Alemtuzumab – Campath; Lemtrada; Campath-1H; CD52 monoclonal antibody, recombinant humanized rat; ACZ885
Status - Campath was withdrawn from the U.S. market in Aug. 2012 in preparation for relaunch as Lemtrada for MS; Lemtrada sBLA was filed and rejected, requiring refiling; In July 2013, recommended by EMA for EU approval
Organizations involved:
Genzyme Corp. – Manuf.; R&D; Tech.; Parent; World mark.
Bayer HealthCare Pharmaceuticals – Former
Bayer Schering Pharma AG – Former; Parent
Hospira – Manuf. other
ILEX Partners LLP – Former
ILEX Oncology Inc. – R&D; Tech.; Parent; Former
BTG International – Tech.
Berlex Laboratories – Former
Schering AG – Parent; Former
LeukoSite, Inc. – Former
Millennium Pharmaceuticals, Inc. – Tech.; Former
Cambridge University – R&D; Tech.
Oxford University – Tech.
Medical Research Council (U.K.) – R&D; Tech.
Protein Design Laboratories, Inc. (PDL) – Tech.
Wellcome Foundation, Ltd. – R&D; Former
Lonza Biologics plc – Tech.
Alusuise-Lonza Group – Parent
University of Glasgow – Tech.
Cross ref.: See Monoclonal Antibodies (entry #300).
Description: Alemtuzumab or Campath is an aqueous formulation of a recombinant humanized IgG1 kappa monoclonal antibody (Campath-1H) with specificity for the CAMPATH-1 antigen (CDw52 antigen; CD52 antigen; YTH66.9 antigen) expressed by a transformed Chinese hamster ovary cell (CHO) cell line. The Campath-1H molecule has a human variable framework and constant regions, and complementarity-determining regions (CDRs; antigen-binding epitopes) conferring antigen specificity from a rodent (rat) monoclonal antibody (Campath-1G). Campath-1H has a molecular weight of 145.2 kDa (also reported as ~150 kDa), and a calculated molecular formula of C6452H9958N1722O2010S42. The Mab is used to eliminate lymphocytes, e.g., for treatment of chronic lymphocytic leukemia (CLL).
Campath was originally packaged in single-use glass ampoules containing 30 mg of Campath-1H in 3 mL of solution. Each vial also contained 24.0 mg sodium chloride, 3.5 mg dibasic sodium phosphate, 0.6 mg potassium dichloride, 0.6 mg monobasic potassium phosphate, 0.3 mg polysorbate 80 (Tween 80), and 0.036 mg disodium edetate (EDT In late 2004, a new formulation was launched and has replaced the prior formulation/packaging. Campath is now packaged in vials containing 30 mg in 1 mL of solution, i.e., at a concentration of 30 mg/mL, three times the concentration of the prior formulation. This change does not affect is use, e.g., two hour intravenous administration, safety or efficacy. The new vial is more convenient, because no filtering is required during preparation. Campath contains no preservatives, and is stored at 2-8˚C (refrigerated).
Biological.: The CAMPATH-1 (CDw52; CD52) antigen is a 21-28 kDa glycoprotein expressed on the surface of normal and malignant B and T lymphocytes, natural killer (NK) cells, monocytes, macrophages, and tissues of the male reproductive system. The antigen is strongly expressed on the surface of all human lymphocytes and most monocytes (see Hale et al., Blood, 1983, 62, 873-882). Antibodies against CAMPATH-1 bind to all lymphocytes and monocytes, but lyse only lymphocytes (T- and B-cells) in vivo. CAMPATH-1 is absent from other blood cells including hematopoietic stem cells. A number of monoclonal antibodies have been developed directed against CAMPATH-1, which is an unusually good target for complement-mediated attack. Antigens similar to CAMPATH-1 are expressed in other mammalian species. CAMPATH-1 antigen is available as a reagent from Serotec, Oxford, U.K., as YTH66.9 HL.
As described in the History section, a series of monoclonal antibodies to CAMPATH-1 antigen were originally produced, including rat monoclonal antibodies of IgM, IgG2a, and IgG2c isotypes. IgG2b isotypes directed to CAMPATH-1 antigen were isolated as class switch variants from the IgG2a-secreting hybridoma cell line YTH 34.5HL. The rat IgG2b monoclonal antibody YTH 34.5HL-G2b (CAMPATH-1G), but not the other isotypes, was effective in vitro and in vivo for inducing antibody dependent cell mediated cytotoxicity (ADCC) with human effector cells.
CAMPATH-1H is a genetically modified IgG1 antibody obtained by grafting the complementarity determining region (CDR; epitope recognition site) gene sequences from CAMPATH-1G into a human IgG framework region gene sequence. The resulting “humanized” antibody is highly effective in vitro, being equivalent to the rat monoclonal antibody at complement lysis and two to four times better at cell-mediated lysis of human lymphocytes. Expression of CAMPATH-1H was achieved initially in rat myeloma cells by placing DNA encoding the antibody chains under control of the immunoglobulin promoter/enhancer. CAMPATH-1H was subsequently expressed to high levels in Chinese hamster ovary (CHO) cells.
Nomenclature: CD52 Mab, rDNA [BIO]; Campath [TR current U.S.]; Lemtrada [TR U.S. for MS treatment]; Reopro alemtuzumab [FDA]; MabCampath [TR EU; reg. to Roche]; CAMPATH-1H [TR former; reg. to Millennium]; CAMPATH-1 [TR former; reg. to Wellcome Foundation]; LDP-03 [SY]; CD52 monoclonal antibody, humanized [SY]; NDC 50419-355-12 [NDC]
The term ‘CAMPATH’ is derived from Cambridge Pathology, a name coined in the early 1980s to refer to antibodies developed by Dr. H. Waldmann, Dept. of Pathology, Cambridge University, and collaborators. CAMPATH was the name for a family of antibody molecules initially raised in rats.
History: In the late 1970s, Dr. C. Meilstein, Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge University, and collaborators developed the Y3/Ag1.2.3 rat myeloma cell line for making rat hybridomas. In the early 1980s, Dr. A. Munro, Pathology Dept., Cambridge University, fused splenocytes from rats immunized with human T-cells with the Y3/Ag1.2.3 rat myeloma cell line, producing the YTH hybridoma expressing YTH66.9 rat IgM monoclonal antibody (Mab), which lysed human lymphocytes. A key aspect of this development was the use of human complement mediated lysis to screen for functional killing of lymphocytes. The rat IgM YTH66.9 Mab became known as CAMPATH-1 and later CAMPATH-1M to distinguish it from other similar antibodies. CAMPATH-1M showed promise for treatment of graft-vs.-host disease (transplant rejection) in clinical studies, but CAMPATH-1M was not effective for leukemia treatment. For desired antibody dependent cell-mediated cytotoxicity (ADCC; a type of cellular immunity), antibody isotype was found to be very important, with IgG2b antibodies having the most activity.
A variant of rat T-cell-specific IgG2b Mab (CAMPATH-1G) secreted by a variant of YTH34.5 hybridoma was developed. CAMPATH-1G showed great promise in clinical trials for lymphoma and leukemia (generally a 10 day course of treatment), unlike similarly-targeted earlier rat IgG2a and IgM Mabs. However, the CAMPATH-1G rat Mab was found to induce human neutralizing antibodies against itself when used for longer than 10 days, such as is required for immune suppression in organ transplant recipients. CAMPATH-1G was tested in clinical trials for immunosuppression (for graft-vs. host disease) in more than 100 patients undergoing organ and bone marrow transplantation, for management of organ rejection, and for treatment of hematologic malignancies with a high level of success. However, the rapid development of an human anti-rat immunoglobulin response, including the possibility of anaphylaxis, limited the clinical use of rat Mabs.
Researchers from the Pathology Dept., and the MRC Lab. of Molecular Biology, Cambridge University, collaborated to construct recombinant humanized versions of CAMPATH-1G incorporating rat variable (V) regions and human constant (framework) regions. Using recombinant methods, it was found that transferring rodent complementarity determining (CDR; epitope-binding) regions into the human constant framework regions resulted in monoclonal antibodies with much less human immunogenicity. This technology was termed antibody ‘V-region reshaping’ or recombinant antibody ‘humanisation’ (‘humanization’ is the Americanized term).
CAMPATH-1H (Campath) was developed as a humanized version of the rat monoclonal antibody CAMPATH-1G. See Reichemann, L., Clark, M.R., Waldmann, H, and Winter, G., “Reshaping Human Antibodies for Therapy,” Nature, vol. 332, p. 323-7, 1988. CAMPATH-1H was “the first fully humanised antibody (humanised immunoglobulin heavy and light chain) against a protein antigen, against a cell surface molecule and of therapeutic potential.”
Wellcome Foundation (Burroughs Wellcome plc) licensed CAMPATH-1H in 1994 for commercial development from Cambridge University and the Medical Research Council (MRC) through BTG International (acting as patent licensing agent for MRC and Cambridge Univ.). Development, including manufacture of supplies for use in clinical trials, was continued by Dr. Waldmann (and collaborators), who had left Cambridge Univ. to head the Therapeutic Antibody Centre, University of Oxford. CAMPATH-1H was subsequently adapted to recombinant expression in a transformed Chinese hamster ovary (CHO) cell line, which was adapted to large-scale culture in airlift fermenters.
Burroughs Wellcome conducted clinical trials and promising results were reported for rheumatoid arthritis, non-Hodgkin’s lymphoma (NHL), chronic lymphocytic leukemia (CML) and solid organ transplantation. Problems were observed with CAMPATH-1H use for treatment of rheumatoid arthritis (attributed to induction of antibodies to CAMPATH-1H with longer use of the Mab than for cancer indications:). The product was working too well, eliminating too many lymphocytes, potentially increasing the risk of opportunistic infections. Burroughs Wellcome, preferring a first-line product with a very large market (e.g., rheumatoid arthritis), abandoned development of CAMPATH-1H.
Leukosite subsequently licensed CAMPATH-1H from BTG plc in 1997, along with Wellcome’s clinical trial and manufacturing data. For further historical information (the story of CAMPATH-1H development some of those involved), see sources including “The CAMPATH Story & Therapeutic Links,” by Dr. M. Clark, 2000, http://www.path.cam.ac.uk/~mrc7/campath/; and “From Laboratory to Clinic: The Story of CAMPATH-1,” by G. Hale and H. Waldmann, in Methods in Molecular Medicine, vol. 40, p. 243-66, 2000. See also, “Campath’s Path To Stardom, Signals, Recombinant Capital, Sept. 1999.
Companies.: CAMPATH-1H is manufactured by Genzyme Corp. It was originally commerically developed and manufactured by ILEX Partners LLP (Cambridge, MA; formerly Millennium & ILEX Partners LLP or M&I), CBER/FDA est. 1289, a subsidiary of ILEX Oncology Inc., which was acquired and became a subsidiary of Genzyme in Dec. 2004. With Genzyme’s acquisition of ILEX, it divested all marketing rights to Campath to Schering AG (now Bayer Schering Pharma), including its Berlex Labs. U.S. subsidiary. CAMPATH-1H is manufactured by Genzyme at facilities in Allston, MA. CAMPATH-1H will also be manufactured at a new facility in Geel, Belgium, with first production runs in 2006.
Campath was originally marketed in the U.S. by Berlex Laboratories, and internationally by its parent company, Bayer Schering AG. CAMPATH-1H was then approved in the U.S. for B-cell chronic lymphocytic leukemia (CLL) and in late-stage development for multiple sclerosis (MS).
In March 2009, Genzyme assumed full worldwide marketing rights for Campath from Bayer (Bayer Schering). Bayer could earn up to $1.9 billion from this transaction. There were no up-front fees for this transaction, which is structured as an earn-out arrangement. Under the terms of the deal, Bayer will continue to pay for 33% of the product's development costs, but Genzyme gains control of the program. If CAMPATH-1H is approved for MS, Genzyme will market the drug and make contingent revenue-based payments to Bayer, which are capped at $1.25 billion or 10 years. Bayer also will receive an undisclosed amount of sales-based milestone payments beginning in 2021 unless Genzyme exercises a $900 million buyout option in 2020. Further milestone payments will be earned as a percentage of worldwide sales beginning in 2021 if Genzyme does not exercise a buyout option in 2020 for up to $900 million. Bayer will receive payments contingent on annual revenue, capped at $500 million or eight years. Bayer, which currently markets Betaseron (interferon beta-1b) for MS, will continue to fund a portion of development and retains the right to co-promote alemtuzumab for MS in the U.S. Genzyme will take the lead on the alemtuzumab MS program. Genzyme reported it expected the transaction to provide ~$185 million in 2009 and up to $700 million over the next three years. Genzyme assumed primary responsibility for the development and commercialization of CAMPATH-1H in MS.
Genzyme and Bayer already had been partners on CAMPATH-1H, with Genzyme receiving two-thirds of net profits in the U.S. and a significant ex-U.S. royalty. Both partners had inherited this arrangement through acquisitions - Genzyme's of ILEX Oncology Inc. in 2004 and Bayer's of Schering AG in 2006.
CAMPATH-1H was originally developed by researchers from the Pathology Department, Cambridge University, in collaboration with the Medical Research Council (MRC) Laboratory of Molecular Biology, Cambridge University. Subsequent development, included high-level CHO expression, was performed by the Therapeutic Antibody Centre (TAC), University of Oxford. BTG plc, acting as licensing agent for Cambridge University and MRC, licensed CAMPATH-1H to Wellcome plc (Burroughs Wellcome), which later returned its license (before merging with Glaxo). BTG later exclusively licensed CAMPATH-1H for cancer indications: to Millennium and ILEX Partners LLP. In March 2003, BTG extended its licensing agreement with ILEX is include exclusive worldwide rights for all non-oncology human therapeutic uses of CAMPATH-1H, e.g., autoimmune diseases involving CD52+ lymphocytes.
BTG licensed CAMPATH-1H to LeukoSite, Inc. in 1997. LeukoSite sublicensed CAMPATH-1H to a joint venture of Millennium Pharmaceuticals, Inc. and ILEX Products Inc. (a subsidiary of ILEX Oncology Inc.). The joint venture was named Millennium & ILEX Partners, L.P. (M&I Partners) after the 1999 acquisition of LeukoSite by Millennium Pharmaceuticals. In Jan. 2002, ILEX completed acquisition of Millennium’s interest in the joint venture (providing it with full ownership of M&I Partners, now ILEX Partners LLP).
In 1999, Schering AG licensed exclusive worldwide development and marketing rights for Campath for B-cell chronic lymphocytic leukemia, except for Japan and East Asia, where M&I Partners retained marketing rights. Schering’s U.S. subsidiary, Berlex Laboratories, markets Campath in the U.S. In Feb. 2003, Schering AG licensed rights in Japan, China and other Pacific Basin countries, effectively providing it with exclusive worldwide rights, and extended its agreement to include rights for new indications:. Berlex/Bayer Schering also markets fludarabine (Fludara), the leading first-line treatment for chronic lymphocytic leukemia.
In Dec. 2004, Campath was divested to Schering AG, including its Berlex Labs. U.S. subsidiary; and Ilex was acquired by Genzyme Corp. in a stock exchange valued at $1 billion. The acquisition of Ilex by Genzyme had originally been expected to be completed in mid-2004, but was delayed to due Federal Trade Commission (FTC) concerns about Genzyme marketing Campath with its solid organ transplant indications:, with Genzyme already marketing Thymoglobulin (#715) for much the same indications:. Genzyme had obtained Thymoglobulin through its acquisition of SangStat. These are two of only four products in the U.S. market for treatment of solid organ transplant rejection, with Thymoglobulin being the most-used product and with Campath having a similar mechanism of activity and a growing market. As part of a settlement with the FTC, Genzyme transferred to Schering AG (now Bayer Schering Pharma, including its Berlex Labs. U.S. subsidiary) all rights to Campath for solid organ transplantation. Genzyme does not receive royalties. Bayer AG acquired Schering AG, including Berlex Labs., in late 2006, becoming Bayer Schering AG. Bayer HealthCare Pharmaceuticals, Bayer Schering AG’s U.S. subsidiary, continues to market Campath in the U.S., and Bayer Schering AG markets it internationally.
In Sept. 2005, Genzyme reported expansion of its European manufacturing infrastructure, including a new plant in Geel, Belgium, for manufacture of humanized antibodies, starting with Campath. Genzyme began preparations to produce in-house batches of Campath in 2005, and anticipates that it will produce the first complete production runs within a year. This plant is located on the site of a facility acquired in 2001 from Pharming, N.V., which was working to develop a different therapeutic for Pompe disease.
In Spring 2006, Bayer acquired Schering AG, with the company renamed Bayer Schering Pharma AG.
In April 2008, Takeda Pharmaceutical Co. acquired Millennium Pharmaceuticals, Inc., and the company continues to operate as an independent subsidiary.
In July 2010, plagued by manufacturing problems, Genzyme extended its fill and finishing contract with Hospira, including for Campath.
In Aug. 2012, Genzyme/Sanofit withdrew Campath to prepare for its launch under a different dosage and as a multiple sclerosis treatment that will be branded as Lemtrada. The withdrawal, meant to prevent the off-label use of Campath as a multiple sclerosis drug, effective in the U.S. on September 4. Lemtrada, which Sanofi submitted for MAA approval in Europe and sBLA approval the United States in June, could be launched in 2013 if it wins approval. If approved, it will be given far less frequently and in lower doses than Campath.
Manufacture: Recombinant constructs and the preparation of CAMPATH-1H are described in Example 1 of U.S. patent 5,846,534, assigned to British Technology Group Ltd (now BTG Ltd.). The recombinant monoclonal antibodies were obtained from culture supernatant of CHO cells grown in a hollow fiber perfusion bioreactor (e.g., Acusyst-Jr, from Endotronics) and purified by affinity chromatography on Protein A-Sepharose media. Commercial manufacture uses large-scale air lift fermentors with a culture medium containing neomycin (not detectable in the final product). The monoclonal antibodies are dissolved in phosphate-buffered saline, sterile filtered, and tested for pyrogen and sterility.
FDA class: Biologic BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 20010507; first approval; BLA; orphan designation (expires 5/2008); Indication = the treatment of B-cell chronic lymphocytic leukemia (B-CLL) in patients who have been treated with alkylating agents and who have failed fludarabine therapy
Date = 20041018; BLA supplement; Indication = new single-dose vial
Date = 20070920; BLA supplement; Indication = single-agent use for treatment of B-cell chronic lymphocytic leukemia (B-CLL)
indications: [full text of "INDICATIONS AND USAGE” section of the product insert/labeling, 9/2/2008]:
Campath is indicated as a single agent for the treatment of B-cell chronic lymphocytic leukemia (B-CLL).
Status: The BLA was filed by M&I Partners on Dec. 13, 1999. The application was accepted in Feb. 2000 and granted priority review (six-month approval decision target). On Dec. 14, 2000, the Oncologic Drug Advisory Committee, FDA, voted 14-to-1 to recommend approval. Accelerated approval was granted on May 21, 2001 (approval time = ~1.52 years). Campath has orphan designation for its chronic lymphocytic leukemia (CLL) indication. M&I Partners started a post-approval clinical trial in CLL patients in 2001 with results to be submitted to FDA by Nov. 2006. In order to retain approval, this trial must (and did) show superior disease-free survival compared to chlorambucil treatment with comparable or acceptable toxicity. Campath is exempt from CBER/FDA lot release requirements.
A Marketing Authorization Application (MAA) for European Union approval was submitted in late March 2000; accepted for review on April 17, 2000; and was granted to Schering AG on July 17, 2002 for treatment for patients with B-cell chronic lymphocytic leukemia who have been treated with alkylating agents and have failed fludarabine therapy.
In mid-2005, Genzyme launched a new diagnostic test to detect low levels of disease in patients with B-cell chronic lymphocytic leukemia (CLL). The test can indicate whether patients are candidates for Campath.
In April 2007, Bayer HealthCare submitted a supplemental BLA to expand the approved indications: for Campath to include first-line treatment of B-cell chronic lymphocytic leukemia. Genzyme made a similar filing in Europe within weeks. The Sept. 2007 approval of the BLA supplement meant that Campath use for B-CLL is unrestricted, including use for first line and monotherapy.
On Jan. 3, 2008, the European Union approved MabCampath (alemtuzumab) for the treatment of patients with B-cell chronic lymphocytic leukemia (B-CLL) for whom fludarabine combination chemotherapy is not appropriate. MabCampath is the first and only monoclonal antibody approved in Europe for the treatment of B-CLL.
In late Aug. 2012, FDA issued as Refuse to File letter to Sanofi for its sBLA for Lemtrada. FDA requested the company to change the presentation of the data so the agency can "better navigate the application." FDA did not requested additional data or further studies, Genzyme antipated resubmitting the application as soon as possible.
Tech. transfer: The product insert/labeling cites U.S. patents: 5,545,403; 5,545,405; 5,654,403; and 5,846,534, with other patents pending.
BTG plc acted as patent licensing agent and licensed CAMPATH-related inventions from Cambridge University (and the Medical Research Council) to Wellcome plc, which later returned all rights (prior to merging with Glaxo to form Glaxo Wellcome). BTG subsequently (re)licensed the technology to LeukoSite, Inc. in 1997. LeukoSite sublicensed rights to a joint venture of Millennium Pharmaceuticals, Inc. and ILEX Products Inc., a subsidiary of ILEX Oncology Inc. The joint venture was named Millennium & ILEX Partners LLP (M&I Partners) after the 1999 acquisition of LeukoSite by Millennium Pharmaceuticals. ILEX subsequently acquired full rights. See the Companies and History sections for further information about corporate involvement. In March 2003, BTG granted ILEX the option to broaden its exclusive worldwide patent rights to Campath to include treatment of B-cell chronic lymphocytic leukemia (B-CLL) and the option to acquire rights for non-cancer therapeutic indications:. ILEX is in the process of completing its merger into Genzyme Corp.
Commercial scale CHO cell manufacture of CAMPATH-1H was pioneered at the Therapeutic Antibody Centre (TAC), University of Oxford, England, in 1995 by Dr. Waldmann, formerly with the Department of Pathology, Cambridge University, and collaborators. High yield expression of CAMPATH-1H in a CHO cell line is reported in Bio/Technology, 9, 64-68 (1991).
U.S. patent 5,846,534, H. Waldmann, et al., “Antibodies to the Antigen Campath-1,” issued December 8, 1998, assigned to British Technology Group Ltd. (now BTG plc.), includes coverage of CAMPATH-1H. See also U.S. 5,786,176. Recombinant humanized CDw52 (CAMPATH-1) monoclonal antibody, CAMPATH-1H, is disclosed in U.S. 5,786,176. Claim 1 states, “An antibody which binds effectively to the antigen Campath-1, having a constant region of human origin, heavy and light chain variable domain framework regions which are of human origin, and complementarity determining regions defined by amino acid residues 31 to 35, 50 to 65 and 95 to 102 of the heavy chain as shown in FIG. 2a, and amino acid residues 24 to 34, 50 to 56 and 89 to 97 of the light chain as shown in FIG. 2b, the heavy chain variable domain framework region having a phenylalanine residue at 27.” Example 1 of 5,846,534 describes manufacture of CAMPATH-1H in transformed CHO cells.
The Wolfson Industrial Liaison Office, Cambridge University’s technology transfer office, handles Campath intellectual property rights for the University (and MRC). Agreements have been signed by the University under the names Lynxvale Ltd and CUTS Ltd. (Cambridge University Technical Services).
ILEX has apparently licensed U.S. patent 5,846,534, originally assigned to Celltech Group plc, now assigned to Lonza Biologics plc, a subsidiary of Alusuise-Lonza Group, concerning use of the glutamine synthetase (GS system) as a selectable marker for identification and amplification of transformed CHO cells. Related patents include U.S. 5,770,359 and 5,747,308. The technology is coassigned to the University of Glasgow (which presumably receives a share of royalties). The GS system involves use of glutamine synthetase as a dominant selectable marker for use in co-amplification of non-selected genes and in transforming host cell lines to glutamine independence. The GS gene is spliced into recombinant vectors as a marker along with the gene(s) for the desired protein, with only successfully transformed cells capable of producing their own GS enzyme and surviving in glutamine-deficient culture media. Over forty companies have licensed GS System technology for various uses.
ILEX has nonexclusively licensed recombinant monoclonal antibody humanization patents/technology from Protein Design Labs., Inc., including its “Queen” and “Winter” patents. The situation concerning recombinant monoclonal antibody patents, licensing, cross-licensing and disputes is very complex. See the “Tech. transfer (rDNA)” section of the Monoclonal Antibodies entry (#300) for further information about these and other recombinant antibody patents and disputes. Recently, Genentech has attained a very strong, if not dominant, position in recombinant monoclonal antibody design/construction and expression U.S. patents through its “New Cabilly” patent, including claims from a revoked Celltech Group patent, and from cross-licensing of patents with Celltech. Genentech may pressure (or bring suit against) Millennium & ILEX Partners/ILEX/Genzyme to take a license, if a license has not already been taken for Campath.
Trials: The pivotal trial supporting the BLA was a Phase II clinical trial (and two earlier supporting studies) involving a total of 149 patients with CLL. Of these, 147 had received at least one regimen containing an alkylating agent, 128 patients had received fludarabine, and 126 patients had received both types of chemotherapy. The study results showed that 33% achieved a response to Campath, exceeding the protocol target response rate of 20%.
In May 2005, 5-year follow-up results were published in the Journal of Clinical Oncology from a trial in 91 patients showing that 84% of patients who had no detectable traces of CLL after receiving alemtuzumab had survived for at least 5 years. The study suggested that the complete elimination of detectable diseased cells in CLL patients is associated with prolonged overall and treatment-free survival. Of the 91 patients in the trial, 18 (20%) had achieved the minimal residual disease-free endpoint.
In July 2004, results from two studies confirmed the ability of Campath to clear leukemic cells from the bone marrow of CLL patients, a result known as eradication of minimal residual disease or MRD negativity. Attaining MRD-negative remission is associated with increased overall survival. Results from one study showed the correlation between the eradication of MRD following treatment and an increase in overall survival with a majority of MRD-negative patients surviving for at least five years. The other study in CLL patients who did not respond to therapy and others who had progressed after an initial response showed that the chance of achieving an MRD-negative response was associated with lymph node size. After reducing the bulk of these nodes, using high-dose steroids, Campath was effective in achieving an MRD-negative complete response in some of these patients.
In Oct. 2005, results were reported in the Journal of Clinical Oncology from a Phase II trial in 36 patients showing that Campath plus Fludara (fludarabine) or the FluCam regimen provided an 83% overall response rate in patients not responding to prior therapy. Of the 30 responders, 11 had a complete response and 19 had a partial response. Also, 1 patient had stable disease and 5 had progressive disease. Median overall survival for all patients was 35.6 months, but overall survival had not been reached for the 11 complete responders. The combination regimen was well-tolerated. Based on these promising results, a prospective, randomized, Phase III trial was initiated in late 2005 comparing FluCam to single agent fludarabine, as second-line therapy for patients with B-CLL.
In Dec. 2005, results were reported from a 25-center, 108-patient Austrian study of MabCampath use in routine clinical settings for treatment of B-CLL. Patients having received a median of three prior treatments (range 1-11) experienced encouraging survival benefit of up to 31 months after treatment with MabCampath, depending on pre-treatment risk. Even patients with stabilization of disease was documented had prolongation of survival.
In Dec. 2006, results were reported from a 297-patient Phase III trial wiht Campath for first-line therapy of B-cell chronic lymphocytic leukemia. Campath resulted in superior progression free survival (the primary endpoint) compared to chlorambucil in previously untreated patients, reducing the risk of disease progression or death by 42%. Campath also met secondary endpoints including significantly increasing overall and complete response rates, with a nearly 30% greater overall response rate among patients treated with Campath and a 12-fold increase in complete response rates. Genzyme expected to file a BLA supplement for this indication based of these trial results.
In Oct. 2007, results from a 3-year Phase II clinical trial involving 334 patients were reported showing that Campath was more effective than Rebif in treating multiple sclerosis (an unapproved indication for Campath). Patients taking Campath experienced at least a 73% reduction in the risk of relapsing and at least a 70% reduction in the risk of progressing into clinically significant disablilty.
Medical: Campath is generally administered at an induction dose of 3 mg (one vial) as a 2 hour daily intravenous infusion. When this dose is tolerated (infusion-related toxicities ≤ Grade 2), the daily dose is escalated to 10 mg and continued until tolerated, after which the patient is administered a maintenance dose of 30 mg/day three times weekly on alternate days for up to 12 weeks. Most patients can be escalated up to the 30 mg dose in 3-7 days.
In Dec. 2005, FDA issued a letter to U.S. healthcare providers and patients informing them of adverse events reported from a one year interim analysis of data from a three-year, 334-patient Phase II trial comparing Campath vs. vs. Rebif (interferon beta-1a) for treatment of relapsing-remitting multiple sclerosis (MS). This was reported and the trial dosing suspended in Sept. 2005. There were 3 cases of severe idiopathic thrombocytopenia purpura (ITP) in the Campath arm, 1 of which was fatal. Campath already had a boxed warning that includes ITP (so this is not new a new adverse effect). Two of the patients, including the one that died, had received cumulative doses of Campath exceeding the recommended dosing limit in the boxed warning. Otherwise, results from this trial were positive, showing a large treatment effect in favor of alemtuzumab. Patients taking alemtuzumab at high and low doses experienced at least a 75% reduction in the risk for relapse after at least one year of follow up when compared to patients treated with interferon beta-1 (Rebif). In the other co-primary endpoint, patients treated with the high and low doses experienced at least a 60% reduction in the risk for progression of clinically significant disability (p <0.05) compared to patients treated with interferon beta-1a. Dosing at the high-dose Campath arm was suspended. This did not affect Campath marketing, and treatment with Rebif in the control arm continued without interruption, but the trial on clinical hold in the U.S.
In Sept. 2006, updated two-year interim results from 334 patients were reported from a previously-suspended three-year trial Phase II trial (CAMMS223) comparing Campath with Rebif for the treatment of MS. Patients taking alemtuzumab at high and low doses experienced >75% reduction in the risk for relapse after at least two years vs. Rebif (meeting a co-primary endpoint; p=0.00328), and patients taking Campath at high and low doses experienced at least >65% reduction in risk for progression of clinically significant disability vs. Rebif. (meeting another co-primary endpoint). Results of additional secondary and tertiary efficacy endpoints, including MRI data, functional assessments, and quality of life measures, support the findings seen in the co-primary endpoints. Based on these results, Campath appears to be more efficacious than Rebif in treating MS, but its immunological adverse effects, e.g., ITP (although treatable) affecting several percent of patients, may be at a level high enough to prevent approval for this indication or limit the market for MS treatment. Off-label use of Campath is likely to increase for those failing other therapies.
In Sept. 2007, Bayer Schering initiated the first of two planned Phase III trials examining the safety and efficacy of alemtuzumab for the treatment of MS. The Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis (CARE-MS I) study is comparing Campath with Rebif (interferon beta-1a) in patients with relapsing-remitting MS. CARE-MS I will enroll a maximum of 525 patients at approximately 60 medical centers throughout North America, Australia, Latin America and Europe. Alemtuzumab will be dosed at 12 mg/day for five days by intravenous infusion with a second dosing 12 months later of 12 mg/day for three days. All patients will be followed for two years starting the day the last patient is randomized to treatment.
In Oct. 2007, top-line, 3-year positive results were reported from a completed international, multi-center, Phase II clinical trial (CAMMS223) that compared alemtuzumab with Rebif in 334 treatment-naive patients. Patients receiving alemtuzumab had a 73% reduction in the risk of relapse compared with those taking Rebif. This was consistent with data presented after two years. Unlike six cases of idiophatic thrombocytopenic purpura (ITP) reported from prior 2-year data (1 patient died, 4 were successfully treated, and 1 recovered without treatment), there were no new cases of ITP at 3 years. Data from CAMMS223 provided the rationale for the Phase III CARE-MS I clinical trial initiated shortly thereafter in untreated patients with relapsing-remitting multiple sclerosis However, Phase III trial results are not expected until 2011-2012.
In July 2011, positive top-line results were reported from CARE-MS I, the first of two randomized, Phase 3 clinical trials comparing alemtuzumab to the approved multiple sclerosis therapy Rebif (high dose subcutaneous interferon beta-1a) in patients with relapsing-remitting multiple sclerosis (RRMS). Genzyme is developing alemtuzumab in MS in collaboration with Bayer HealthCare. In the CARE-MS I trial, 2 annual cycles of alemtuzumab treatment resulted in a 55 percent reduction in relapse rate compared to Rebif over the two years of the study (p<0.0001), meeting the first primary endpoint and the predefined protocol criteria for success. Statistical significance was not achieved for the second primary endpoint, time to six month sustained accumulation of disability, as compared to Rebif. At the two year time point, 8 percent of alemtuzumab treated patients had a sustained increase in their Expanded Disability Status Scale (EDSS) score (or worsening) as compared to 11 percent of those who received Rebif (Hazard Ratio=0.70, p=0.22). Based on this and expected results from another Phase III trials, Genzyme expected to file for U.S. and E.U. approval of alemtuzumab in MS in early 2012, and has been granted fast track designation by the FDA.
Disease: Chronic lymphocytic leukemia (CLL) is characterized by an accumulation of leukemic cells in the bone marrow, blood and other tissues, causing bone marrow dysfunction and enlargement of the lymph nodes, liver and spleen. Campath targets the CD52 antigen, which is prevalent on cancerous B-lymphocytes, and acts to clear the blood and bone marrow of these cells. Chronic lymphocytic leukemia (CLL) is the most prevalent form of adult leukemia, affecting approximately 120,000 patients in the U.S. and Europe.
Medical: Regarding Lemtrada, currently-available treatments for relapsing-remitting MS are either oral daily tablets or injections which are given several times a week and can have unpleasant side effects. Lemtrada is taken intravenously once a year for two years, the first course being administered for five consecutive days and the second for three consecutive days, allowing patients to lead their lives without treatment for the rest of the time.
The Campath administration regimen generally involves premedication with diphenhydramine (50 mg) and acetaminophen (500-1000 mg) 30 minutes prior to first infusion and each dose escalation. Trimethoprim/sulfamethoxazole DS is adminstered twice daily (BID) 3-times per week (or equivalent) as prophylaxis against Pneumocystis jiroveci pneumonia (PCP), an opportunistic lung infection associated with immune suppression. Famciclovir (Famvir) 250 mg BID or equivalent is given for prophylaxis against herpesvirus, e.g, herpes simplex virus and cytomegalovirus, infections.
Campath administration is during the first week as intravenous infusion over two hours, 3 mg/day, until injection reactions are ≤ grade 2; and then administered at 10 mg/day until injection reactions are ≤ grade 2. Escalation to 30 mg ordinarily can be accomplished in 3-7 days. Starting week 2, Campath is administered at 30 mg/day on alternate days, 3-times weekly to the end of 12 weeks. Single doses greater than 30 mg or cumulative doses greater than 90 mg per week increase the incidence of pancytopenia. PCP and herpes viral prophylaxis should be continued for a minimum of 2 months after completion of Campath or until the CD4+ count is ≥200 cells/µL, whichever occurs later.
Market: In early 2012, it was reported that Campath for leukemia treatment typically costs $30,000. But treatment for multiple sclerosis (i.e., Lemtrada) uses much lower dose (less protein. It is estimated that Campath used for MS treatment would cost about $7,000. This is one of the reasons why Lemtrada is being positioned as a different product (with its own pricing), so it can be priced competitive with other MS treatments (e.g., with new Gilenya from Novartis costing about $48,000/year). The withdrawal of Campath from the market enabled Sanofi to adjust Lemtrada's price closer to that of rival multiple sclerosis drugs such as Novartis's Gilenya.
The 2007 Average Wholesale Price (AWP) for Campath was $5,537.69/vial (Red Book, 2007), with no change in AWP since 2004 or earlier.
Total Campath sales were only $76 million in 2011.
In 2008, Campath sales (as reported by Genzyme) totaled $112 million. The author’s rough estimate (guess, with no information to base this on) for 2007 sales is about $100-110 million. Total Campath sales by ILEX were ~$77 million in 2004, $71.7 million in 2003, with ILEX reporting profits and royalties of $23.3 million. Total sales were 34.8 million in 2002, and $27 million in 2001 (approved in U.S. in May).
Campath has not been big seller. However, Lemtrada, with a modified formulation, may have sales of $3 billion to $3.5 billion by 2017 if approved for multiple sclerosis (while other analysts, seemingly more realistic ones, have projected sales of $400 million in 2018). But with Campath/Lemtrada treatment still obviously involving risk of serious adverse effects, it may remain largely a niche product. This could have become a situation similar to Lucentis and Avastin, with both containing essentially identical-acting active agents, but inherently cheaper Avastin commonly diluted, used off-label and costing much less than Lucentis for its specific indication (wet AMD). Lemtrada will compete against Tysabri (see related entry) and Gilenya, an oral drug from Novartis.
In Dec. 2011, the National Institute for Health and Clinical Excellence (NICE), U.K., issued new draft guidance on MabThera accepting it as an option when used in combination with a wide range of chemotherapy products for people with advanced follicular lymphoma.
In Aprill 2014, the National Institute for Health and Care Excellence (NICE) is recommended the use of Genzyme’s Lemtrada (alemtuzumab) in the treatment of relapsing-remitting multiple sclerosis (MS).
Companies involvement:
Full monograph
119 CD52 Mab, rDNA
Nomenclature:
CD52 Mab, rDNA [BIO]
CAMPATH [TR]
Lemtrada [TR for MS indications]
CAMPATH-1H [TR former reg. to Millenium]
CAMPATH-1 [TR former; reg. to Wellcome Foundation]
Alemtuzumab [FDA]
CD52 monoclonal antibody, humanized [SY]
LDP-03 [SY]
MabCampath [TR Europe; reg. to Roche]
NDC 50419-355-12 [NDC]
molecular weight (kDa) = 150
FDA Class: Biologic BLA
Year of approval (FDA) = 2001
Date of 1st FDA approval = 20010507
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2015, Dec., based on 5,846,534 and 6,569,430; filed for 632 day patent extension for 5,545,403, but not granted (yet)
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm., had reported 2014-20. |
U.S. Patent Expiration Year: | 2015 |
U.S. Biosimilars Data Exclusivity Expiration: | 2013 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2008 |
U.S. Biosimilars Launchability Year: | 2015 |
U.S. Biobetters Launchability Year: | 2015 |
Biosimilars/biobetters-related EU Patents: | expired, based on EP 0328404
Tech. Catalysts Intl., affiliated with Harvest Moon Pharm., had reported patent/SPC expiry in 2014.
|
EU Patent Expiration Year: | 2011 |
EU Biosimilars Data Exclusivity Expiration: | 2012 |
EU Biosimilars Orphan Exclusivity Expiration: | 2012 |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | zzzz |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
exempt from CBER lot release requirements
hamster source materials
monoclonal antibodies
monoclonal antibodies, recombinant
recombinant DNA
rodent source materials
ACUSYST perfusion bioreactors
bioreactors, 10,000 Liter
Chinese hamster ovary (CHO) cells
glutamine synthetase (GS) expression system
mammalian cell culture
Neisseria mennigitidis outer membrane protein (OMP)
percutaneous transluminal coronary angioplasty (PTCA)
petrolatum gauze
lyophilized (freeze-dried)
Protein A affinity chromatography
Sephadex
accelerated approval (based on surrogate endpoints) (FDAapproved)
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
orphan status
priority review status
EU200 Currently Approved in EU
UM999 Not Available/Not Marketed in US
US002 FDA application pending
EM001 Marketed Product in EU
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