Panitumumab - Vectibix; ABX-EGF; epidermal growth factor receptor monoclonal antibody, human, recombinant; E7.6.3; rHuMAb-EGFr; transgenic XenoMouse-derived human EGF receptor Mab
Status: marketed in U.S. and EU
Organizations involved:
Amgen, Inc. – Manuf.: R&D; Tech.; World mark.; Parent
Abgenix, Inc. – R&D; Tech.; Former
Immunex Corp. – R&D; Tech.
Cell Genesys, Inc. – R&D; Tech.; Former
Wyeth – Parent; Former
Genentech, Inc. –Tech.
Yeda Research And Development Co. –Tech.
Weizmann Institute of Science –Tech.
University of Iowa Research Foundation (UIRF) – Tech.; Patent dispute
Cross ref.: See the entry above for the currently approved epidermal growth factor receptor monoclonal antibody, cetuximab (Erbitux) from ImClone and Bristol-Myers Squibb, a recombinant chimeric mouse-human monoclonal antibody, unlike this product, which is a fully human recombinant monoclonal antibody.
Description: Vectibix (E7.6.3) is an aqueous formulation of panitumumab, a fully human IgG2k (IgG2 kappa) monoclonal antibody (Mab) with specificity for the human epidermal growth factor (EGF) receptor (EGFr) expressed by a transformed Chinese hamster ovary (CHO) line containing fully human antibody gene sequences obtained from the E7.6.3 hybridoma cell line resulting from fusion of a transgenic XenoMouse cell expressing high-binding EGFr Mab with a human myeloma cell line. Panitumumab, much like native human antibodies, is composed of two gamma heavy chains and two kappa light chains, and has a molecular weight of ~147 kDa and a calculated molecular formula of C6398H9878N1694O2016S48. Panitumumab is expressed as a glycoprotein with a single consensus N-linked glycosylation site located on the heavy chain. The predominant glycan structures found correspond to complex bi-antennary structures terminating with or without galactose residues. Fucosylated forms have also been observed. No O-linked glycosylation was detected.
Vectibix is packaged in 5 mL, 10 mL and 20 mL vials for intravenous infusion at a concentration of 20 mg/mL. The 5 mL vials contain 100 mg of panitumumab, 29 mg sodium chloride, 34 mg sodium acetate, and Water for Injection, USP; at a pH 5.6 to 6.0. The product is formulated with sodium acetate trihydrate as buffering agent, sodium chloride as tonicity modifier, acetic acid for pH adjustment and water for injection as solvent. The 10 mL and 20 mL vials, respectively, contain double and quadruple the amounts of each ingredient. Vials are stored at 2-8°C (36-46°F; refrigerated). Vectibix does not contain any antimicrobial preservatives (with vials being for one-time use only). The European Union shelf life is 2 years.
Panitumumab was generated using XenoMouse transgenic mice with the mouse antibody genes deleted and insertion of human antibody genes (>80% of immunoglobulin genes), resulting in fully human monoclonal antibodies with no murine (mouse)-derived sequences. These mice produce significant levels of fully human antibodies with a diverse adult-like repertoire and, upon immunization with antigens, generate antigen-specific fully human monoclonal antibodies. Yeast artificial chromosome (YAC) vectors were used to transform the antibody gene-deleted mice with human antibody genes.
Nomenclature: EGF receptor Mab, human, rDNA/Amgen [BIO]; Vectibix [TR]; panitumumab [USAN INN BAN JAN]; immunoglobulin, anti-(human epidermal growth factor receptor) (human monoclonal ABX-EGF heavy chain), disulfide with human monoclonal ABX-EGF light chain, dimer [CAS]; 339177-26-3 [CAS RN]; ABX-EGF [SY]; HuMAb-EGFr [SY]; E7.6.3 [SY]; epidermal growth factor receptor monoclonal antibody, human [SY]; NDC 55513-954-01; NDC 55513-955-01; NDC 55513-956-01 [NDC]
Biological.: See the cetuximab (Erbitux) entry for further information about epidermal growth factor (EGF) and EGF receptor (EGFr).
Panitumumab exhibits high affinity (KD = 5 x 10-11 M: IC50 = 3 nM) to the EGF receptor, and completely blocks the binding of both EGF and transforming growth factor alpha (TGF-alpha) to various EGFr–expressing human carcinoma cell lines. In comparison, the binding affinity of EGF reported in the literature is 3 x 10-9 M. Panitumumab also inhibits EGF-dependent tumor cell activation, including EGFr tyrosine phosphorylation, increases in extracellular acidification, and cell proliferation. Panitumumab is also active against tumor cells expressing lower levels of EGFr. Since this IgG2 monoclonal antibody lacks effector functions, complement-mediated cytotoxicity and antibody-dependent cell mediated cytotoxicity are probably not involved in its antitumor activity. Panitumumab’s mechanism of action likely involves induction of apoptosis (programed cell death) by blocking EGFr signaling pathways, inhibition of angiogenesis, and/or inhibition of tumor cell differentiation. With EGFr overexpressing tumors likely relying on EGFr signalling for proliferation, blocking EGFr blocks this pathway and results in antitumor activity. Tumors expressing over 17,000 EGFr molecules/cell have shown significant inhibition when treated with ABX-EGF. Normal cells have lower levels of EGFr expression, e.g., keratinocytes express about 9,000 EGFr/cell.
Inhibition of binding of EGF has been shown in A431 cells, a human epidermal carcinoma cell line that expresses EGFr. Intracellular acidification, phosphorylation and internalisation of the EGFr, that occur upon binding of EGF to EGFR, are blocked in a dose-dependent manner by panitumumab in A431 cells. Panitumumab has also been shown to inhibit cell growth in vitro and in vivo (xenotransplants in mice) in the same cell line. The ability of panitumumab to inhibit growth of a range of tumour types when these were transplanted into athymic mice was shown. Comparisons of cell surface levels of EGFr versus Her2 and response to panitumumab treatment indicate a correlation between a higher EGFR:Her2 ratio and responsiveness to panitumumab. Tumour types that express 17,000 EGFR per cell or more may respond to panitumumab.
Unlike chimeric and humanized antibodies, XenoMouse-derived antibodies, e.g., panitumumab, contain 100% human protein sequences. XenoMouse-derived antibodies are not expected to cause human anti-mouse antibody (HAMA) responses, i.e., immune rejection-like reactions against murine portions of the molecule, offering a better safety profile.
XenoMouse transgenic technology developed by Abgenix (now merged into Amgen) was used to develop Panitumumab. To reconstitute a robust human humoral immune system in mice, mouse endogenous Ig gene loci were functionally inactivated by gene targeted deletions of crucial cis-acting JH and Ck sequences of heavy and light (k) chains involved in the mouse Ig gene rearrangement and expression, respectively. Mouse embryonic stem (ES) cells containing the targeted heavy or k chain allele were used to generate mice homozygous for each of the JH or Ck deletions. Crossbreeding of these mice yielded double-inactivated (DI) mice, homozygous for both mutations. In order to preserve variable gene diversity and to maintain the regulatory elements that control antibody recombination and expression, DNA fragments spanning the majority of the human heavy and light chain loci were cloned and recombined into yeast artificial chromosomes (YACs) in germline configuration. Large DNA molecules cloned into YACs are stable and genetically manipulable within yeast, and yeast-cell fusion enables transfer of large DNA segments into mammalian cells. Heavy chain YACs encompassed 66 different consecutive VH genes (representing about 80% of the human VH gene repertoire), all 30 D segments, and all six JH genes. The Cd region was retrofitted with the human g1, g2 or g4 constant region.
The heavy and light chain YACs were introduced into mice via fusion of YAC-containing Saccharomyces cerevisiea (yeast) spheroplasts with mouse ES cells. Crossbreeding of resulting mouse strains yielded transgenic mice producing human antibodies in the presence of mouse antibodies. Finally, the XenoMouse strains homozygous for the inactivated mouse heavy and k-chain genes and bearing one allele each of the human heavy and the k chain were created by breeding the human antibody-producing transgenic mice with the DI mouse strain.
Analysis of XenoMouse lymphoid organs and serum reveals that B cell development and the serum human antibody responses are restored. More importantly, diverse human antibody responses to multiple antigens have been demonstrated in XenoMouse strains. Upon immunization with either soluble antigens, such as cell-bound EGFr, high affinity fully human monoclonal antibodies can be generated using standard hybridoma technology, i.e., murine (in this case transgenic) B-cells expressing antibody to the desired target antigen (EGFr) are fused with a human myeloma cell line, with the resulting hybridomas capable of being cultured and expressing target antigen-specific (EGRr-specific) monoclonal antibodies (for further selection of the optimal Mab).
A panel of human IgG2 EGFr-specific monoclonal antibodies was generated by immunizing the XenoMouse IgG2 strain with cells of the human cervical epidermal carcinoma cell line A431, which expresses more than 106 EGFr molecules/cell. A total of 70 EGFr-specific hybridomas were established from five cell fusions, with at least 15 expressing EGFr-neutralizing antibodies. ABX-EGF (clone E7.6.3; expressing panitumumab) was selected for its EGFr with binding affinity of 5 x10-11 M, blocking of the binding of both EGF and TGF-alpha to EGRr, and inhibition of EGF-activated EGFr tyrosine phosphorylation and tumor cell activation. Panitumumab does not activate EGFr tyrosine kinase. Upon binding to EGFr, panitumumab causes EGFr internalization in tumor cells. The E7.6.3 panitumumab-producing hybridoma has a relatively high productivity of 12 pg/cell/day in serum-free medium.
Abgenix’s XenoMouse is a relatively quick and efficient process. The process from immunization to generation and selection of a fully human antibody product candidate takes 18-24 months. Having “humanized” the XenoMouse itself, it is not necessary to “humanize” each individual antibody that the mouse generates. Because no further antibody engineering is necessary after the antibodies are selected, full functionality of the antibodies is easily attained. Multiple strains of XenoMouse animals have been developed, each of which produces a different class of human antibody, e.g., IgG1, IgG2 and IgG4, to perform different therapeutic functions. Hybridoma cells generated from XenoMouse animals are stable producers of monoclonal antibody. The stability of the hybridomas eliminates a need to perform tedious and labor-intensive “rescue” of antibody genes after fusion.
Panitumumab has been shown to inhibit tumor cell proliferation in mouse models and cause eradication of EGF-dependent human tumors in mice; and eradicate established tumors in mice, even when administered after significant tumor growth has occurred.
Panitumumab, as an IgG2 antibody, lacks the “effector” function that IgG1 antibodies have, including Erbitux and all other currently marketed recombinant monoclonal antibodies. Effector function enables IgG1 antibodies to mark cancer cells for destruction, e.g., by antibody-dependent cell-mediated cytotoxicity (ADCC) immune responses in which antibodies, by coating target cells, make them vulnerable to attack by T-cells.
The methods used for the evaluation of the biological activity of panitumumab are based on its ability to bind directly to the extracellular domain of EGFr and inhibit ligand binding and subsequent cellular responses..
KRAS plays an important role in cell growth regulation and oncogenesis. Anti-EGFr therapies work by blocking the activation of EGFr, thereby inhibiting downstream events that lead to malignant signaling. However, in patients with tumors harboring a mutated or activated KRAS, the KRAS protein is always turned “on” regardless of whether EGFr has been activated or therapeutically inhibited. Thus, in patients with mutated KRAS, signaling continues despite anti-EGFr therapy, and EGRr inhibitors are generally ineffective. Mutant KRAS is detected in approximately 40% of colorectal tumors..
Companies.: Panitumumab was co-developed by Cell Genesys (which became Abgenix, which was acquired by Amgen for $2.2 billion in Dec. 2006) which provided the E7.6.3 XenoMouse-based hybridoma; and by Immunex Corp. (formerly a subsidiary of Wyeth (American Home Products Corp. acquired by Amgen, Inc. in Dec. 2001). Abgenix and Immunex (then a wholly owned subsidiary of Amgen) worked together to develop and commercialize panitumumab for various oncology indications:. Note, both original developers of panitumumab, Immunex and Cell Genesys/Abgenix, are now merged into Amgen.
In July 2000, Abgenix and Immunex concluded a joint development and commercialization agreement for panitumumab. Immunex paid an initial licensing fee to Abgenix, and another upon initiation of Phase II trials. Product development costs, tasks and profits would be shared equally. In Nov. 2000, this agreement was extended to development of other fully human antibodies for cancer treatment.
In Oct. 2003, Immunex/Amgen and Abgenix clarified their involvement in the codevelopment of panitumumab. Development costs are shared equally by the two companies, along with any future profits from product sales worldwide. Immunex/Amgen leads clinical development and commercialization activities, while Abgenix is responsible for clinical and commercial manufacturing, with some assistance from Immunex. Abgenix also retains copromotion rights. Immunex made available to Abgenix $60 million in advances that may be used by Abgenix to fund its share of development and commercialization costs for panitumumab after Abgenix has contributed $20 million toward development costs in 2004. The amount of any advances drawn by Abgenix, plus interest, may be repaid out of profits resulting from future product sales. However, Abgenix is not obligated to repay any portion of the loan if panitumumab does not reach commercialization. Abgenix has been drawing against this $60 million line of credit, e.g., drawing $14.2 million in Feb. 2005.
In Dec. 2006, Amgen formally completed its acquisition of Abgenix for ~$2.2 billion in cash plus the assumption of debt.
Abgenix, now Amgen, manufactures panitumumab at its 100,000-square-foot state-of-the-art manufacturing facility in Fremont, CA, including four 2,000 L and two 12,000 L bioreactors, with two parallel cell culture and recovery suites, and complete cell banking, purification and fill/finish capabilities. The facility can produce up to hundreds of kilograms per year at scales up to 12,000 liters.
Manufacture: At the initiation of its clinical program, panitumumab was produced by a human hybridoma cell line. Later, a decision was made to shift to CHO cells. The change took place in two steps. The first was from hybridoma to small scale CHO fermentation (2,000 L), and subsequently to a commercial scale production (12,000 L). Thus, the clinical program involved patients receiving panitumumab of all three origins, with steps in between seeking to show equivalence between them. EMEA/EU reports that several other manufacturing changes were introduced during development, including various changes to the purification process and a change of manufacturing site. The comparability exercises and the overall data provided to support the different changes were considered acceptable.
One vial of WCB is thawed and the CHO cells are expanded in a selective serum-free growth medium to generate the cell inoculum. A series of bioreactors with increasing volumes is then used to expand the cell mass to generate sufficient cells for the inoculation of the production bioreactor. Following the production phase in serum-free media, the bioreactor contents are harvested and clarified to generate a cell-free intermediate designated as harvested cell culture fluid. Panitumumab is purified using a series of chromatography, concentration and diafiltration and viral inactivation and filtration steps.
Fully human antibody is produced using a E7.6.3-derived antibody gene-containing transformed Chinese hamster ovary (CHO) cell line cultured in ABX-CHO2-P media. As described in a poster discussing adoption of Q membrane chromatography for purification of panitumumab, purification involves obtaining Harvested Cell Culture Fluid (HCCF); Protein A affinity chromatography (involving Mab binding to media-bound Protein A, and subsequent release); low pH (acid) viral inactivation; Q membrane chromatography or membrane anion exchange chromatography; viral filtration; chromatographic separation; and tangential flow filtration. Anion exchange column chromatography had originally been used in flowthrough mode in Abgenix’s human antibody purification process to remove process-related impurities and to provide viral removal capability. The Q membrane step was implemented in the purification process, resulting in successful production in the pilot plant for toxicology studies. The Q membrane process was shown to be robust. Pilot plant results showed consistent removal of host cell protein (HCP) regardless of the varying HCP level in the upstream, and also endotoxin removal. One advantage of the Q membrane ion exchangers is convective mass transport rather than pore diffusion in anion exchange chromatographic resin. Q membrane ion exchange ligands are located along the through-pores where they are more exposed and easily bound than in ion exchange resins, where the long torturous path of small resin pores contain the binding ligands. Thus, dynamic binding capacity of the membranes is flow rate independent. These disposable membrane devices provide other potential advantages such as reduced cost, increased throughput, and their use can eliminate traditional column packing and reuse/cleaning validation studies.
Panitumumab is purified using a series of chromatography, concentration and diafiltration and viral inactivation and filtration steps. Potential product-related impurities include protein aggregates, fragments and other product variants. Potential process-related impurities include cell substrate derived impurities (host cell proteins, DNA), cell culture-derived and downstream-derived impurities.
FDA class: Biologic BLA
Approvals: Date = 20060927; original BLA
Indications: [Full text of the “ "Indications and USAGE” section of product insert/labeling; 3/6/2007]:
Vectibix is indicated for the treatment of EGFR-expressing, metastatic colorectal carcinoma with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens.
The effectiveness of Vectibix™ for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progression-free survival (see CLINICAL STUDIES). Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix.
Status: A BLA submission for treatment of colorectal cancer in patients having failed prior standard chemotherapy with accelerated approval and fast track status (allowing submission of sections of the BLA as completed) was inititated by Abgenix and Amgen in Dec. 2005, and was accepted for filing on June 12, 2006. Approval, essentially for third-line monotherapy use, was granted on Sept. 27, 2006 (approval time = ~9.5 months after filing; ~6 months after acceptance). Vectibix was launched in the U.S. in Oct. 2006.
FDA approval of Vectibix was based on a progression-free survival endpoint. Vectibix is the first EGFr antibody shown to significantly improve progression-free survival in patients with metastatic colorectal cancer. Upon approval, no data were available showing an improvement in disease-related symptoms or increased survival with Vectibix. As part of the approval, Amgen committed to conduct a postmarketing (Phase IV) trial to show whether Vectibix improves survival in patients with fewer prior chemotherapies.
Similtaneously with FDA approval of Vectibix, Dako A/S received approval from FDA for its EGFR pharmDx(TM) kit. This diagnostic is used to assess patient eligibility for treatment with Vectibix.
In April 2006, Amgen filed a MAA for European Union (EU) approval, and for approval in Canada, Australia and Switzerland in May 2006. This immunodiagnostic kit remains the only FDA-approved test available for detection of EGFR protein expression. Colorectal cancer patients enrolled in clinical studies with Vectibix(TM) were tested for EGFR expression with this kit.
In May 2007, Amgen received notice from the European Medicines Agency (EMEA), European Union (EU), that the European Committee for Medicinal Products for Human Use (CHMP) had adopted a negative opinion for Amgen’s MAA for Vectibix for patients with metastatic colorectal cancer who have failed chemotherapy (i.e., Vectibix would not be approved in the EU). Amgen promptly filed an appeal, i.e, requested a re-examination of the CHMP opinion through the formal appeal procedure. Amgen admitted that, “Currently no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Vectibix,” which could be part of the problem with its MAA.
On Sept, 25, 2007, EMEA/EU reversed its prior ruling and ruled in favor of allowing Vectibix on the market for treatment of metastatic carcinoma of the colon or rectum after failure of oxaliplatin- and/or irinotecan-containing chemotherapy regimens in patients whose tumors contain a EGFr gene, which appears to affect Vectibix's effectiveness, but lack a KRAS mutation. Patients can be screened to see if they have this gene, so it will be easy to determine which patients will benefit from the drug - another case of personalized medicine. The agency's approval was conditional on pending new data about the safety and efficacy of Vectibix.
On Dec. 5, 2007, the European Commission granted conditional approval to Vectibix for treatment of EGFr+/KRAS- patients having failed standard chemotherapy regimens and who have colon tumor(s) that expresses epidermal growth factor receptor (EGFr), but lack a mutation of a gene known as KRAS, i.e., have a normal or wild-type KRAS gene.
In July 2009, after reviewing evidence on the effect of K-RAS mutations on patients using Vectibix and Bristol- Myers Squibb Co.’s Erbitux, FDA changed the prescribing information for the two products to discourage use by patients with K-RAS (KRAS) variants from using them.
As of Aug. 2010, Vectibix had been launched in over 20 countries, and applications in the rest of the world were pending.
In March 2011, Amgen reported that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) had adopted a negative opinion regarding extending marketing authorization in Europe to include combination with chemotherapy for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC). Amgen formally filed an appeal against the EMA recommendation against extending the marketing authorization for Vectibix to include combination with chemotherapy for the treatment of patients with wild-type KRAS metastatic colorectal cancer (mCRC). Amgen asserts that clinical trials have clearly shown that adding Vectibix to FOLFOX or FOLFIRI chemotherapy improved progression-free survival when compared with chemotherapy alone in patients with wild-type KRAS mCRC.
Tech. transfer: Panitumumab-related patents assigned to Abgenix (now merged into Amgen) include 6,235,883 (WO9850433), “Human Monoclonal Antibodies To Epidermal Growth Factor Receptor.” U.S. 6,235,883 is the only patent explicitly cited in the U.S. product insert. Pending U.S. application 2002173629 has the same title. Nucleotide sequences encoding and amino acid sequences comprising heavy and light chain immunoglobulin molecules, particularly sequences corresponding to contiguous heavy and light chain sequences from CDR1 through CDR3, are provided. Hybridomas expressing immunoglobulins and monoclonal antibodies are also provided.
Pending U.S. applications assigned to Abgenix concerning XenoMouse technology include 20040093622 and 20040010810, "Generation of xenogeneic antibodies."
Amgen and Genentech cross-licensed multiple patents relating to the manufacture and use of antibodies and related technologies in Jan. 2006. This included Amgen receiving license to the Cabilly (Cabilly-Boss; e.g., U.S. 6,331,415) recombinant monoclonal antibody patents held by Genentech. See the Monoclonal Antibodies entry for discussion of Cabilly-Boss and its current status.
In late 2006, Yeda Research And Development Co. (Rehovot, Israel), acting as licensing/legal representative for the Weizmann Institute of Science (Rehovot, Israel), won an infringement suit in U.S. District Court, New York, and became the assignee/owner of U.S. 6,217,866, assigned to Sanofi Aventis and ImClone Corp. This is the main patent concerning use of cetuximab (Erbitux), another EGFr monoclonal antibody, in combination with chemotherapy agents for treatment of cancer. See the Tech. Transfer section of the Erbitux entry for further information about this patent. After Yeda/Weizmann was ruled the rightful owner of the patent, Amgen took a concluded a license agreement with Yeda as a defensive measure.
In Aug. 2009, the University of Iowa Research Foundation (UIRF) announced a settlement in its dispute with Amgen Inc. over alleged patent infringement of two UIRF patents covering a cytomegalovirus (CMV) promoter used in the design and manufacture of panitumumab. The two patents, 5,168,062 and 5,385,839, are collectively known as the Stinski patents after inventor Dr. Mark Stinski, an IU Carver College of Medicine professor of microbiology. UIRF originally filed suit in Sept. 2008 in the U.S. District Court for the Southern District of Iowa. he terms of the settlement have not made public. But at least one news source, the Iowa Press-Citizen, has reported that the settlement was for an aggregate amount of $19 million. UIRF cannot comment on the settlement due to a confidentiality agreement in place between the parties.
Trials: The IND for Phase I trials was submitted in July 1999. Phase II trials for kidney/renal cancer and non-small cell lung cancer were underway by mid-2001. A Phase II trial for colorectal chance began in Dec. 2001. In Jan. 2002, a Phase II trial for prostate cancer and a second Phase II trial for colorectal cancer were initiated.
Panitumumab is being tested in clinical trials as monotherapy and in combination with standard chemotherapy in several types of cancer. This currently includes studies in renal, colorectal, and non-small cell lung cancers. In March 2005, patient enrollment was completed for the pivotal Phase III trial designed to support approval for monotherapy for metastatic colorectal cancer patients. This randomized, controlled trial has enrolled more than 460 patients in Europe, Australia and Canada. Best supportive care plus panitumumab monotherapy administered every other week is being compared to best supportive care alone in patients with advanced metastatic colorectal cancer having failed previous therapies (third- or fourth-line monotherapy). Panitumumab is also currently in Phase I for 2nd or 3rd line rectal cancer; and Phase II for 1st line lung cancer.
Panitumumab is also being tested both as a monotherapy and in combination with other agents for the treatment of various types of tumors. In Phase II studies to date, panitumumab has shown anti-tumor activity as a single agent in advanced, refractory colorectal cancer, with a favorable pharmacokinetic and tolerability profile.
In early 2004, interim data from part one of an ongoing Phase II study were presented suggesting that panitumumab has activity for first-line chemotherapy in patients with metastatic colorectal cancer. Part 2 of this study (n=24) is ongoing to evaluate safety, pharmacokinetics and efficacy of panitumumab administered with the FOLFIRI regimen (FOLinic acid, Fluorouracil, and IRInotecan), currently the most widely used of the various irinotecan-based regimens.
Result of trials to date indicate several major differences between panitumumab and drugs targeting the EGF receptor and pathway. Panitumumab has not shown dose limiting toxicity, while small-molecule drugs targeting the EGFr are dose-limited by the occurrence of severe diarrhea. The current dose of panitumumab has been set at the level that results in 100% of patients achieving an acneiform skin rash that indicates full blockade of the EGFr on the skin. Unlike drugs, panitumumab has single-agent biological activity in patients with solid tumors. In studies of over 500 patients, infusion related reactions have been infrequent.
In April 2005, the PACCE (Panitumumab Advanced Colorectal Cancer Evaluation) Phase III trial was initiated in about 1,000 patients to evaluate adding panitumumab to bevacizumab (Avastin; see related entry) and either oxaliplatin- (Eloxatin) or irinotecan-based (Camptosar) chemotherapy for the first-line treatment of metastatic colorectal cancer. PACCE is a randomized, multi-center, open-label study, with endpoints of progression-free survival, overall survival and response rate.
In Nov. 2005, results were reported from the pivotal Phase III trial in 463 metastatic colorectal cancer (mCRC) patients who received Vectibix every two weeks. Patients were randomized to receive 6 mg/kg Vectibix plus best supportive care (BSC) (n=231) every two weeks or BSC alone (n=232) until disease progression or unacceptable toxicity. The primary endpoint of this study was an improvement in progression-free survival. Co-secondary study endpoints were best objective response by blinded central review and overall survival time. The primary endpoint of improving progression-free survival in patients was met with high statistical signnificance, with a 46% decrease in tumor progression rate versus those who received best supportive care alone (p <0.000000001). A secondary endpoint of objective response rate, as assessed by central radiology review, was also met. The mean time to disease progression or death in patients receiving Vectibix was 96 days vs. 60 days in patients receiving the best standard supportive care. In addition, 8% of the patients on Vectibix experienced a tumor shrinkage that in some cases exceeded 50% of the pre-treatment size of the tumor. In the primary analysis of overall survival, there was no significant difference between the groups. The median follow-up time was 72 weeks for all patients. A blinded central review showed that 10% of patients in the Vectibix group had an objective response, while no patients in the BSC group demonstrated an objective response. Median time to response was 7.9 weeks and median duration of response was 17 weeks.
In March 2007, Amgen halted the PACCE Phase III trial of Vectibix (in combination with Avastin) for first-line treatment of metastatic colorectal cancer due to safety and efficacy concerns. Grades 3/4 infections and diarrhea were the issues in the trial. This toxicity could have resulted in a reduced Vectibix dose in the trial, which could explain why the non-Vectibix arm showed better efficacy. Analysis revealed a statistically significant difference in progression-free survival in favor of the study’s control arm; and an unplanned analysis of overall survival demonstrated a statistically significant difference favoring the control arm. These results were expected to increase sales of competing Erbitux. Amgen stated its clinical program to expand Vectibix’s use as a first- and second-line treatment for metastatic colorectal cancer was not affected by the discontinuation of the Avastin-Vectibix combination trial (although it was widely interpreted as significantly affecting Vectibix’s development and use for colorectal cancer). Two ongoing Phase III registration studies assessing Vectibix in combination with chemotherapy regimens in the first- and second-line treatment settings were affected by the trial cancellation. Amgen anticipates publication of results for these Phase III studies in 2009 or 2010.
A study published in the May 2007 issue of The Lancet Oncology reported 97% of patients with cancer treated with EGFr monoclonal antibodies (cetuximab or panitumumab) have some degree of magnesium loss (hypomagnesaemia) and “magnesium wasting will occur in all patients.”
In the May 2007 of the Journal of Clinical Oncology, final results were published from the 463-patient pivotal Phase III trial (discussed above) which showed that Vectibix prolonged progression-free survival (PFS) compared to best supportive care (BSC) in metastatic colorectal cancer patients who had failed fluoropyrimidine, irinotecan, and oxaliplatin containing chemotherapy regimens.
The biomarker data supporting the conditional EU approval were generated from a prospectively defined analysis of the Phase 3, randomized, controlled clinical trial (408) that investigated the treatment effect of KRAS status (non-mutated versus mutated) in Vectibix patients with metastatic colorectal cancer (mCRC). Analysis showed that the effect of Vectibix on progression-free survival (PFS) was confined exclusively to the ~60% of patients whose tumors harbored a normal, non-mutated (wild-type) KRAS gene. Vectibix had no clinical benefit in patients who had tumors with mutations in KRAS regardless of the endpoint studied. Previously reported pivotal results from 408 had shown that Vectibix monotherapy significantly improves PFS and response rates in heavily pre-treated patients with mCRC after failure of standard chemotherapy versus best supportive care.
In Aug. 2009, results were reported from Amgen's second Phase IIItrial, with this evaluating Vectibix as a second-line treatment for patients with advanced colorectal cancer. Vectibix met only one of its primary endpoints. When combined with the FOLFIRI chemotherapy regimen, Vectibix delayed cancer progression in patients withtumors that carrynormal or wild-type KRas genes. However, Vectibix failedto produce a statistically significantincreasein overall survival. The global trial involved 1,186 patients, more than 90% of whom were tested for KRas gene mutations. Patients with a mutated KRas gene experience more aggressive cancers and tend to have lower rates of survival. The combined treatment had no impact on the progression of cancer or overall survival of patients with a mutated KRas gene. These results added to the growing body of evidence confirming the utility of KRAS as a predictive biomarker.
In Aug. 2010, it was reported that Vectibix had not meet the primary endpoint in the SPECTRUM Phase III trial evaluating its use as a first-line treatment for recurrent and/or metastatic squamous cell head and neck cancer. The data showed that the addition of Vectibix to platinum-based chemotherapy did not result in a statistically significant improvement in overall survival (OS) compared to chemotherapy alone. The median OS for the Vectibix group was 11.1 months versus 9.0 months for those receiving only chemotherapy. Secondary endpoints of progression-free survival (PFS) and objective response rate (ORR) were numerically improved but were not tested for statistical significance. Median PFS was 5.8 months versus 4.6 months and ORR was 36% versus 25% for the Vectibix and chemotherapy groups, respectively. SPECTRUM had enrolled 658 patients randomized to receive a standard platinum-based chemotherapy (cisplatin and 5-FU) with or without Vectibix (9 mg/kg) every three weeks. The most frequently reported adverse events in the Vectibix plus chemotherapy arm included nausea, rash, neutropenia, and vomiting (which had been expected).
Medical: The recommended dose is 6 mg/kg administered over 60 minutes as an intravenous infusion every 14 days. A patient weighing 50 kg (~110 lb.) would receive a dose of 300 mg. Doses higher than 1,000 mg should be administered over 90 minutes. Vectibix is diluted in 0.9% sodium chloride and administered via an infusion pump, using an 0.2 µm in-line filter to reduce sub-visible particles, through a peripheral line or indwelling catheter.
The most serious adverse events in the studies of Vectibix included pulmonary fibrosis, severe skin rash complicated by infections, infusion reactions, abdominal pain, nausea, vomiting and constipation. Around 90% of patients receiving Vectibix have side effects affecting the skin, although most of these are mild or moderate. The most common side effects with Vectibix (seen in more than 1 patient in 10) are rash, erythema (redness of the skin), skin exfoliation (skin flaking), pruritus (itching), dry skin, skin fissures (cracks in the skin), paronychia (nail bed infection), diarrhea, fatigue (tiredness), nausea (feeling sick), vomiting, dyspnoea (difficulty breathing) and cough.
Market:
Total 2012 sales as reported by Amgen were $91 million, including $30 million in the U.S.
Total 2011 sales were $525 million, $384 million in 201; 233 million in 2009, $153 million in 2008, and and estimated $168 million in 2007. Total 2006 worldwide sales of Vectibix were $36 million (with U.S. approval granted in late Sept.).
Total sales of Vectibix have been much less than most, including Amgen, had originally expected, presuming that Vectibix would find broad use including for earlier and not second-line treatment.
In March 2007, Friedman, Billings and Ramsey (FBR) analysts had estimated total worldwide sales for Vectibix will be $365 million in 2007, $617 million in 2008, $761 million in 2009, $856 million in 2010, $883 million in 2011, and $912 million in 2012.
The Average Wholesale Price (AWP) is not available (not reported in the 2007 edition of the Red Book).
Amgen has set prices for Vectibix ~20% below those of Erbitux, i.e., ~$8,000 a month (~$96,000/year). Such undercutting competitive pricing is rare for biopharmaceuticals. Amgen also capped out-of-pocket costs for Vectibix at a level equal to 5% of the patients’ adjusted gross income. Amgen stated that program is the first of its kind in the industry.
In Nov. 2011, the National Institute for Health and Clinical Excellence (NICE), U.K., rejected Vectibix as second-line treatment for advanced colon cancer (treatment of metastatic colorectal cancer that has progressed after first-line chemotherapy). NICE noted that there were already 6 colon cancer therapeutics available in the U.K. NICE had previously recommended irinotecan, oxaliplatin, capecitabine, tegafur with uracil and cetuximab for the treatment of various stages of colorectal cancer.
Amgen has noted, “ Panitumumab is the first epidermal growth factor receptor (EGFr) inhibitor to demonstrate a statistically significant improvement in progression-free survival for metastatic colorectal cancer patients who have failed standard chemotherapy. Panitumumab is also the first fully human monoclonal antibody in cancer clinical trials that targets the epidermal growth factor receptor. Amgen believes that potential peak worldwide sales for panitumumab could reach $2 billion or more, assuming success of panitumumab in several clinical trials evaluating multiple lines of therapy in colorectal cancer and head and neck cancer.”
Presuming a potential market of nearly 300,000 colorectal patients, $2 billion implies only a 16% market share (assuming pricing comparable to Erbitux at around $40,000 per year). The market is easily large enough for both Erbitux and panitumumab to be blockbusters.
Cross ref.: See the Competition and Market sections of the Erbitux entry (above) for further information about the current market for this EGRr monoclonal antibodies and competition between Vectibix and Erbitux. As a fully human, rather than murine-human chimeric monoclonal antibody, panitumumab has a number of theoretical safety advantages, but it remains to be seen whether these are relevant in comparison with Erbitux, particularly in the real world of pateint use. Depending on results from clinical trials and post-marketing studies and with its lower price and more convenient dosing schedule, Vectibix could capture significant the market currently held by Erbitux, in addition to future approval for new indications:. The real competition between the products will be after for first line colorectal cancer treatment (for which Vectibix has not yet received approval).
Companies involvement:
Full monograph
129 EGF receptor Mab, human, rDNA/Amgen
Nomenclature:
EGF receptor Mab, human, rDNA/Amgen [BIO]
Vectibix [TR]
panitumumab [USAN INN]
immunoglobulin, anti-(human epidermal growth factor receptor) (human monoclonal ABX-EGF heavy chain), disulfide with human monoclonal ABX-EGF light chain, dimer [CAS]
339177-26-3 [CAS RN]
ABX-EGF [SY]
E7.6.3 [SY]
epidermal growth factor receptor monoclonal antibody, human [SY]
HuMAb-EGFr [SY]
NDC 55513-954-01; NDC 55513-955-01; NDC 55513-956-01 [NDC]
molecular weight (kDa) = 147
FDA Class: BLA Biologic
Year of approval (FDA) = 2006
Date of 1st FDA approval = 20060927
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2017, based on 6,235,883.
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm, had reported 2010-2017 |
U.S. Patent Expiration Year: | 2017 |
U.S. Biosimilars Data Exclusivity Expiration: | 2018 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2013 |
U.S. Biosimilars Launchability Year: | 2018 |
U.S. Biobetters Launchability Year: | 2017 |
Biosimilars/biobetters-related EU Patents: | 2018, based on EP 0979246.
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm, had reported EU patent/SPC expiry as 2010-2016 |
EU Patent Expiration Year: | 2018 |
EU Biosimilars Data Exclusivity Expiration: | 2017 |
EU Biosimilars Orphan Exclusivity Expiration: | 2017 |
EU Biosimilars Launchability Year: | 2018 |
EU Biobetters Launchability Year: | 2018 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
apheresis (hemapheresis)
biopharmaceutical products
exempt from CBER lot release requirements
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies
monoclonal antibodies, recombinant
monoclonal antibodies, recombinant, chimeric
rattlesnakes
recombinant DNA
rodent source materials
tuberculosis prophylaxis
Absorbable Gelatin Sponge, USP
Chinese hamster ovary (CHO) cells
DG5.3, Chinese hamster ovary (CHO) cells
Dynabeads
ellagic acid
enzymes, fibrinolytic/thrombolytic
media, serum-based
Moraxella catarrhalis
mumps virus Jeryl Lynn strain
murine brains
murine feeder cells
Protein A affinity chromatography
Saccharomyces cerevisiae (yeast)
SPGA (sucrose, phosphate, glutamate, albumin)
transgenic goats
x-linked immunodeficiency
XV2181, Saccharomyces cerevisiae (yeast) strain
Namalva cells
PYinsl yeast cells
SNAP-2
sodium chloride
Tac subunit of IL-2 receptor
viral (nano)filtration
viral inactivation, acid (low pH)
yeast source materials
accelerated approval (based on surrogate endpoints) (FDAapproved)
apheresis (hemapheresis)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
North American coral snake
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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