submitted an updated safety database with data on 995 treated patients with up to 9.5 years of follow up in April 2003. The PDUFA was then further extended for 3 months with a new PDUFA date of Aug. 1, 2003, with FDA citing the need to make Corixa’s post-marketing commitments and Bexxar’s package insert consistent with the updated safety database.
FDA approved Bexxar on June 30, 2003, with orphan status; approval time = ~48 months (4.0 years). FDA had granted orphan status to Bexxar for treatment of follicular lymphoma in Feb. 2003. Tositumomab and Iodine I 131 tositumomab are both exempt from CBER lot release requirements. FDA approval included requirements for a number of post-approval clinical studies in particular patient groups. Bexxar was launched in July 2003.
In March 2004, FDA sent a letter to Corixa criticizing the it for overstating the effectiveness of Bexxar in a promotional video and leaving out information about risks.
On Jan. 3. 2005, FDA approved a BLA supplement (filed July 1, 2004) for accelerated approval of the Bexxar therapeutic regimen in patients with relapsed or refractory low grade, follicular or transformed CD20 positive non-Hodgkin’s lymphoma (NHL), whose disease has relapsed following chemotherapy (i.e., without patients needing to be refractory to Rituximab). Corixa and the FDA had previously (Jan. 2004) reached mutual agreement regarding the contents of the supplemental BLA. The original indication had specified that patients have disease that was refractory to Rituximab and had relapsed following chemotherapy. The Bexxar Therapeutic Regimen is still not indicated for the initial (first-line) treatment of patients with CD20 positive non-Hodgkin’s lymphoma. Bexxar Therapeutic Regimen remains approved only for a single course of treatment.
Bexxar has not been approved in European Union.
Tech. transfer: U.S. patents entitled, “Radioimmunotherapy of lymphoma using anti-CD20 antibodies,” covering aspects of Bexxar (tositumomab and Iodine I 131 tosi-tumomab), its uses, and including inventors from the University of Michigan and Coulter and assigned to Coulter and/or the university include 6,565,827; 6,287,537; 6,090,365; 6,015,542; 5,843,398; and a similar patent, 5,595,721. Coulter/Corixa has also received patents covering aspects of Bexxar including U.S. 6,251,362 concerning methods for administration of radiolabeled monoclonal antibodies and individual patient determination of radioisotope levels to optimize therapeutic effects and minimize toxicity (Bexxar regimen). Together these patents, all licensed to Coulter/Corixa, include composition-of-matter and methods of use claims for radiolabeled CD20 monoclonal antibody for treatment of non-Hodgkin’s lymphoma. Corixa has stated its U.S. patents for Bexxar expire in 2013 and 2014.
In Sept. 2001, IDEC (now Biogen Idec) filed two suits in US. District Court. One suit against Coulter and the University of Michigan sought a declaratory judgement that Zevalin (see related entry) does not infringe Coulter/Corixa’s four main patents covering Bexxar (or that the patents are invalid). The other suit against GlaxoSmithKline plc (GSK) sought a declaratory judgement that Zevalin does not infringe GSK’s patents concerning cell culture media. The next day, Corixa Corp. and GSK filed a counter suit against IDEC alleging that Zevalin infringes their Bexxar-related patents – 5,595,721; 6,090,365; and 6.015,542.
In Feb. 2003, IDEC Pharmaceuticals filed a follow-on infringement suit in U.S. District Court against Corixia and GlaxoSmithKline (GSK) concerning Bexxar and its use in the treatment of B-cell non-Hodgkin’s lymphomas (NHL), alleging infringement of newly-issued U.S. patent RE 38,008, which covers methods for the use of radiolabeled antibodies in the treatment of non-Hodgkin’s lymphoma (NHL). In Oct. 2003, the court granted summary judgement in favor of IDEC (became Biogen Idec in Nov. 2003), ruling that the four main U.S. patents from Coulter/Corixa covering aspects of Bexxar are unenforceable because of the inventors’ “inequitable conduct in the prosecution of the underlying patent applications.” In Feb. 2004, the U.S. District Court vacated its Oct. 2003 summary judgment in favor of Biogen Idec, based on new evidence and evidence not previously considered, reviving the litigation.
In March 2004, Corixa and GSK settled their disputes with Biogen Idec, with Biogen Idec paying $20 million equally shared between Corixa and GSK, and paying a one-time milestone fee and unspecified royalties on Zevalin (not Bexxar) sales starting Jan. 1, 2004 and until all Bexxar-related patents expire. The companies also cross-licensed their Bexxar- and Zevalin-related patents.
In April 2005, GSK acquired Corixa, and no longer needs to pay royalties to Corixa.
Disease: See the Zevalin entry for discussion of non-Hodgkin’s lymphoma.
Trials: In Dec. 2003, a study was reported confirming that 20-25% of patients with follicular non-Hodgkin’s lymphoma treated with Bexxar achieve a complete response lasting a minimum of 12 months, with the majority remaining in complete response for nearly five years. Researchers presented an analysis of independently confirmed long-term durable responses, defined as responses with a time to progression of 12 or more months, from the five clinical trials that supported regulatory approval of the Bexxar regimen. Of 230 patients with relapsed or refractory follicular non-Hodgkin’s lymphoma who were treated with Bexxar and evaluable for response, 55 (24%) met the definition of a durable complete response (complete resolution of radiological abnormalities and disappearance of signs and symptoms related to the disease); and 75% of these patients (41/55) still showed no sign of disease after a median follow-up of nearly 5 years. Independently assessed durable complete responses were noted with similar frequency in patients who relapsed after or who were refractory to Rituximab therapy and in patients who had not received Rituximab prior to receiving the Bexxar therapeutic regimen.
In one clinical trial in patients who had a median of 4 prior chemotherapies and Rituximab-refractory disease, 63% responded to Bexxar, with half of these patients having a response that lasted 25 months or longer. Determination of clinical benefit was based on evidence of durable responses without evidence of an effect on survival.
Bexxar’s supplemental BLA filing for relapsed or refractory non-Hodgkin’s lymphoma without need for prior Rituxan therapy was supported by an open-label, single-arm, multi-center study of 60 chemotherapy refractory patients with poor response to prior therapy or having a duration of response less than or equal to six months. The primary endpoint was the number of patients with a longer duration of response (>30 days) on Bexxar therapy vs. the number of patients with a longer duration of response following their last qualifying chemotherapy regimen. The median number of prior chemotherapy regimens was 4, with a range of 2-13. In the Bexxar group, 26 patients had a longer duration of response following therapy compared to 5 patients who had a longer duration of response following their last qualifying chemotherapy regimen (p <0.001). In the Bexxar group, the overall and complete response rates were 47% (95%CI, 34-60%) and 20% (95% CI, 7-47), respectively. The median duration of response was 47 months (95% CI, 47-not reached) at a median follow-up of 30 months.
In May 2005, GSK reported results from new trial analyses showing that treatment outcomes associated with the Bexxar therapeutic regimen in non-Hodgkin’s lymphoma patients were significantly improved when Bexxar was administered earlier in the treatment sequence. The review compared the treatment responses of 1,177 patients from 10 clinical trials in which Bexxar was used as either first-line, second-line, third-line, or fourth-line (or greater) treatment. The lead investigator reported, “Response rates, complete response rates and associated durations of response to the Bexxar therapeutic regimen all increased significantly as the number of prior therapies decreased...Durable complete responses were observed in every treatment sequence studied. In addition, the frequency of complete responses was much greater when Bexxar was used earlier. These data suggest that Bexxar should be administered early in the course of relapsed lymphoma for optimal outcome, and not reserved as a salvage treatment.” The differences in response rate, median duration of response, complete response rate, median duration of complete response, and progression free survival greater than one year were highly statistically significant (p < 0.001) between each treatment sequence.
In June 2007, GSK reported long-term efficacy data from a Phase II trial of a single one-week course of frontline treatment with the Bexxar Therapeutic Regimen in 76 patients with newly-diagnosed advanced follicular non-Hodgkin’s lymphoma (NHL). The regimen induced durable clinical and molecular remissions. Patients who received a single one-week treatment of Bexxar as monotherapy achieved estimated 8-year and 10-year overall survival (OS) rates of 86%; and 50% of patients survived without progression of disease at 8 years following therapy. For patients who achieved complete remission, the median time before their disease progressed was 9.2 years. An overall response rate and complete remission rate of 95% and 75%, respectively, were observed.
Medical: The Bexxar therapeutic regimen is given in four office visits over 1-2 weeks, culminating in the administration of a patient-specific therapeutic dose. The Bexxar therapeutic regimen consists of four components administered in two discrete steps: the dosimetric step, followed 7-14 days later by the therapeutic step. For the diagnostic step, tositumomab 450 mg is administered intravenously in 50 ml 0.9% Sodium Chloride over 60 minutes; and Iodine I 131 tositumomab (containing 5.0 mCi I-131 and 35 mg tositumomab) is administered intravenously in 30 ml 0.9% Sodium Chloride over 20 minutes. The biodistribution of Iodine I 131 tositumomab is determined by whole body dosimetry (imaging the gamma radiation from I 131) performed on day 0; day 2, 3 or 4; and day 6 or 7. For the therapeutic step, tositumomab 450 mg is administered intravenously in 50 ml 0.9% Sodium Chloride over 60 minutes 7-14 days after the diagnostic dosing, along with Iodine I 131 tositumomab. For patients with ≥ 150,000 platelets/mm3, the recommended dose of Iodine I 131 tositumomab is calculated to deliver 75cGy total body irradiation and 35 mg Tositumomab, administered intravenously over 20 minutes.
For patients who have experienced multiple relapses and endured several courses of Zevalin and/or other (re)treatment, Bexxar can provide five or more disease-free and treatment-free years from a single, short course of therapy. The principal dose limiting toxicity of Bexxar is generally reversible bone marrow suppression that may be prolonged and severe, and requires supportive care in ~25% of patients.
Market Total sales of Bexxar in its first year (7/2003-6/2004) on the market were $7 million, far short of Corixa’s goal of $20 million. More recent sales have not been reported. The author’s rough guess (based on no substantive information) for total 2006 sales is in the range of $15-$20 million. With the sBLA removing some restrictions, but still not approving Bexxar for first-line use and with recent trials indicating it may be useful for first-line use (an off-label indication), sales have likely increased.
Corixa had reported that its sales were not even enough to cover its cost of production. The high (in hindsight) cost Corixa paid for Coulter (and Bexxar) and the delay in obtaining approval for Bexxar combined with low sales caused considerable financial difficulties for Corixa, which divested rights to Bexxar in Dec. 2004 and its other cancer programs and is now concentrating on its vaccine adjuvant business; and later was acquired by GlaxoSmithKline (which probably primarily wanted access to MPL and other Corixa vaccine adjuvants).
Corixa has reported that treatment typically costs $27,000/patient.
The 2005 Average Wholesale Price (AWP) is $2,700 for a dosimetric 20 mL vial, and $23,400 for a labeled 20 mL therapeutic vial (2005 Red Book). These prices are unchanged from 2004. The total for the full regiment cost comes to $31,100 (presuming single vials provide needed components).
The Center for Medicare & Medicaid Services (CMS) approved Medicare coverage (reimbursement) for Bexxar in Sept. 2003 under the hospital outpatient prospective payment system (OPPS). This was published in the agency’s first “One-Time Special Notification,” with reimbursement codes valid retrospectively to July 1 (since approval). Coverage includes all the procedures necessary to administer the Bexxar therapeutic regimen, including gamma camera scans, dosimetric calculations for the unique patient-specific therapeutic dose, and product administration. Generally, CMS has not been as responsive to covering new, expensive therapeutic regimens such as Bexxar.
Bexxar and Zevalin (see related entry) are currently the only therapeutic radioimmune products marketed in the U.S. Despite research showing these products work well, fewer than 10% of lymphoma patients who are candidates for Zevalin and Bexxar ever use them. Specialists cite a complex list of reasons for this, including that most oncologists are not licensed to administer the radioactive infusion and must send their patients to a nuclear-medicine specialist. There’s also confusion about the risks of radiation, which studies suggest are minimal, and when the drugs work best (early, not as a last-ditch therapy). Rituxan (see related entry) is considered to have revolutionized lymphoma care, but NHL patients eventually relapse, and Zevalin and Bexxar are good options for treatment. About 20% of these patients who receive Zevalin or Bexxar have extremely long remissions, five to eight years, with this more likely when these are used for a first relapse, not later when repeated chemotherapy has ravaged the immune system. There’s mounting evidence from small studies that even more patients have long-term remission if they use radioimmunotherapy first, instead of waiting to relapse. If this is confirmed by larger studies, many use of Zevalin and Bexxar will significantly increase.
Competition: Bexxar competes, in some respects, with rituximab (Rituxan) from Biogen Idec. Rutiximab is a non-radiolabeled recombinant CD20 monoclonal antibody cultured in Chinese hamster ovary (CHO) cells. Rituximab can cause toxicity requiring halt or slowing of administration, while Bexxar is not associated with infusion-related toxicity and can be administered in an hour or less. Most lymphoma patients receiving Bexxar are treated by nuclear medicine specialists, while most patients receiving Rituxan receive it from their oncologist.
Bexxar has not competed well against Rituxan (see related entry). Sales were initially limited by the product not receiving Medicare reimbursement approval until mid-Sept. 2003. Also, Corixa had eliminated most of its sales and marketing staff in 2001 to conserve finances (and the company had to rehire and train a new sales force).
Companies involvement:
Full monograph
306 CD20 Mab–I 131 radioconj.
Nomenclature:
CD20 Mab, rDNA–I 131 radioconj. [BIO]
Bexxar [TR]
208921-02-2 [CAS for tositumomab]
anti-(human CD20 antigen) immunoglobulin G2a (mouse monoclonal clone B1R1 chain) disulfide with mouse monoclonal clone B1R1 x-chain, dimer [CAS for tositumomab]
192391-48-3 [CAS RN for conjugate]
B1 therapy [SY]
CD20 monoclonal antibody I-131 radioimmune conjugate [SY]
I-131 Anti-B1 Antibody [SY]
Iodine I 131 tositumomab [FDA not official; based on similar products]
SB-393229 [SY]
tositumomab iodine-131 [SY]
molecular weight (kDa) = 150
FDA Class: Biologic BLA
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20030627
(in format YYYYMMDD)
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
conjugates
monoclonal antibodies
murine (mouse) materials used
murine (mouse) monoclonal antibodies
radioimmune conjugates<!-- radioconjugates -->
monoclonal antibody, murine
murine (mouse) hybridoma cells
catheter clearance
intestinal motility
magnetic microspheres
potato medium, glycerinized
sodium chloride
Tohama strain, Bordetella pertussis
accelerated approval (based on surrogate endpoints) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
North American coral snake
orphan status
priority review status
EU000 Not yet/Never filed with EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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