Status - approved; marketed

Organizations involved:

Biogen Idec, Inc. – Manuf.; R&D; Tech.;

Spectrum Pharmaceuticals, Inc. – World mark.

Cell Therapeutics, Inc. – Former

Bayer Schering Pharma AG – Former

IDEC Pharmaceuticals Corp. – R&D; Tech.; Former

Genentech, Inc. – R&D; Tech.

Schering AG – Former

Baxter Healthcare Corp. – Manuf. other

DSM Catalytica Pharmaceuticals. – Manuf. other

MDS Nordion – Manuf. other

Hauser, Inc. – Manuf. other

Medi-Physics, Inc. – Manuf. other

Amersham plc – Parent; Former

GE Healthcare – Parent

National Cancer Institute (NCI) – Tech.

National Institutes of Health (NIH) – Parent org.

Corixa Corp. – Tech.; Patent dispute

GlaxoSmithKline plc – Tech.; Patent dispute; Parent

University of Michigan – Patent dispute

Cross ref.: See the entry for Rituximab (Rutuxan) (#115) [and also Rituximab Formulated Bulk (For Further Manufacturing Use) (#116)], a recombinant chimeric murine-human CD20 monoclonal antibody product, while Zevalin involves a recombinant murine CD20 monoclonal antibody. Rutuxan is administered as part of the Zevalin treatment regimen. See also the entry for Iodine-131 tositumomab (Bexxar), another CD20 monoclonal antibody radioimmune conjugate.

Description: Ibritumomab tiuxetan (Zevalin) is a non-radioactive immunoconjugate with a stable covalent thiourea bond between ibritumomab (IDEC-2B8), a recombinant murine IgG1kappa monoclonal antibody expressed by Chinese hamster ovary (CHO) cells with specificity for CD20, and the linker-chelator group tiuxetan (MX) or [N-[2-bis(carboxymethyl)amino]-3-(p-isothiocyanatophenyl)-propyl]-[N-[2-bis(carboxymethyl)amino]-2-(methyl)-ethyl]glycine. Tiuxetan is covalently linked to the amino groups of exposed lysine and arginine residues within the ibritumomab monoclonal antibody. The tiuxetan moiety of the conjugate molecule provides a high affinity, conformationally restricted chelation (attachment) site for binding of Indium-111 or Yttrium-90 radioisotopes (via DTPA, a bifunctional chelating agent)

Prior to use, Zevalin (ibritumomab tiuxetan; IDEC-2B8-MX) is chemically conjugated in an on-site or local nuclear pharmacy to either Yttrium-90 (Y-90) or Indium-111 (In-111) radioisotope using the bifunctional ligand chelating agent, cyclohexyl diethylenetriaminepentaacetic acid (DTPA). The ibritumomab monoclonal antibody is bonded via the tiuxetan linker-chelator group to DTPA, forming IDEC-2B8-MX-DTPA or ibritumomab-MX-DTPA, which binds Y-90 or In-111. The resulting radioimmune conjugate for patient administration has a monoclonal antibody moiety conferring binding affinity for CD20 antigen, which is found on the surface of normal and malignant B lymphocytes (antibody-producing B-cells), allowing preferential attachment to CD20 and delivery of ionizing radiation to these cells.

Ibritumomab, the monoclonal antibody moiety, is a recombinant fully murine (not chimeric or humanized) IgG1 kappa monoclonal antibody glycoprotein with binding specificity for the CD20 antigen on the surface of B-lymphocytes (B-cells). Ibritumomab is produced in Chinese hamster ovary (CHO) cells and is composed of two murine gamma1 heavy chains (445 amino acids each) and two kappa light chains (213 amino acids each). The monoclonal antibody contains the entire murine light and heavy chain variable (epitope-binding) regions, and murine gamma1 heavy chain and kappa light china constant (framework) regions. The molecular weight calculated from the primary sequence of the reduced non-glycosylated antibody is 144,248 Daltons (144.25 kDa). Ibritumomab exhibits minor variability due to different glycoform (glycosylation patterns), but microheterogeneities have no impact on its binding activity or efficacy. After conjugation of ibritumomab with tiuxetan, ibritumomab tiuxetan has a molecular weight of ~148 kDa.

The ibritumomab monoclonal antibody is similar to rituximab (see the Rituxan entry in the Recombinant DNA Products section), a recombinant chimeric human-mouse CD20 monoclonal antibody also from IDEC and marketed for first-line indications: similar to those of Zevalin; and Rituxan is used as part of the Zevalin treatment regimen. Both rituximab and ibritumomab have specificity for the same CD20 epitopes. Ibritumomab and Zevalin (and also rituximab) are also similar to tositumomab, a nonrecombinant murine CD20 monoclonal antibody, used to form Iodine I 131 tositumomab or Bexxar (see related entry).

Zevalin was the first radioimmune conjugate approved by FDA for therapeutic, rather than radiodiagnostic, indications:. It is approved only for patients not responding to prior chemotherapy or Rituxan treatment. Zevalin (like Rituxan) is used for treatment of CD20-associated non-Hodgkin’s lymphoma (NHL) and similar tumors associated with high levels of expression of CD20-bearing B-cells. The two-step Zevalin therapeutic regimen targets CD20+ tumor cells with a high dose of radiation, reducing the amount of full body radiation exposure, compared to radiotreatments using external radiation sources.

Zevalin is administered in two steps: 1) infusion of rituximab (Rituxan) followed by In-111 Zevalin (ibritumomab tiuxetan linked to Indium-111, a gamma-emitting radionuclide) and 2) a second infusion of Rituxan followed by Y-90 Zevalin (Ibritumomab tiuxetan linked to Yttrium-90 radioisotope) seven to nine days later. The first step provides a low radiation dose for radiodiagnostic whole body imaging to determine CD20+ tumor burden and whether tumors are being properly targeted. This is followed by infusion of Rituxan and Y-90 Zevalin, which delivers a higher therapeutic radiation dose. Y-90 Zevalin binds to and eliminates both malignant and normal CD20+ B cells. Normal, fully functional B-cells are replenished by CD20-negative progenitor cells within six to nine months following therapy.

Zevalin is supplied as separate kits containing the nonradioactive ingredients to produce single doses of In-111 Zevalin and Y-90 Zevalin. Indium-111 chloride and Rituximab are ordered separately. Yttrium-90 Chloride Sterile Solution for preparation of Y-90 Zevalin is supplied by MDS Nordion when the Y-90 Zevalin kit is ordered. Each of the two Zevalin kits contains four vials that are used to produce a single dose of either In-111 Zevalin or Y-90 Zevalin. This includes one Zevalin vial containing 3.2 mg of ibritumomab tiuxetan in 2 mL of 0.9% sodium chloride solution with no preservatives; one 50 mM Sodium Acetate Vial containing 13.6 mg of sodium acetate trihydrate in 2 mL of Water for Injection; one Formulation Buffer Vial containing 750 mg of Albumin (Human), 76 mg of sodium chloride, 21 mg of sodium phosphate dibasic heptahydrate, 4 mg of pentetic acid, 2 mg of potassium phosphate monobasic and 2 mg of potassium chloride in 10 mL of Water for Injection adjusted to pH 7.1 with either sodium hydroxide or hydrochloric acid; and an empty Reaction Vial. Albumin (Human) is used as a stabilizer in the formulation buffer to protect the monoclonal antibody against radiolysis. No other products of animal origin are used in manufacture. Zevalin is stored at 2-8˚C (refrigerated) and has no specified half-life (since it is ordered and prepared only as needed).

The dating period for ibritumomab tiuxetan (kit) is 24 months from the date of manufacture when stored at 2-8°C (refrigerated). The date of manufacture is the date of final sterile filtration of the formulated bulk. The expiration date is 24 months or less, dependent on the shortest expiration date of any of the components stored at 2-8°C. The dating periods of the non-biological kit components stored at 2-8°C is 24 months for sodium acetate buffer, 30 months for formulation buffer, and 30 months for the reaction vials. The dating period of the Yttrium-90 Chloride Sterile Solution is 5 days when stored at 15-30°C.

Nomenclature: CD20 Mab, rDNA/Y-90 & In-111 radioconj. [BIO]; ibritumomab tiuxetan [FDA USAN INN]; Zevalin [TR; retained by Biogen Idec]; pan-B-yttrium [SY]; IDEC-Y2B8 [SY]; IDEC-2B8-MX-DTPA [SY]; CD20 monoclonal antibody, recombinant–Yttrium Y 90 radioimmune conjugate [SY]; Y-90 Zevalin kit [SY]; In-111 Zevalin kit [SY]; NDC 64406-104-04 [NDC for In-111 kit]; NDC 64406-103-03 [NDC for Y-90 kit]

Biology: Ibritumomab tiuxetan (and its Y-90 and In-111 radioimmune conjugates) binds specifically to the CD20 antigen (human B-lymphocyte-restricted differentiation antigen, Bp35) expressed on pre-B and mature B lymphocytes and on over 90% of B-cell non-Hodgkin’s lymphomas (NHL). The CD20 antigen is not shed from the cell surface and does not internalize upon antibody binding. The apparent affinity (KD) of ibritumomab tiuxetan for the CD20 antigen ranges between ~14-18 nM. The complementarity-determining regions (CDR; epitope-binding regions) of the ibritumomab moiety bind to the CD20 antigen on the surface of B lymphocytes. Like CD20-bound rituximab (see Rituxan entry), binding of radiolabeled ibritumomab tiuxetan can induce apoptosis (programmed cell death) in bound CD20+ B-cells in vitro. The Yttrium-90 radioisotope decays by emission of beta particles, with a physical half-life of 64.1 hours (2.67 days). The beta particles induce cellular damage and death by the formation of free radicals in the target and neighboring cells.

Companies.: Zevalin was co-developed by IDEC Pharmaceuticals Corp., now Biogen Idec, and Genentech, Inc. Zevalin is manufactured by Biogen Idec at former IDEC facilities in San Diego, CA; and, until recently, was marketed in the U.S. by Biogen Idec. It is now marketed in the U.S. by Cell Therapeutics, Inc. IDEC had reported that DSM Catalytica Pharmaceuticals (formerly Catalytica, Inc.) performs product/kit finishing, filling, and packaging. However, the more recent European Product Assessment Report (for product marketed in the European Union) reports filling and finishing are performed by Baxter Pharmaceutical Solutions LLC (Bloomington, IN).

IDEC, later Biogen Idec, exclusively marketed Zevalin; in the U.S. In June 1999, IDEC granted Schering AG (now Bayer Schering Pharma) exclusive worldwide marketing international rights outside of the U.S. for Zevalin for treatment of non-Hodgkin’s lymphoma. IDEC received a $13 million up-front payment, was eligible for additional milestone payments of up to $19.5 million, and receives royalties on sales.

In Spring 2006, Bayer AG acquired Schering AG, with the new company renamed Bayer Schering Pharma.

In Dec. 2006, with disappointing sales, Biogen Idec announced it was actively seeking to divest Zevalin (marketing).

In Dec. 2007, Cell Therapeutics, Inc. acquired U.S. marketing and development rights for Zevalin from Biogen Idec for $10 million in cash up front, up to an additional $20 million in milestone payments when the product receives approval for a first-line indication in NHL, plus unspecified royalties on sales. CTI has also agreed to share the cost of certain clinical trials with Bayer Schering.

The Yttrium-90 Chloride Sterile Solution component of the kit is manufactured and distributed under contract by MDS Nordion. The Indium In-111 Chloride Solution (Indiclor) is manufactured and distributed under contract by Medi-Physics, Inc., now Amersham Health, a subsidiary of Amersham plc, now a subsidiary of GE Healthcare. The MX-DTPA chelating agent for linking the monoclonal antibody and radioisotope is manufactured under contract for Biogen Idec by Hauser Contract Research Organization, a subsidiary of Hauser, Inc.

In March 2009, Spectrum Pharmaceuticals, Inc. completed purchase from Cell Therapeutics of 100% interest in Zevalin paying a total of $31.5 million. The companies in Dec. 2008 had originally formed a 50/50 joint venture with Cell Therapeutics. Cell Therapeutics had previously purchased Zevalin from Biogen Idec Inc. in Dec. 2007 for $10 million (plus certain milestone payments, all of which are not the responsibility of Spectrum). Spectrum Pharmaceuticals assumed100% ownership of RIT Oncology, LLC, which for a short time was a 50/50 joint venture for Zevalin marketing between the companies, and will be responsible for all activities relating to Zevalin.

On Jan. 25, 2012 I Spectrum Pharmaceuticals acquired full licensing rights to market Zevalin for intravenous use outside of the United States of America from Bayer Healthcare, with Spectrum now having full worldwide marketing rights. A the time, Zevalin was approved in more than 40 countries outside the U.S. for the treatment of follicular B-cell non-Hodgkin's lymphoma, including countries in Europe, Latin America and Asia.

FDA class: Biologic BLA

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 20020219; BLA, first approval (BL 103737/5005) for Zevalin; orphan designation (granted 9/6/1994, expires 2/19/2009)

Date = 20020219; BLA; first approval of Indium In-111 Chloride Sterile Solution granted to Amersham Health

Date = 20090904; BLA supplement; Indication = treatment of patients with previously untreated follicular non-Hodgkin's Lymphoma (NHL), who achieve a partial or complete response to first-line chemotherapy

Date = 20111121; BLA supplement; Indication = to remove the pre-treatment biodistribution evaluation requirement using Indium-111 ZEVALIN imaging dose followed by a gamma scan before administering the ZEVALIN therapeutic dose. This pre-treatment biodistribution evaluation requirement is more commonly referred to as the “bioscan.”

indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling; 10/28/2010]:

1.1 Relapsed or Refractory, Low-grade or Follicular NHL

Zevalin is indicated for the treatment of relapsed or refractory, low-grade or follicular B-cell non-Hodgkin's lymphoma (NHL).

1.2 Previously Untreated Follicular NHL

Zevalin is indicated for the treatment of previously untreated follicular NHL in patients who achieve a partial or complete response to first-line chemotherapy.

Status: IDEC filed a BLA on Nov. 1, 2000; it was accepted for filing on Dec. 29, 2000 with priority designation (six month review target); and was granted accelerated approval on Feb. 19, 2002 (approval time ~1.3 years). The BLA consisted of seven compact disks (CDs) and ~30 more CDs of digitized computer tomography (CT) scans and nuclear medicine images. This was one of the first BLAs submitted to CBER, FDA, in a completely electronic format (with no paper version required to accompany the CDs). The accelerated approval was based on effects on surrogate markers, rather than demonstration of clinical efficacy (e.g., improved survival). Zevalin is exempt from CBER lot release requirements.

Schering AG submitted a Marketing Authorization Application (MAA) for European Union (EU) approval in Jan. 2001. In mid-2002, European approval of Zevalin was delayed due to certain technical compliance issues at the fill/finish provider. Schering had hoped to launch Zevalin in the second half of 2002, but its European launch was postponed. On Jan. 16, 2004, Schering AG received EU approval of Zevalin for the treatment of adult patients with CD20+ follicular B-cell NHL who are refractory to or have relapsed following Rituxan therapy. European launch followed several months later.

In Oct. 2005, FDA issued a warning letter to Biogen Idec and the company issued a “Dear Healthcare Provider” letter regarding severe cutaneous or mucocutaneous reactions in patients treated with Zevalin for non-Hodgkin’s lymphoma.

On April 28, 2008, the EU granted supplemental approval to Zevalin for use in the course of a first-line therapy after remission induction in previously untreated patients with follicular lymphoma (consolidation therapy). This was largely based on the FIT trial (see the Trials section below). In this trial, one single infusion of Zevalin prolonged median progression-free survival by ~2 years, with a favorable toxicity profile.

On Oct. 2, 2008, Cell Therapeutics, Inc. (CTI) filed a sBLA for use of Zevalin as consolidation therapy after remission induction in previously untreated patients with follicular non-Hodgkin's lymphoma, based largely on the FIT trial (see Trials section below). CTI defines "consolidation therapy" as "a treatment given after initial induction therapy and is aimed to improve the quality of the patient response by further diminishing the number of cancer cells with the goal of extending the response duration." If approved, Zevalin would be the only radioimmunotherapy in the U.S. with approval for use as first-line consolidation therapy, and this would add a potential 18,000 users/year.

On Nov. 28, 2008, the FDA accepted for filing and granted priority review status for a supplemental BLA for use of Zevalin as a first line consolidation therapy for patients with non-Hodgkin's lymphoma (NHL). Priority review was granted. A PDUFA) target date of July 2, 2009 was set.

On July 9, 2009, FDA issued a Complete Response Letter regarding the sBLA in the first-line consolidation setting. FDA requested Specturm submit data files from the FIT study to support and verify a subset of the data that were under review to support the proposed labeling. No additional clinical studies have been requested. The additional data requested do not involve new data analyses.

In March 2011, Spectrum reported FDA had accepted for review the Prior Approval Supplement (PAS) containing data providing for the removal of the Indium-111 ZEVALIN (ibritumomab tiuxetan) pre-treatment imaging evaluation, more commonly referred to as the "bioscan" requirement. A decision was expected by Nov. 20, 2011. According to Spectrum, "We were able to show them [FDA] that out of over 8,000 patients that received Zevalin in he last 5,6 years, the data that we have, less than 1%,, less than 0.5% patients had abnormal bioscan, number one. Numbber two, even when bioscan was abnormal and if Zevalin was given, these patients still had complete responses and partial responses and the side effect profile was no different than other patients."

The Nov. 2011 approval of removal of the bioscan requirement will simplify Zevalin treatment. Typically, patients previously received an infusion of rituximab on Day 1, followed by a diagnostic dose of radiolabeled Indium-111 ZEVALIN and a full-body scan at a nuclear imaging center within ten minutes and again on Day 3 or 4. Patients would then receive another infusion of rituximab and a 10-minute injection of the therapeutic dose of ZEVALIN on Day 7, 8, or 9. With the bioscan requirement removed, patients undergoing treatment with ZEVALIN will receive the two infusions of rituximab followed by a 10-minute injection of ZEVALIN. This simplified regimen will be called “RRZ” – rituximab, rituximab, ZEVALIN.

Tech. transfer: U.S. patent 6,399,061, “Chimeric and radiolabelled antibodies specific to human CD20 antigen and use thereof for treatment of B-cell lymphoma,” assigned to IDEC (now Biogen IDEC), expiring on Jun 4, 2019, describes the CD20 murine hybridoma (and monoclonal antibody) 2B8 deposited as ATCC HB11388 and the monoclonal antibody’s conjugation to radioisotopes. 2B8 was prepared from mice immunized with human lymphoblastoid cell line SB, with extracted spleen cells fused with the mouse myeloma SP2/0 cell line. The patent also describes use of this monoclonal antibody to derive chimeric CD20 (c2B8) antibody. IDEC has received U.S. RE 38,008 covering methods for the use of radiolabeled CD20 antibodies in the treatment of non-Hodgkin’s lymphoma (NHL).

U.S. 5,776,456, "Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma," assigned to IDEC, has been extended to Feb. 19, 2016.

EP2000149, "Chimeric anti-CD20 antibody," expires in 2013.

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 does not infringe Coulter/Corixa’s four main patents covering Bexxar or that the patents are invalid (see the Bexxar entry for discussion of Coulter/Corixa patents). 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 (both companies involved in development, manufacture, and marketing of Bexxar; GSK acquired Corixa in April 2005), filed a countersuit against IDEC alleging that Zevalin infringes three patents assigned to Corixa (U.S. 5,595,721; 6,090,365; and 6.015,542). These patents include composition-of-matter and methods of use claims for radiolabeled CD20 monoclonal antibody for treatment of non-Hodgkin’s lymphoma.

In Feb. 2003, IDEC filed a follow-on infringement suit against Corixa 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 NHL. In Oct. 2003, a U.S. District Court granted summary judgement in favor of IDEC, 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.” However, in Feb. 2004, the U.S. District Court vacated its Oct. 2003 judgment in favor of Biogen Idec (i.e., ruled in favor of Corixa and GSK), based on new evidence and evidence not previously considered.

In March 2004, Corixa and GSK settled their disputes with Biogen Idec, with Biogen Idec paying $20 million to be equally shared between Corixa and GSK, and paying a one-time milestone fee and unspecified royalties on Zevalin sales starting Jan. 1, 2004 until all Bexxar-related patents expire. The companies also cross-licensed their disputed Bexxar- and Zevalin-related patents (and GSK later, in April 2005, acquired Corixa).

IDEC has licensed radioimmune conjugation technology from the National Cancer Institute (NCI), National Institutes of Health (NIH). U.S. 5,434,287, July 18, 1995, and 5,124,471, June 23, 1992, both entitled “Bifunctional DTPA-type ligand,” and 5,286,850, “Antibody DTPA-type ligand conjugates,” Feb. 15, 1994, each assigned to NIH, describe bifunctional cyclohexyl diethylenetriaminepentaacetic acid (DTPA) ligands which facilitate the binding of radioactive metals to proteins and antibodies for the production of metal-chelate protein and metal-antibody radioimmune conjugates. DTPA derivatives form metal chelate conjugates with monoclonal antibodies that are highly stable, both with respect to the metal chelate binding and with respect to chelate-antibody conjugate – properties of great importance for in vivo applications. If the chelate releases the metal ion after introduction into the blood, these ions tend to be bound by transferrin, or the like and are distributed throughout the circulatory system. Released ions ultimately tend to collect and remain in organs such as the liver and spleen, bone or kidney with toxic effects depending on the metal and its radioactivity. If the chelate does not form a highly stable conjugate with the antibody, there is a significant reduction in the amount of metal delivered to the target site and a corresponding decrease in efficacy.

IDEC received a patent term extension of 227 days for U.S. patent 4,784,950. This was based on FDA determination that 2,887 days occurred during the product’s testing period and 476 days during the approval phase (filing to approval), with the short extension period due to the relatively late granting date of the patent.

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 and humanized monoclonal antibodies. Currently, Genentech, with its “New Cabilly” or Cabilly II patent (6,113,415), including claims copied from a revoked Celltech Group patent, appears to hold a very strong position with U.S. patents covering recombinant expression of monoclonal antibodies (co-expression of heavy and light chains). IDEC/Biogen Idec may likely have licensed this and other recombinant antibody technology from Genentech.

Disease: Non-Hodgkin’s lymphoma (NHL) is a form of cancer that affects the blood, bone marrow and lymphatic tissues. Non-Hodgkin’s lymphoma currently is the sixth-leading cause of cancer-related deaths in the U.S., caused the death of an estimated 23,400 patients in the U.S. in 2003. NHL has the second-fastest-growing mortality rate among types of cancer in the U.S. The National Cancer Institute (NCI) estimates approximately 300,000 people are afflicted with NHL in the U.S., with 25-40% having follicular non-Hodgkin’s lymphoma. Transformed non-Hodgkin’s lymphoma is an aggressive and difficult to treat form of follicular non-Hodgkin’s lymphoma with a particularly poor prognosis.

Approximately 55,000 people are diagnosed in the U.S. with NHL each year. About 65% of this group are of the low-grade or follicular subgroup of NHL, which is ultimately incurable. These tumors grow slowly and are less susceptible to treatment with chemotherapy drugs. Patients with this type of NHL may remain in remission for years, but eventually have relapses that occur more frequently over the course of the disease. As patients are treated for subsequent relapses, their responses to standard treatments diminish. Zevalin provides another treatment option for these patients (and Bexxar provides an option for those having failed to respond to Zevalin).

Trials: In clinical studies, administration of the current two-step Zevalin therapeutic regimen resulted in sustained depletion of circulating B-cells. At four weeks, the median number of circulating B-cells was zero (range, 0-1,084 cell/mm3). B-cell recovery began at approximately 12 weeks following treatment, and the median level of B-cells was within the normal range (32 to 341 cells/mm3) by 9 months after treatment. Median serum levels of IgG and IgA remained within the normal range throughout the period of B-cell depletion. Median IgM serum levels dropped below normal (median 49 mg/dL, range 13-3990 mg/dL) after treatment and recovered to normal values by 6-month post therapy. The loss of antibody-forming B-cells increased patient susceptibility to infections.

The Zevalin therapeutic regimen was tested in two multi-center trials enrolling 197 subjects. Study 1 was a single arm study of 54 patients with relapsed follicular lymphoma refractory to rituximab (Rituxan) treatment. Patients were considered refractory if their last prior treatment with Rituxan did not result in a complete or partial response, or if time to disease progression (TTP) was < 6 months. The primary endpoint was the overall response rate (ORR) using International Workshop Response Criteria (IWRC). Secondary efficacy endpoints included TTP and duration of response (DR). In a secondary analysis comparing objective response to the Zevalin therapeutic regimen with that observed with recent treatment with Rituxan, the median duration of response following the Zevalin therapeutic regimen was 6 vs. 4 months (50% extension).

Study 2 was a randomized, controlled, multicenter, Phase III study (the primary pivotal study supporting approval) also comparing the Zevalin therapeutic regimen to treatment with Rituxan in 143 patients with relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma (NHL), or transformed B-cell NHL. A total of 73 patients received the Zevalin therapeutic regimen, and 70 patients received Rituxan therapy. The primary efficacy endpoint was the ORR using IWRC criteria. The ORR was significantly higher (80% vs. 56%, p = 0.002) for patients treated with Zevalin. The secondary endpoints, duration of response and time to progression, were comparable between the two arms. The activity and toxicity of a Zevalin therapeutic regimen using a reduced dose of Y-90 Zevalin was further defined in a third study in 30 patients with mild thrombocytopenia (platelet count 100,000-149,000 cells/mm3).

IDEC/Biogen Idec has conducted post-approval studies of whether Zevalin improves patient survival. Extended response duration data from Study 2 were presented in Nov. 2002. After 34 to 49 months of follow-up, 32.1% of Zevalin complete responders remained in remission, while 36% of Rituxan complete responders remained in remission after 36-51 months of follow-up. (but overall, Rituxan provided fewer complete responses with shorter median durations).

In Dec. 2005, Biogen Idec reported further data showing that patients may benefit from earlier and consolidated use of Zevalin radioimmunotherapy in refractory and hard-to-treat lymphomas, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular non-Hodgkin’s lymphoma (FL), when integrated into the current standard of care.

In Oct. 2006, Biogen Idec and Schering AG initiated a Phase III international multicenter, open-label prospective, randomized, two-armed, group-sequential study (ZEAL; Zevalin as consolidation therapy in Aggressive Lymphoma) in 400 patients. This is evaluating the efficacy and safety of Zevalin treatment versus observation in patients with diffuse large-B-cell lymphoma (DLBCL) — the most common type of aggressive non-Hodgkin’s lymphoma (NHL) — who are in complete remission (CR) or unconfirmed complete remission (CRu) after first-line CHOP-rituximab (CHOP-R) therapy. Treatment consists of two treatment days one week apart followed by a 12-week safety follow-up period. The study will last about four years. The primary endpoint is overall survival, with disease-free survival and health-related quality of life as secondary endpoints. Once the trial is completed, the companies expect to file to expand the product’s current label to include first-line therapy for patients with aggressive DLBCL.

In June 2008, Cell Therapeutics, Inc. (CTI), U.S. marketer of Zevalin, acquired access from Bayer to its Phase III First-line Indolent Trial (FIT) data. CTI expects that the data from the trial will support a sBLA for use as consolidation therapy after remission induction in previously untreated patients with follicular lymphoma. The FIT study, which evaluated the use of Zevalin as first-line consolidation therapy in follicular lymphoma patients, was sponsored by Bayer Schering Pharma AG, which has exclusive rights to Zevalin in all countries of the world except the U.S. Under the terms of the agreement, CTI will make an initial payment to Bayer Schering Pharma with an additional payment upon FDA approval of a sBLA. CTI also will pay Bayer royalties on net product sales up to a specified aggregate amount.

FIT evaluated the benefit and safety of a single infusion of Zevalin in patients with CD20-positive follicular lymphoma who had achieved a partial remission or a complete remission after receiving standard first-line chemotherapy regimens. The trial demonstrated that when used as a first-line consolidation therapy for patients with follicular lymphoma, Zevalin significantly improved the median progression-free survival time from 13.5 months (control arm) to 37 months (p<0.0001). Zevalin resulting in a total complete response (CR + CRu) rate of 87% and prolongation of median progression-free survival (PFS) by ~2 years, with a toxicity profile comparable to that seen with Zevalin's use in approved indications:. Zevalin-treated patients had reversible Grade 3 or 4 hematologic side effects including neutropenia in 67%, thrombocytopenia in 61%, and anemia in 3%. Nonhematologic toxicities were 23.5% Grade 3, and Grade 3/4 infection was 7.9%..

In late 2008, studies to determine whether the Zevalin therapeutic regimen confers an effect on progression-free survival are ongoing.

Medical: The Zevalin Therapeutic Regimen involves intravenous infusion of rituximab (Rituxan) at a dose of 250 mg/m2, followed by intravenous injection of In-111 Zevalin within 4 hours following completion of the Rituxan dose, providing a radiation dose of 5.0 mCi (1.6 mg total antibody dose). The biodistribution of In-111 Zevalin is assessed/assured by a visual evaluation of whole body gamma images at 2-24 hours and 48-72 hours after injection. Then 7-9 days after the first infusion, a second intravenous infusion of Rituxan is administered followed by intravenous injection of Y-90 Zevalin within four hours, e.g., at a dose of 0.4 mCi/kg (14.8 MBq/kg) body weight. The dose of Y-90 Zevalin must not exceed the absolute maximum allowable dose of 32.0 mCi (1184 MBq), regardless of the patient’s body weight.

The Zevalin treatment regimen is more toxic than treatment with Rituxan alone. More than half of the patients in clinical trials experienced serious reductions in blood-cell counts (cytopenias), including lymphocytes and platelets, lasting for 3-4 weeks. Hemorrhages, some fatal, and life threatening infections occurred in a small number of patients. Because of this, the Zevalin therapeutic regimen is only approved for patients having failed other treatments. Unlike standard chemotherapy, which is given over as many as four to six months, Zevalin can be administered in an outpatient setting over eight days with approximately 12 weeks of follow-up.

Trials: Few head-to-head clinical trials have been conducted to attempt to show that Bexxar (and Zevalin) are as effective as Rituxan (see related entry), if not better..

Disease: About 332,000 persons in the U.S. have lymphoma and 23,400 die annually (making it the sixth leading cause of cancer deaths), according to the Lymphoma Research Foundation. Standard NHL treatments primarily consist of traditional multidrug chemotherapy, radiation or, depending on the lymphoma type (there are over 30 types), watching and waiting for further developments. U.S. incidence rates for lymphoma have nearly doubled since the early 1970s. See the Rituxan entry for further disease information.

In Jan. 2012, Spectrum reported "The global market for Zevalin is several times larger than the US, with more than 350,000 cases of non-Hodgkin's lymphoma diagnosed every year.

Market: Sales of Zevalin have been very disappointing for Biogen Idec, leading the company to begin to divest the product, and Bayer later also divesting it.

Total 2008 sales by Spectrum were $11 million. In Nov. 2007, Cell Therapeutics, Inc. reported 2007 U.S. sales of about $15 million, and projected 2008 to be much the same.

Schering AG had originally projected its European sales would eventually reach (peak) at 50 million euros.

Total Zevalin U.S. sales in 2006 (reported by Biogen Idec) were $16.4 million. Total U.S. sales were $23 million in 2003, and $20 million in 2002 (launched in April 2002).

In Jan. 2012, Spectrum reported, "Since acquiring the U.S. rights to Zevalin in 2008, we have successfully reversed the declining sales trajectory and nearly tripled 2008 sales.

The 2007 Average Wholesale Price (AWP) for Zevalin In-111 is $2,915.40/kit and the Direct Price (Manufacturer’s discount price) is $2,260.00/kit (Red Book, 2007; no changes since at least 2004). The AWP for Zevalin Y-90 is $25,238.83/kit, and the Direct Cost is $19,625/kit (no significant changes since at least 2004)..

The Centers for Medicare & Medicaid Services (CMS) reimburses $21,000 for Zevalin (covering the cost for most persons under Medicare). Zevalin kits are sold exclusively to radiopharmacies, which prepare (including radiolabeling) the product and resell it to hospitals, usually for $21,800 or more.

A variety of factors have contributed to the small market penetration of Zevalin (and Bexxar). Both products have not been clinically proven to prolong survival, compared with other therapies. Patients are more likely to respond to them than standard treatments, and trials to test whether the drugs do have a survival. Other, more thoroughly tested lymphoma drugs are preferred as first-line treatments, and physicians often repeatedly prescribe these drugs even after they have lost their effectiveness — and when Bexxar and Zevalin might work better. Because they are radioactive, these treatments are almost always administered in large hospitals, not doctors’ offices. As a result, doctors are not paid by Medicare and private insurers for prescribing them, as they are when they give patients more common chemotherapy. Oncologists have financial incentives to use drugs other than Bexxar and Zevalin, for which they receive no insurance (e.g.,Medicare) payments to administer. In addition, using either Zevalin or Bexxar usually requires oncologists to coordinate treatment with academic hospitals, which the physicians may view as competitors. Also, most oncologists outside academic hospitals treat many different cancers and may be only vaguely familiar with the products. Thus, many prescribe Bexxar and Zevalin only as a last resort.

At the start of 2003, with the Center for Medicare/Medicaid Services (CMS) implementing 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 Zevalin (also Rituxan). Medicare simply was paying (reimbursing) less than the actual acquisition cost of Rituxan, so someone, 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, a method that short-changes coverage for expensive therapeutics. Hospitals in some locations are reimbursed (and lose) as much as $4,000 for every Zevalin procedure. Shifting treatment to physicians offices (more fully reimbursed) is not practical for Zevalin and other nuclear medicine therapies.

In July 2005, the Center for Medicare/Medicaid Services (CMS), which set policies for Medicare and Medicaid coverage, announced continued off-label Medicare coverage of Zevalin for treatment of non-Hodgkin’s lymphoma (NHL), but still at a rate less than its cost.

In Dec. 2007, the U.S. Congress passed legislation that included extending the 2007 reimbursement methodology for radiopharmaceuticals into 2008, with this continuing Medicare reimbursement for Zevalin at a rate less than its cost, while providing the opportunity for companies, e.g., CTI, to work with CMS to seek higher reimbursement rates..

In Jan 2008, Cell Therapeutics, Inc. (CTI) reported it was adding 13 positions in Zevalin sales and marketing (while otherwise reducing its staff)/\.

In Oct. 2009, the Center for Medicare/Medicaid Services (CMS) ruled in favor of Zevalin as a first-line treatment for patients with non-Hodgkin's lymphoma (NHL). This favorable resolved for Spectrum the issue of whether the company can sell Zevalin at the average sales price (ASP) like competitive chemotherapeutics. The favorable decision allows Zevalin to compete with other products selling with a CMS-assigned ASP. At the time, Zevalin was being sold at (1) invoice or (2) the average wholesale price (AWP) at costs between $24,000 and $31,000 per treatment. Unlike most chemotherapy regimens that can last six months or longer, Zevalin is a one time treatment that takes about three to five hours to administer.

Zevalin and Bexxar (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 products 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: There are now three therapeutics available for treatment of non-Hodgkin’s lymphoma – Rituxan, Zevalin and Bexxar. Both Bexxar and Zevalin are radioimmune conjugates, while Rituxan is an unconjugated monoclonal antibody. Both Zevalin and Bexxar are approved only for treatment of patients not responding to or having failed on Rituxan; and Zevalin and Bexxar essentially compete with each other. Zevalin treatment may be repeated (maintenance therapy) and is particularly effective for patients with indolent or slow-growth forms of NHL, affecting about 45-50% of NHL patients.