ofatumumab - Arzerra; HuMax-CD20; CD20 monoclonal antibody, human, recombinant
Status - U.S. approval granted in Oct. 2009; conditionally approved in EU in April 2010
Organizations involved:
GlaxoSmithKline plc – Manuf. other; R&D; Tech.; World mark.
Lonza Biologics plc – Manuf.
Genmab A/S – R&D; Tech.
Medarex, Inc. – Tech.
Genentech/Roche – Patent dispute
City of Hope – Patent dispute
Hoffmann-La Roche Ltd. – Parent
Biogen Idec Inc.– Patent dispute
Cross ref.: See the entry for Rituximab (Rutuxan), another CD20 monoclonal antibody. Note, a separate entry is provided for this active agent/drug substance, since FDA granted this a full BLA.
Description: Arzerra (HuMax-CD20) is a formulation of ofatumumab, a fully IgG1 human monoclonal antibody with binding specificity for the small loop epitope (specific antibody binding site) of human CD20 expressed by transformed Chinese hamster ovary (CHO) cells. Ofatumumab has a calculated molecular mass of 149 kDa and molecular formula of C6480-N10022-N1742-O2020-S44. Ofatumumab was developed using UltiMAb or HuMAb-Mouse technology licensed from Medarex, Inc., with transgenic mice expressing fully-human monoclonal antibodies.
Each vial contains 100 mg ofatumumab in 5 mL of solution in a single-use vial. Arzerra is stored refrigerated between 2° to 8°C (36° to 46°F). Arzerrais a sterile, colorless, preservative-free liquid concentrate (20 mg/mL) for dilution and intravenous administration provided in single-use glass vials with a latex-free rubber stopper and an aluminum overseal
Biological.: See the Rituximab entry for information about CD20. HuMax-CD20 is a fully human, high-affinity antibody targeted at the CD20 molecule in the cell membrane of B-cells. In certain types of cancer, these cells can proliferate too much and treatment is needed to reduce the number of B-cells. HuMax-CD20 is effective at binding to the disease target, and releases only very slowly from the target over time. Preclinical studies showed that ofatumumab inhibited the growth of B-cell tumors in SCID mice more efficiently than rituximab, and ofatumumab infusion in cynomolgus monkeys led to profound, long-lasting and dose-dependent B-cell depletion. Pharmacokinetic analysis has shown that in patients with non-Hodgkin's lymphoma (NHL) ofatumumab had a longer half-life than rituximab. HuMax-CD20 has been shown to deplete B-cells effectively and bind to a unique site on the CD20 target when compared to other known CD20 antibodies.
Nomenclature: CD20 Mab, human, rDNA [BIO]; Arzerra [TR]; ofatumumab [INN]; immunoglobulin G1, anti-(human CD20 (antigen))(human monoclonal HuMax-CD20 heavy chain), disulfide with human monoclonal HuMax-CD20 kappa-chain, dimer [CAS]; 679818-59-8 [CAS RN]; CD20 Mab, human, rDNA [BIO]; CD20 monoclonal antibody, human, recombinant [SY]; NDC 0173-0808-02 and NDC 0173-0808-05 [NDC]
Companies.: HuMax-CD20 was initially developed by Genmab A/S. In Dec. 2006, Genmab entered into an agreement with GlaxoSmithKline plc (GSK), which granted GSK exclusive worldwide rights to co-develop and commercialize HuMax-CD20. GSK and Genmab share the development costs equally from 2008 forward. GSK will be solely responsible for manufacturing and commercialization. Genmab received a license fee of ~$102 million and GSK invested ~$357 million through a direct private placement. Genmab also receives milestone payments, and the total of these payments and the initial license fee and equity investment could exceed ~$1.6 billion. The total potential value of this agreement, in the event of full success in cancer and various autoimmune and inflammatory diseases, could exceed ~$2.1 billion. In addition, Genmab will be entitled to receive tiered double digit royalties on global sales of HuMax-CD20. As of Aug. 2008, Genmab had received ~$110 million in milestone payments from GSK. Genmab will have an option to co-promote, in a targeted oncology setting, HuMax-CD20 and two GSK products, Bexxar and Arranon, in the U.S.; and HuMax-CD20 and Atriance (from GSK) in the Nordic region.
In Dec. 2008, GSK amended its agreement with Genmab. Genmab received a one-time payment of $4.5 million from GSK upon FDA's acceptance for review of the filing of the first BLA for Arzerra in an oncology indication. In exchange, Genmab terminated its option to co-promote Arzerra [Genmab sold its co-promotion option rights to GSK] and also requirements to co-market several GSK products in foreign markets. GSK is now fully responsible for all sales of Arzerra.
In July 2010, GlaxoSmithKline (GSK) and Genmab amended their fatumumab co-development and commercialisation agreement. GSK assumed responsibility for developing ofatumumab in autoimmune indications: while continuing to jointly develop ofatumumab with Genmab in oncology indications:. In total, Genmab will fund 145 million UK pounds for development in oncology indications:, including 17 million as a yearly spending cap for each of the next six years starting with 2010. There will be 50% reduction in future milestone under the oncology development program, but there were no changes in royalty tiers to Genmab in the oncology program. GSK is expected to conduct a number of Phase II clinical trials to evaluate the safety and efficacy of ofatumumab in autoimmune indications:.
Lonza manufactures ofatumumab (drug substance) for GSK under a long-term contract. Lonza also carried out a program of process development and cGMP manufacturing services to support licensure. GSK does its own fill and finishing.
FDA class: Biologic BLA
Approvals: Date = 20091027; BLA no. 125326
indications: [Full text of the "Indications and USAGE" section of the product labeling/insert]:
ARZERRA (ofatumumab) is a CD20-directed cytolytic monoclonal antibody indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease related symptoms or increased survival with ARZERRA.
Status: With positive results from a pivotal trial reported for chronic lymphocytic leukaemia (CLL), regulatory filings in the U.S. and Europe were expected in late 2008 or early 2009. Ofatumumab had been designated a Fast Track Product by the FDA for patients with CLL who have failed fludarabine therapy, including those who are refractory to available treatments.
On Jan., 30, 2009,GSK filed a Biologics License Application (BLA) for Arzerra for the treatment of chronic lymphocytic leukaemia (CLL) patients who have previously failed, or are inappropriate for, standard therapies. On April 3, 2009, FDA accepted the BLA for filing and granted ofatumumab priority review status (six month target review time).
On Feb. 9, 2009, GSK and Genmab reported submission of a Marketing Authorisation Application (MAA) to the European Medicines Agency (EMEA), European Union, for Arzerra for the treatment of chronic lymphocytic leukaemia (CLL) patients who have previously failed, or are inappropriate for, standard therapies. In Europe, ofatumumab has been granted orphan designation for CLL as it affects approximately 3.5 in 10,000 persons in the European Union.
On May 29, 2009 , Oncologic Drugs Advisory Committee (ODAC), FDA, voted 10-3 that the Arzerra data were likely to predict clinical benefit for patients with CLL whose disease is refractory to fludarabine and alemtuzumab (CAMPATH).
On Oct. 26, 2009, FDA granted accelerated approval to Arzerra for treatment of CLL in patients refractory to Campath (see related entry) or fludarabine
On April 10, 2010, Arzerra received European Union (EU) approval for treatment of patients with refractory chronic lymphocytic leukaemia (CLL) who have not responded to standard therapies fludarabine and alemtuzumab (CAMPATH). The MAA approval was conditional, with the CHMP deciding the benefit of immediate availability outweighed the fact that additional trials' data were still required. GSK was required to carry out an open-label multi-center study on Arzerra’s safety and efficacy versus a physician’s choice of drug; and a pPhase IV observational study of Arzerra. There is no timescale set for this data to be produced, although Arzerra’s conditional authorisation is subject to an annual review and a pharmacovigilance plan will also be implemented. The CHMP stated that Arzerra should only be prescribed by experienced cancer physicians in an environment where full resuscitation facilities are immediately available.
In Sept. 2010, GSK and GenMab reported that they would refocus the development of ofatumumab on the treatment of autoimmune diseases (with none approved at the time). This was done with the markets for rheumatoid arthritis (RA) and multiple sclerosis (MS) becoming rather crowded. Autoimmune development is focused on the subcutaneous delivery of ofatumumab, because GSK believes this route of administration has the potential to offer added convenience and improved tolerability.
Tech. transfer: GenMab has filed U.S. application 20090226421, "Recombinant monovalent antibodies and methods for production thereo," covering aspects of CD20 and other recombinant monoclonal antibody manufacture. Claims 1-228 have been canceled, but 229-268 remain.
In Oct. 2009, GSK filed a declaratory judgment action in U.S. federal court seeking a declaration that the U.S. Patent 6,331,415 (the "Cabilly" patent) is invalid, unenforceable and not infringed by Arzerra. The Cabilly Patent (see the Tech. transfer section of the Monoclonal Antibodies monograph), held by Genentech/Roche (and the and City of Hope), broadly covers aspects of recombinant antibody expression.
In March 2010, Genentech/Roche and Biogen Idec filed a patent infringement suit in federal court against GSK alleging that ofatumumab infringed a patent the companies received on March 23. U.S. 7,682,612, "Treatment of Hematologic Malignancies Associated with Circulating Tumor Cells Using Chimeric Anti-CD20 Antibody," includes claims for treating CLL with anti-CD20 antibodies. The suit did not request an injunction to prevent the sale of Arzerra.
In Nov. 2011, 2011, the US District Court entered final judgment in favor of GSK (non-infringement) in the patent infringement case involving Arzerra brought by Genentech and Biogen Idec. In Dec. 2011, Genentech and Biogen Idec initiated an appeal of this verdict, apparently still in progress (in early 2013).
In April 2011, Genentech (Roche) and the City of Hope filed a patent infringement suit against HGSI, GSK and Lonza alleging infringement of 7,923,221, " Methods of Making Antibody Heavy and Light Chains Having Specificity for a Desired Antigen," more commonly known as Cabilly III (see the Monoclonal Antibodies, recombinant entry) and also Cabilly II., 6,331,415. Cabilly III broadly covers recombinant antibody expression and expires in 2018.
In May 2012, this dispute over Cabilly patents was settled, with details not disclosed, but Arzerra obviously remaining on the market. Presumably, HGSI/GSK/Lonza are now paying royalties to Genentech/Roche.
GenMab has received European patents, Human monoclonal antibodies against CD20, assigned to GenMab, each "Human monoclonal antibodies against CD20"-- EP2330130, expiring in 2023; EP2316856,, expiring in 2023; EP1740946, expiring in 2005 and; EP1558648, expiring in 2023.
In May 2013, n Biogen Idec v. GlaxoSmithKline, a divided panel of the Federal Circuit affirmed a district court’s decision that GSK's monoclonal antibody product Arzerra does not infringe Biogen's patent number 7,682,612.
Trials: In Aug. 2009, results were reported from a trial of the 1,000 milligram dose (after initial dose) of Arzerra in patients with non-Hodgkin's lymphoma who did not respond to the established drug Rituxan. An overall response rate of just 10% was reported.
FDA approval was based on results from a pivotal study in which 42% of patients with CLL who were refractory to both fludarabine and alemtuzumab (two therapies used in treating CLL) responded to treatment with ofatumumab. These patients had a median duration of response of 6.5 months. The most common adverse reactions (≥10%) seen were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions seen were infections (including pneumonia and sepsis), neutropenia, and pyrexia.
FDA has reported, "Arzerra's effectiveness was evaluated in 59 patients with CLL whose disease no longer responded to the available therapies. The product’s safety was evaluated in 181 patients in two studies in patients with cancer." At the time of FDA approval, GSK was conducting a clinical trial in CLL patients to confirm that the addition of Arzerra to standard chemotherapy delays the progression of the disease.
In July 2008, an interim analyses were reported from the Phase III pivotal study evaluating HuMax-CD20 in two difficult to treat groups of patients with chronic lymphocytic leukaemia (CLL). The activity of ofatumumab was evaluated in 154 patients in this interim analysis, of whom 138 patients with refractory CLL were evaluable. About half of the patients (59) in the study were refractory to both fludarabine and Campath. The analysis also included a second group (79) refractory to fludarabine and considered inappropriate candidates for Campath due to bulky tumor in their lymph nodes. All patients in the study received 8 weekly infusions of ofatumumab, followed by 4 monthly infusions of ofatumumab. Patients received 300 mg of ofatumumab at the first infusion and 2,000 mg of ofatumumab at each subsequent infusion. The primary endpoint of the study was objective response over a 24 week period from start of treatment as assessed according to the National Cancer Institute Working Group guidelines. The secondary endpoints were duration of response, progression free survival, time to next CLL therapy, overall survival and adverse events. The study met the primary endpoint in both populations and the results from the secondary endpoints also supported the primary endpoint. An objective response rate of 51% (p<0.0001) consisting of 30 partial responses (PR) was achieved in the group of patients refractory to fludarabine and alemtuzumab. In the fludarabine refractory, Campath-inappropriate patient group, an objective response rate of 44% (p<0.0001) was achieved, including 1 complete response (CR) and 34 PRs. Ofatumumab was generally well tolerated. The most frequently reported adverse events (a greater than 15% frequency) were: pyrexia, diarrhoea, fatigue, cough, neutropenia, anaemia and pneumonia. There were no unexpected safety findings. None of the 14 patients tested had human anti-human antibodies (HAHA) at 12 months.
In Oct. 2010, Genmab initiated a head-to-head Phase III study of single agent ofatumumab compared to single agent rituximab (Rituxan) in patients with follicular non-Hodgkin’s lymphoma (NHL) that has relapsed at least 6 months after completion of treatment with a rituximab-containing regimen to which they responded. Approximately 516 patients in this open-label study were randomized to receive ofatumumab (1000 mg) or rituximab (375 mg/m2) by intravenous infusion for four weekly doses. Patients who have stable or responsive disease then receive single infusions of ofatumumab or rituximab every two months for four additional doses for a total of eight doses over nine months. The primary endpoint of the study is progression free survival.
Medical: Arzerra is administered as an intravenous infusion. The recommended dose and schedule is 12 doses administered as follows: 300 mg initial dose, followed 1 week later by 2,000 mg weekly for 7 doses, followed 4 weeks later by 2,000 mg every 4 weeks for 4 doses.
The most serious side effects of Arzerra are increased chance of infections, including progressive multifocal leukoencephalopathy (PML), a brain infection that is generally fatal. Patients at high risk for hepatitis B should be screened before being treated with Arzerra. Patients with evidence of inactive hepatitis should be monitored for re-activation of the infection during and after completing treatment.
Market: In June 2010, the U.K. National Institute for Health and Clinical Excellence (NICE) it would not approve Arzerra for use by the National Health Service, citing a lack of hard evidence on disease-free and overall survival rates.
In early 2010, Rituxan (rituximab) was approved by the FDA in combination with the chemotherapy regime fludarabine and cyclophosphamide for treatment of previously untreated as well as treated CD20-positive CLL. Thus, Arzerra has some competition.
Arzerra sales may reach $462 million/year by 2012, according to the average estimate of four analysts surveyed by Bloomberg. It will primarily compete with Cephalon Inc.’s Treanda and Roche Holding AG’s Rituxan. Sales are projected to reach $2 billion/year, if it is more broadly approved for CLL.
In Oct. 2010, the National Institute for Health and Clinical Excellence (NICE), U.K., published negative guidance for National Health Service use of Arzerra for chronic lymphocytic leukaemia in patients who have failed to respond to therapy with fludarabine and Campath (alemtuzumab). T he incremental cost of Arzerra was calculated to be between more than £60,500 and £81,500 per QALY gained, and NICE's appraisal committee felt that “the benefit it offers over and above current NHS treatments does not justify its cost”.
Trials: In Nov. 2009, GenMab initiated a Phase III study of Arzerra plus chemotherapy versus rituximab plus chemotherapy to treat patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). This is the first head to head study of ofatumumab against another CD20 antibody. The study included 380 patients who are refractory to or have relapsed following first line treatment with rituximab in combination with a chemotherapy regimen containing anthracycline and are eligible for autologous stem cell transplant (ASCT). Patients in the study were randomized to receive three cycles of either ofatumumab or rituximab in addition to chemotherapy. After the third treatment cycle patients who obtain a complete or partial response receive high dose chemotherapy followed by ASCT. The primary endpoint of the study is progression free survival.
Companies involvement:
Full monograph
116.5 CD20 Mab, human, rDNA
Nomenclature:
CD20 Mab, human, rDNA [BIO]
Arzerra [TR]
ofatumumab [FDA]
ofatumumab [INN]
immunoglobulin G1, anti-(human CD20 (antigen))(human monoclonal HuMax-CD20 heavy chain), disulfide with human monoclonal HuMax-CD20 kappa-chain, dimer [CAS]
679818-59-8 [CAS RN]
CD20 monoclonal antibody, human, recombinant [SY]
NDC 0173-0808-02 and NDC 0173-0808-05 [NDC]
molecular weight (kDa) = 149
FDA Class: Biologic BLA
Year of approval (FDA) = 2009
Date of 1st FDA approval = 20091026
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2018, if Cabilly III applies; Caution: various patents may be pending |
U.S. Patent Expiration Year: | 2025 |
U.S. Biosimilars Data Exclusivity Expiration: | 2021 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2016 |
U.S. Biosimilars Launchability Year: | 2021 |
U.S. Biobetters Launchability Year: | 2018 |
Biosimilars/biobetters-related EU Patents: | 2023, based on EP2330130, EP2316856 and EP1558648; Caution: various patents may be pending |
EU Patent Expiration Year: | 2023 |
EU Biosimilars Data Exclusivity Expiration: | 2020 |
EU Biosimilars Orphan Exclusivity Expiration: | 2020 |
EU Biosimilars Launchability Year: | 2023 |
EU Biobetters Launchability Year: | 2023 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
apheresis (hemapheresis)
biopharmaceutical products
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies, recombinant
monoclonal antibodies, recombinant, chimeric
rattlesnakes
recombinant DNA
Chinese hamster ovary (CHO) cells
hP67.6, monoclonal antibody
mammalian cell culture
rodent cells <!-- rodentcells -->
transgenic goats
U.S. Standard Rabies Vaccine
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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