PEG-Certolizumab pegol - Cimzia; CDP 870; tumor necrosis factor monoclonal antibody Fab' fragment–polyethylene glycol (PEG) polymer conjugate;
Status - FDA approval in April 2008, EU approval in Oct. 2009
Organizations involved:
l
UCB Group S.A. – R&D; Tech.; World mark.
Celltech Group plc – R&D; Tech.; Former
Lonza Biologics plc – Manuf.
BioReliance Corp. – Manuf.
Invitrogen Corp. – Parent
Sandoz AG – Manuf.
Novartis AG – Parent
Otsuka Pharmaceutical Co., Ltd. – Japan mark.
NewBridge Pharmaceuticals – Mid. East/Africa mark.
Pharmacia Corp. – R&D; Tech.; Former
Pharmacia AB – Parent; Former
Royalty Pharma AG – Tech.
Xoma Corp. – Tech.
Enzon Corp.. – Tech.
PDL Biopharma – Tech.
Pfizer Inc. – R&D; Tech.; Parent; Former
Nektar Therapeutics, Inc. – Manuf. other; R&D; Tech.
University of Alabama – Tech.; Patent dispute
Cross ref.: See the entries for the other approved tumor necrosis inhibitor products – etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira).
Description: Cimzia is a lyophilized (freeze-dried) formulation of certolizumab pegol, a recombinant Fc region-free Fab’ portion of the recombinant humanized TNF40 murine (mouse) monoclonal antibody (certolizumab; hTNF40) with specificity for tumor necrosis factor-alpha (TNF-alpha) expressed in Escherichia coli (E. coli) bacteria site-specifically chemically conjugated to a polyethylene glycol (PEG) polymer strand (PEG2MAL40K). The Fab’ fragment is composed of light chain with 221 amino acids and a heavy chain of 229 amino acids, both selected and derived from the TNF40 murine antibody with high TNF-alpha affinity and neutralizing activity. The affinity of certolizumab for TNF-alpha is comparable to that of the parent hTNF40 antibody. The modified Fab fragment derived from antibody hTNF40 is covalently linked via a cysteine residue at position 221 to a lysyl-maleimide linker. A cross-linked methoxypoly(ethyleneglycol) polymer (methoxy-PEG), i.e., two linked PEG stands, each having a molecular weight of ~20,000 Dalton (~20 kDa), is attached to the two amine groups on the Fab’ antibody’s hinge region lysine residue. The total molecular weight of the resulting certolizumab pegol molecule is ~91 kDa. Certolizumab pegol has an estimated molecular formula of C2115H3252N556O673S16.
Certolizumab pegol comprises an antibody fragment with a light chain and a heavy chain derived from the humanized TNF40 mouse monoclonal antibody having specificity for human TNF-alpha covalently linked to a maleimide group, that is converted to a succinimide group, that is in turn covalently linked to a lysine residue, the succinimide and lysine residues forming the linker group, that is covalently linked to two methoxypropyl-(ethyleneglycol) polymers (mPEG2-MAL; each approximately 20 kDa). The Fab’ fragment is reacted with mPEG2-MAL, a reactive substrate of maleimide covalently linked to two PEG residues through a lysine residue, with the maleimine group covalently bonding a specific thiol group in the hinge region of the Fab’ protein.
PEG is site-specifically attached (PEGylated) to increase circulating half-life while maintaining hTNF40’s original binding activity. The Fab’ fragment has been modified by addition of amino acids to the C-terminal end of its heavy chain. The additional amino acids form a modified hinge region containing the cysteine residue linked to the lysyl-maleimide linker, with the two PEG chains linked to the antibody by a single maleimide group. By utilizing a specific single hinge thiol site with the antibody for conjugation, the antibody fragment retains antigen binding and in vivo activities of the original antibody, hTNF40, and has immunoglobulin-like pharmacokinetic profiles.
After humanization of hTNF40, involving removal of nucleotide/amino acid sequences other than the complimentarity-determining region (CDR; the active binding site of the murine antibody) and their replacement with comparable human gene/protein sequences (for further information, see the Monoclonal Antibodies entry, #300), about 95% of the redesigned certolizumab is composed of gene/protein sequences of human origin and 5% of murine (mouse) origin [in comparison, infliximab (Remicade) is about 25% of murine origin)]. This humanized antibody fragment is an antibody (immunoglobulin) molecule that includes not only murine variable domains (CDRs; immunogen binding sites) fused to human constant regions, but also contains altered selected variable domain framework residues that more closely match the most related available human variable template sequence. This CDR grafted antibody has non-human CDR domains from an hTNF40 murine antibody grafted into the most closely related human antibody sequence available so that only the CDR domains are non-human in origin. CDR grafting antibodies have reduced immunogenicity and human-anti-mouse (HAMA) immune response, increasing the safety and tolerability of the resulting humanized antibody
Cimzia is packaged in single-use vials containing 200 mg of certolizumab pegol, along with 100 mg sucrose, 0.9 mg lactic acid and 0.1 mg polysorbate, with no preservatives used. Cimzia is stored refrigerated, with its expiration date on the vial.
Nomenclature: TNF Mab Fab', rDNA, PEG- [BIO]; Cimzia [TR]; certolizumab pegol [INN]; immunoglobulin, anti-(human tumor necrosis factor) Fab’ fragment (human-mouse monoclonal CDP870 heavy chain), disulfide with human-mouse monoclonal CDP870 light chain, pegylated at Cys-221 [CAS]; 428863-50-7 [CAS RN]; tumor necrosis factor monoclonal antibody Fab’ fragment–polyethylene glycol (PEG) polymer conjugate [SY]; CDP870 [SY]; CDP-870 [SY]; PHA-738144 [SY]; peg-antiTNF alpha antibody [SY]
Biological.: See the entries for etanercept (Enbrel), infliximab (Remicade), and adalimumab (Humira) for further information about tumor necrosis factor-alpha (TNF-alpha) and its inhibition. The basic biological activity of certolizumab pegol is much the same as other tumor necrosis factor monoclonal antibodies used for much the same indications:. hTNF40 has high affinity for both soluble and cellular membrane-bound TNF-alpha. The certolizumab antibody fragment has affinity for TNF-alpha (Kd = ~1.32 x 10-10M), but it does not neutralize TNF-beta (lymphotoxin), a related cytokine produced predominantly by T-cells that displays similar biological activities as TNF-alpha but is often less potent.
ertolizumab pegol binds to human TNF-alpha with a KD of 90pM. The Fc portion of hTNF40 has been removed, so certolizumab exerts its activities exclusively through binding to TNF-alpha, without binding to cellular antibody receptors. This is one of the major differences between Cimzia and other TNF antibody products (Remicade and Humira) that can fix complement, lyse cells and activate other components of the immune system through their Fc portions.
As with other pegylated protein biopharmaceuticals, pegylation results in the PEG polymer wrapping around the protein portion and protecting it from enzymatic degradation by steric inhibition and also reducing immunogenicity by making the protein portion less available for contact with immune system cells. Conjugation of the PEG moiety to certolizumab increases the plasma half-life of the resulting molecule, certolizumab pegol, to nearly 14 days, allowing for less frequent dosing.
Companies.: All worldwide rights, including manufacturing and marketing, are currently held by UCB Group (originally Celltech Group), which has contracted out commercial manufacture to multiple companies. Proprietary PEG intermediates and assistance are obtained from Nektar Therapeutics, Inc. (originally Shearwater Corp., later became Inhale Therapeutic Systems, Inc., which merged into Nektar in 2003). Shearwater/Nektar also collaborated with Celltech in development of certolizumab pegol.
Certolizumab (known primarily as CDP870 during development) was originally developed, including its composition-of-matter (recombinant humanized antibody fragment and its pegylation) by Pharmacia Corp., then a subsidiary of Pharmacia AB, which merged into Pfizer Corp. in 2002, in collaboration with Celltech Group, now part of UCB Group. Pharmacia, later Pfizer for a short period, was responsible for worldwide marketing and two pivotal Phase III trials in rheumatoid arthritis. Celltech had responsibility for manufacture and clinical development for Crohn’s disease. The agreement between Celltech and Pharmacia for CDP870, at the time, was one of the most lucrative deals between a U.K./European biotech company and a multinational pharmaceutical company.
Pegylation technology used with Cimzia was developed by Shearwater Corp., now later Nektar Therapeutics, Inc., a subsidiary of Inhale Therapeutic Systems, Inc. See the Pegasys entry for further background about PEGylation technology. UCB has rights to Nektar’s patents through is development collaboration and licensing agreement with Shearwater/Nektar
Pegylation technology from Enzon has apparently also been licensed, with Enzon reportng that it receives royalties on sales of Cimzia. See the Tech. transfer section of the PEG-Intron (#208) monograph for information concerning Enzon's pegylation technology.
In Nov. 2003 Pfizer announced that it wanted to renegotiate financial terms and that it was delaying clinical development of CDP870. Celltech refused to renegotiate with Pfizer, and all rights to CDP870 reverted to the Celltech in Dec. 2003. Celltech was acquired and merged into the UCB Group in May 2004. Cimzia was the Celltech’s primary asset. Unconfirmed sources report that Pfizer will receive a royalty of 20% on sales of Cimzia for patent licensing and its role in clinical development.
In 2002, Celltech entered into long-term large-scale certolizumab pegol bulk contract manufacturing and supply agreements with Biochemie GmbH, now Sandoz AG, a subsidiary of Novartis AG; and with BioReliance Corp., formerly Microbiological Associates, now a subsidiary Invitrogen Corp. Celltech has also concluded a long-term supply agreement with Lonza AG. Under the agreement with Sandoz, Celltech has reserved a fixed annual manufacturing capacity in its 3,000 litre and 13,000 L fermenters from Jan. 2004 through 2010, with Sandoz potentially receiving up to ~£41 million (as reported in Celltech’s 2003 annual report; equivalent to $71.6 million in Feb. 2006). Under the agreement with Lonza, Celltech reserved manufacturing capacity through 2010, with Lonza potentially receiving up to ~£14 million (~$24.5 million in Feb. 2006). Celltech also negotiated a contract with BioReliance to reserve manufacturing capacity, if needed, with BioReliance receiving a minimum commitment of £2.2 million (~3.84 million in Feb. 2006).
In May 2005, UCB and Lonza renegotiated a long-term supply agreement for manufacture of certolizumab pegol bulk. Lonza will use the large-scale biopharmaceutical manufacturing facility it is building in Visp, Switzerland. The facility will contain two production trains with a fermentation capacity of 15,000 liters each. These will be operational starting in the second half of 2006. UCB has reserved a fixed annual manufacturing capacity for recombinant microbial products, including certolizumab pegol, covering the period 2006-2012, with an extension option. This will give UCB flexibility in scheduling to meet the clinical and commercial timelines for its portfolio of PEGylated antibody fragment-based products.
Based on size of the contracts (as reported by Celltech), Sandoz apparently will be the primary near-term manufacturer of supplies of certolizumab pegol. However, with UCB having acquired Celltech and UCB being privately-held and disclosing little information about its commercial activities, it is possible that the earlier Celltech agreements with Sandoz and BioReliance have been modified.
In June 2008, UCB signed a co-development and co-marketing agreement for Japan with Otsuka Pharmaceutical Co., Ltd.. A Japanese filing for Crohn's disease is planned for 2009.
In Dec. 2010, UCB initiated a project to build a $335 million microbial manufacturing capacity in Bulle, Switzerland to manufacture Cimzia. The new manufacturing unit should be operational in 2015. The 20,000-square-meter bioprocessing factory in the Swiss state of Fribourg that is expected to be among the largest in Europe. In Jan. 2011, UCB announced initiation of construction of its facility in Bulle.
In Feb. 2012, Royalty Pharma AG acquired Nektar's royaly interests in Mircera and Cimzia for a total cash payment of $124.0 million, with payments starting Jan. 1, 2012.
Manufacture: Transformed E. coli (W3110 strain) are subjected to fed-batch fermentation in L-broth (apparently) supplemented with tetracycline. Manufacture of certolizumab using prokaryotic E. coli significantly reduces costs, compared to manufacture of larger recombinant antibodies using mammalian cell expression systems. Advantages include lower costs, a more rapid production cycle (just 2-3 days fermentation), higher yields and increased reliability. Compared to other TNF inhibitor biopharmaceuticals, Cimzia is reported to have a lower production costs.
The E. coli plasmid vector pTTO is used to express certolizumab. This vector is designed to give rise to soluble, periplasmic accumulation of recombinant proteins, such as certolizumab, in E. coli. pTTO vectors include (as described in patent filings): a gene for tetracycline resistance allowing selection of only transformed plasmid-containing cells; a low copy number origin of replication derived from plasmid p15A; a strong, inducible tac promoter for transcription of the cloned gene; a lacIq gene for constitutive expression of the lac repressor protein, maintaining the tac promoter in the repressed state until induction with IPTG (isopropyl-beta-D- thiogalactopyranoside)/allolactose; an OmpA signal sequence for periplasmic secretion of cloned genes; and translational coupling of OmpA signal sequence to a short lacZ peptide for efficient initiation of translation. The vector was developed for expression of modified Fab’ fragments from a dicistronic message by empirical selection of the optimum intergenic sequence from a series of four purpose-built cassettes. For further information, see the applications/patents cited in the Tech. transfer section below and cited patents.
FDA class: Biologic BLA
Approvals: Date = 2008422; BLA 125160; Indication= Crohn's disease treatment
Date = 20081001; BLA supplement; Indication = clarifications to the package insert including modernization of medical terminology and removal of the volume restriction associated with fluid administration in pediatric patients.
Date = 20090513; BLA supplement; Indication = treatment of adults with moderately to severely active rheumatoid arthritis
Date = 20090804; BLA supplement; Indication = addition of stronger warnings in the prescribing information for all TNF blockers, including a 'black box' warning
Date = 20130930; sBLA; Indication = treatment of adult patients with active psoriatic arthritis (PsA)
Indications: [full text of the "Indications and USAGE" section of product insert/labeling, 10/27/2010]:
CIMZIA is a tumor necrosis factor (TNF) blocker indicated for:
- Reducing signs and symptoms of Crohn’s disease and maintaining clinical
response in adult patients with moderately to severely active disease who
have had an inadequate response to conventional therapy
- Treatment of adults with moderately to severely active rheumatoid arthritis
CIMZIA is indicated for reducing signs and symptoms of Crohn’s disease and maintaining clinical response in adult patients with moderately to severely active disease who have had an inadequate response to conventional therapy.
1.2 Rheumatoid Arthritis:
CIMZIA is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis (RA).
Status: A BLA seeking approval (standard, not priority, review) for the second-line treatment of Crohn’s disease was filed on March 2, 2006. A European Union MAA for Crohn’s disease was filed on April 28, 2006.
The BLA included safety and efficacy data from well-controlled trials in more than 1,500 patients with Crohn’s disease (see the Trials section below). The BLA package represented the largest biologic clinical trial database and broadest, in terms of patient types, submitted to the FDA for Crohn’s disease treatment. FDA requested further information in Dec. 2006.
In Dec. 2006, FDA sent UCB a Complete Response Letter questioning the adequacy of the design of one Crohn’s disease study, with no major concerns raised regarding manufacture or safety. In March 2007, UCB initiated an additional short-term clinical study of CIMZIA to confirm the induction of clinical response in severe active Crohn’s disease. UCB worked closely with FDA regarding the study design, in order to provide additional clinical efficacy data. Results from the study are expected in the second half of 2008.
In Feb. 2008, before full approval was granted, a supplemental BLA (later referred to by the company as a full BLA) for rheumatoid arthritis (RA) was accepted by FDA for filing, with the product then pending approval for Crohn's and RA indications: in the U.S. The filing was based on data from more than 2,367 patients and included three multi-center, placebo-controlled Phase III trials.
On March 24, 2008, EMEA/EU upheld a negative opinion regarding approval of Cimzia. This followed an appeal by UCB after the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) originally advised turning down its application to market Cimzia for Crohn’s back in Nov. 2007. The CHMP was concerned over Cimzia's general safety and effectiveness profile, and concluded that its benefits to patients do not outweigh the potential risks in this setting. This decision was particularly painful for UCB since it had recently released six-week data from a 539-patient Phase IIIb trial showing that Cimzia is effective in treating patients who are intolerant or no longer responding to Remicade. The second rejection by the CHMP certainly represents a major setback for UCB, which has been touted as a likely blockbuster that could help plug the gap in sales resulting from the loss of patent protection on its biggest earners – the allergy drug Zyrtec (cetirizine) and the antiepileptic Keppra (levetiracetam) – in 2007 and 2009, respectively.
On April 22, 2008, FDA granted BLA approval to Cimzia for Crohn's disease, over two years after initial filing. With this, Cimzia became the third TNF inhibitor antibody approved in the U.S., in addition to Remicade and Humira. The U.S. product insert includes a black box warning about serious risks for infection, particularly tuberculosis, invasive fungal diseases and other opportunistic infections. Patients taking Cimzia should be educated about how to identify an infection and be instructed to contact their health care professional at the first sign of infection. UCB launched Cimzia in the U.S. within 48 hours of its FDA approval.
On June 4, 2008, FDA issued an Early Communication About an Ongoing Safety Review regarding the safety of TNF inhibitor biologics (Remicade, Enbrel, Humira, and Cimzia) and the development of lymphoma and other cancers in children and young adults. FDA is investigating ~30 reports of cancer in children and young adults who began taking TNF blockers (along with other immuno-suppressive medicines such as methotrexate, azathioprine or 6-mercaptopurine), when they were ages 18 or less, to treat juvenile idiopathic arthritis, Crohn's disease or other diseases. Approximately half of the cancers were lymphomas, including both Hodgkin's and non-Hodgkin's lymphoma. FDA noted, " Long-term studies are necessary to provide definitive answers about whether TNF blockers increase the occurrence of cancers in children because cancers may take a long time to develop and may not be detected in short-term studies. Until the evaluation is completed, healthcare providers, parents, and caregivers should be aware of the possible risk of lymphoma and other cancers in children and young adults when deciding how to best treat these patients."
On July 2, 2008, an MAA filed by UCB for European Union approval of Cimzia subcutaneous treatment for adults with moderate to severe active rheumatoid arthritis (RA) was accepted for filing. The MAA filing was based on clinical data from more than 2,300 patients involved in several multi-center placebo-controlled Phase III trials totaling over 4,000 patient-years of experience.
On Sept. 4, 2008, FDA announced that the manufacturers of Humira, Cimzia, Enbrel, and Remicade must strengthen the existing warnings, in the Warnings and Precaution sections of the prescribing information and Medication Guide, concerning the risk of developing opportunistic fungal infections. FDA exercised its new authority under the Food and Drug Administration Amendments Act of 2007, under which FDA can require safety label changes and a risk evaluation and mitigation strategy, known as REMS, when the agency becomes aware of new safety information. Medication Guides will become part of a risk evaluation and mitigation strategy (REMS) for Humira and Remicade (which were already part of a REMS for Enbrel and Cimzia). The manufacturers will be required to educate prescribers about the risks.Since the initial approval of the four TNF blockers, the prescribing information for these drugs has included information about the risk of serious infections, including fungal infections. However, based on reports reviewed by FDA, health care professionals had not been consistently recognizing cases of histoplasmosis and other invasive fungal infections, leading to delays in treatment. FDA had reviewed 240 reports of histoplasmosis, an infection caused by the fungus Histoplasma capsulatum, in patients being treated with Enbrel, Humira, or Remicade. The majority of the reports involved people in the Ohio River and Mississippi River valleys (the fungus is commonly found in those areas). In at least 21 of the reports, histoplasmosis was initially not recognized by health care professionals, and antifungal treatment was delayed. Twelve of those patients died. The FDA also had received reports of cases of coccidioidomycosis and blastomycosis, including deaths, in patients treated with TNF blockers. TNF blocker manufacturers must submit safety labeling changes, including strengthened warnings and revisions to the Medication Guides to the FDA within 30 days or to provide a reason why they do not believe labeling changes are necessary.
On Jan. 5, 2009, FDA issued a "Complete Response Letter" (CRL) relating to the BLA of Cimzia for the treatment of rheumatoid arthritis (RA). FDA requested a new safety update with all clinical data including new data generated since the filing of the BLA. About a month later, UCB met with FDA and learned that FDA wanted additional analysis of existing data and a new safety update. No further studies would be needed to fulfill this request, and the company anticiapted submitting the full response for Cimzia in the second quarter of 2009.
It is interesting that neither the approved pre-filled syringe nor the option of dosing both fortnightly or once-monthly were actually tested in all of Cimzia's Phase III trials.
On May 15, 2009, UCB launched the prefilled syringe designed in partnership with OXO in the U.S. The new syringe provides a soft, non-slip grip on the flange which allows the patients to hold the syringe steady using various grip positions so it is easy and comfortable to use. The large and soft thumb pad on the plunger makes it easy to push for patients. The rounded finger loop allows for easy removal of the needle cover. The easy-to-read syringe barrel helps to ensure patients receive the entire dose as they can see the medicine inside and know when they have injected all of the medication. The packaging utilizes Velcro) for easy opening and resealing. The refilled syringe carries the Arthritis Foundation Ease-of-Use Commendation.
On Oct 5, 2009, Cimzia received European Union approval "for the treatment of moderate to severe active rheumatoid arthritis (RA) in adult patients inadequately responsive to disease-modifying antirheumatic drugs (DMARDs) including MTX [methotrexate]. Cimzia can be given as monotherapy in case of intolerance to MTX or when continued treatment with MTX is inappropriate.. Cimzia has been shown to reduce the rate of progression of joint damage as measured by X-ray and to improve physical function, when given in combination with MTX.." Cimzia was approved to be administered as a subcutaneous injection using the prefilled syringe designed in partnership with OXO Good Grips, a redesign of the traditional syringe with the aim of making self-administration easy for people living with RA. The syringe is designed for use by patients with different grip styles and strengths and it provides measurable improvements in the patient experience. The European approval was supported by data from a clinical development program involving more than 2,300 patients with RA and over 4,000 patient-years experience.
Tech. transfer: Cimzia-related patents include U.S. application 20050042219 (and WO 2004053064), “Engineered Fab’ fragment anti-tumor necrosis factor alpha in combination with disease modifying anti-rheumatic drugs,” filed in Dec. 2003, originally assigned to Pharmacia Corp. Claim no. 1 states, “A method of treating an inflammatory disease or inflammatory disorder in a person in need thereof comprising administering an anti-tumor necrosis factor alpha antibody Fab’ fragment CDP870 and at least one disease modifying anti-rheumatic drug to the person in a therapeutically effective amount.” Related patents/applications assigned to Pharmacia include WO 2004053064 (and equivalents, including U.S. 60/431,053), “Engineered Fab’ Fragment Anti-Tumor Necrosis Factor Alpha in Combination with Disease Modifying Anti-Rheumatic Drugs,” claiming combinations of CDP870 with methotrexate and other disease modifying anti-rheumatic drugs (DMARDs).
Applications/patents concerning E. coli expression of CDP870 have been assigned to Celltech, including U.S. applications 20020151682 and 20030026805, both entitled “Biological products.” Claims include expression of various engineered TNF-alpha antibodies, including plasmid pTTO used for expression of certolizumab. Formulations of certolizumab pegol are described in U.S. application 20040091490 (and WO 2004019861), “Stable pH optimized formulation of a modified antibody,” and related US 2004247588 (and WO2004019860), assigned to Pharmacia (Pfizer). These claim methods for stabilizing the succinimide ring structure of modified antibodies having a succinimide moiety, e.g., certolizumab pegol to prevent depegylation over time using a buffered solution.
Cimzia-related EP patent filings include EP1534753, "PEG POSITIONAL ISOMER OF AN ANTI-TNFALPHA ANTIBODY (CDP870)," assigned to Celltech, expiring in 2023.
EP1495056, "METHODS OF ANALYZING ANTIBODY DISULFIDE ISOMERS" perhaps claiming analytical methods critical to showing biosimilarity, expires in 2023.
Celltech, now UCB, has nonexclusively licensed Bacterial cell expression technology (BCE) from Xoma Corp. This involves use of the araB promoter for expression and secretion of antibody domains from bacteria (E. coli) as properly folded, functional proteins. XOMA was the first to demonstrate the secretion of antibody domains directly from bacterial cells as fully functional, properly folded molecules. XOMA has received ten or more U.S. patents relating to aspects of its BCE system, including six patents that broadly cover the secretion of immunoglobulins from bacteria, including antibody fragments such as Fab and single-chain antibodies. Royalty rates reported in association with other products, e.g., Lucentis, are reported to be slightly less than 1%.
In July 2006, the University of Alabama (Huntsville, AL; UAH) settled a patent dispute brought against Nektar and its original founder, Dr. Milton Harris, formerly with the university through a cash payment of $25 million. Nektar and Dr. Harris jointly made an upfront payment totaling $15 million to UAH; and Nektar will pay UAH $1 million/year for ten years. UAH dismissed all claims related to the Nektar’s PEGylation patent portfolio and Nektar dismissed all counterclaims. UAH had sued Nektar in U.S. District Court for patent infringement, breach of contract license, violation of the Alabama Trade Secrets Act and unjust enrichment. Dr. Harris and another researcher developed a PEGylation technology, which was patented by UAH (U.S. 5,252,714, “Preparation and use of polyethylene glycol propionaldehyde “). The university had entered into a royalty agreement with Dr, Harris for products developed from this discovery, and Harris created Shearwater Polymers, now Nektar. UAH claimed that Harris, without UAH’s knowledge, made a number of other discoveries related to the PEG technology in the following years, patented 28 of them, that Harris was required to notify UAH of any discovery related to the original PEG patent, and that the patents were “obvious derivatives” of and “equivalent” to the original UAH PEG patent
UCB has licensed the "Queen" recombinant antibody humanization patents. See the Monoclonal Antibodies entry (#300) for further information about PDL’s broad antibody humanization patents (“Queen” patents). A U.K. SPC application covering Cimzia (certolizumab pegol) was granted on EP0451216, which will expire in Dec. 2014.
Trials: Based on Phase I and II trials, Celltech concluded that subcutaneous and intravenous routes of administration were comparable. Phase III trials all involve administration of Cimzia as a monthly 400 mg subcutaneous injection, after a more intensive short induction dosing period. Phase III trials began in Oct. 2002. Phase III clinical trials of certolizumab pegol have been completed in both monotherapy and combination therapy in the treatment of rheumatoid arthritis.
Cimzia (CDP870) has been studied in the PRECiSE (Pegylated antibody fRagment Evaluation in Crohn’s Disease: Safety and Efficacy) program of Phase III trials for treatment of Crohn’s disease and in rheumatoid arthritis in patients having previously receive therapy with one or more disease-modifying ant-rheumatoid drug (DMARD) therapy. Phase III testing began in Oct. 2002. PRECiSE is composed of four studies (PRECiSE 1, 2, 3 and 4) in over 1,300 patients to assess the impact of Cimzia on induction and maintenance of clinical response in patients with moderate to severe Crohn’s disease. PRECiSE 1 was a 26-week double-blind, placebo-controlled trial, and represents the first long-term fully placebo-controlled trial of a biologic in Crohn’s disease. PRECiSE 1 successfully met its primary endpoints with statistical significance. PRECiSE 2 trial is discussed below. PRECiSE 3 and 4 are both 24-month, open-label trials for patients who participated in either PRECiSE 1 or 2, assessing the longer-term safety and tolerability of CIMZIA.
In Oct. 2005, results were reported from the 26-week PRECiSE 2 Phase III trial of Cimzia in 668 patients with active Crohn’s disease (CDAI score 220-450 points). Clinical response was defined as >100 point decrease in CDAI score, which measures the severity of Crohn’s disease by taking into account a number of factors such as intensity of symptoms, medication and general well-being. Patients with high scores have highly active Crohn’s disease while low scores indicate the disease is less active. Patients who responded at week 6 to open induction therapy with Cimzia 400 mg sc at Weeks 0, 2 and 4 were randomized to maintenance therapy with Cimzia 400 mg or placebo dosed every 4 weeks. The primary endpoint was the percentage of patients at week 26 with a C-reactive protein (CRP) assay of more than 10 mg/L who maintained a clinical response after successful induction. Major secondary endpoints included remission (CDAI <150) in those with CRP >10 mg, and response and remission in the overall population.
In PRECiSE 2, Cimzia maintained clinical response following induction therapy in patients with moderate to severe Crohn’s disease. At week six, 428 responders (64%) were randomized to receive monthly maintenance injections. At week 26, clinical response in the CRP ≥10 mg/L group (112 certolizumab pegol, 101 placebo) was 61.6% for Cimzia vs. 33.7% for placebo (p <0.001). Among these patients, 42.0% in the treatment arm experienced remission, compared with 25.7% of those on placebo (p <0.01). In the overall group, 62.8% of those receiving Cimzia had a clinical response, compared with 36.2% on placebo (p <0.001); and 47.9% of treated patients experienced remission at week 26, compared to 25.7% of those on placebo (p <0.001). The primary endpoints were met with statistical significance, irrespective of CRP status or prior exposure to anti-TNF therapy; and CIMZIA was well-tolerated. Adverse events were mostly mild to moderate, with headache being most frequent, in 12.6% of patients during the induction phase, and in 6.9% of the Cimzia patients and 6.6% of placebo patients in the double-blinded phase.
Results from a company-sponsored Phase II trial were published in Gut, vol. 54 (sup. l7), p. A82, 2005. Results from a non-company-sponsored randomized, double-blind, 36-patient study of intravenous infusion of 1, 5 or 20 mg/kg Cimzia for treatment of rheumatoid arthritis were published in Rheumatology, vol. 41, no.10, p.1133-7, 2002).
In July 2006, positive results were reported from a Phase II trial in patients with moderate to severe chronic plaque psoriasis who were candidates for systemic therapy and/or photo- or photochemo-therapy. Administered at an initial dose of 400 mg followed by 200 mg subcutaneous injection every other week for 12 weeks, Cimzia achieved a PASI 75 response in 75% of patients, rising to 83% if 400 mg was given throughout the course of treatment. Just 7% of those on placebo experienced a similar improvement.
In Oct. 2006, new data were reported from a post hoc analysis of the PRECiSE trial program showing that Cimzia maintained response and remission in patients with moderate to severe Crohn’s disease, regardless of whether or not they had been previously treated with Remicade and irrespective of disease duration. Higher response and remission rates with Cimzia were observed in patients who had been diagnosed with Crohn’s disease for less than one year. In these patients, 89.5% of Cimzia patients maintained their clinical response at Week 26 vs. 37.1% on placebo (p<0.01). Clinical response was defined as a greater than or equal to 100 point decrease in Crohn’s Disease Activity Index (CDAI).
In Feb. 2007, results were reported by the the RAPID Phase III trials. RAPID 1 enrolled 1,000 moderate-to-severe rheumatoid arthritis (RA) patients receiving Cimzia and methotrexate. Cimzia prevented joint damage to a significantly greater degree than placebo plus methotrexate after one year of treatment. RAPID 1 achieved its co-primary endpoint, the inhibition of progression of structural damage, with a statistically significantly smaller change from baseline in modified Total Sharp Score observed at week 52 in both Cimzia treatment arms (400 mg at weeks 0, 2 and 4 followed by 200 mg every two weeks; or 400 mg every two weeks) compared with the placebo treated arm (p<0.001). In both active treatment arms, Cimzia improved the signs and symptoms of RA to a statistically greater degree than the placebo arm in patients who had inadequately responded to methotrexate alone (p<0.001). Similar results were observed with a second pivotal Phase III study, RAPID 2, using Cimzia’s new subcutaneous liquid formulation. RAPID 1 and RAPID 2 demonstrated that effective results in the treatment of RA can be achieved with a 400-mg total monthly dose of Cimzia, showing that a higher dose is not necessary. The RAPID studies also showed that Cimzia has a rapid onset of action, with about three-quarters of treated patients who achieved ACR 20 at week 24 actually reaching ACR 20 within four weeks.
In the July 19, 2007, issue of the New England Journal of Medicine, results from the PRECiSE 1 and 2 trials were published in separate articles
The May 2009 BLA approval for rheumatoid arthritis (RA) was based on four studies involving more >2,300 patients. These demonstrated that Cimzia, together with methotrexate, significantly reduced the signs and symptoms of RA after six months; and that the combination inhibited the progression of joint damage
In May 2010, results of an open-label extension study, PRECiSE 4 (P4) showed that Cimzia provides sustained efficacy over four years in moderate to severe Crohn's Disease patients regardless of whether patients were previously treated with infliximab (IFX) or infliximab-naive.
In Sept. 2013, with approval for PsA, it was reported that
the RAPID™-PsA study supporting the US approval was the first randomized, controlled study of an anti-TNF in PsA to include patients with and without prior anti-TNF exposure. The ACR20 results showed that Cimzia rapidly improved the signs and symptoms of PsA for patients with response observed as early as the first week of treatment for some patients.
Medical: The recommended starting dose (EU) of Cimzia for adult patients with RA is 400mg (as 2 injections of 200mg each on one day) at weeks 0, 2 and 4, followed by a maintenance dose of 200mg every 2 weeks. Methotrexate should be continued during treatment with Cimzia where appropriate.
Cimzia is administered once monthly via subcutaneous injection. Cimzia in an advancement in terms of treatment regime, cost and proprietary technology in comparison to the current marketed biologics. Cimzia’s monthly subcutaneous injection regimen is more practical than Enbrel’s bi-weekly injections and Remicade’s infusion regime. A once-monthly injection is also much less likely to produce injection-site reactions. Cimzia may eventually be approved for home use (patient self-injection).
Market: First-half 2010 sales were $83 million (equiv. to $166 million/year). Total sales were $101.4 million in 2009 and $12.7 million in 2008.
In Feb. 2010, the National Institute for Health and Clinical Excellence (NICE), U.K., published final guidance recommending Cimzia as an option for patients with RA, but only in those who have already tried methotrexate and another disease-modifying anti-rheumatic drug (DMARD) and have severe ‘active’ disease. Accepting its effectiveness as a treatment for severe forms of the disease, NICE ruled that, with a price tag of around £9,295 a year (£10,725 for the first including a loading dose), the therapy is a cost-effective use of resources, but only alongside a patient access scheme proposed by the UCB - under which it picks up the costs for the first 12 weeks of treatment. Thus, Cimzia will cost £5,005 (roughly $8,000) for the first year's treatment rather than £8,580 (about $13,900).
In March 2010, the CEO of UCB stated he expects to market for Cimzia to eventually reach “at least 1.5 billion euros." Cimzia offer patients with RA a new treatment option for managing the disease and comes with the advantage of being available in a pre-filled syringe, designed to address challenges such as limited dexterity patients face when self-injecting.
Cimzia has potential to become a blockbuster (>$1 billion/year sales). However, it will face competition from well-established products (including Enbrel, Remicade, and Humira) marketed by companies among the largest international pharmaceutical companies. Some analysts have questioned whether UCB has the marketing muscle, e.g., number of detail staff, to compete in the highly competitive markets for rheumatoid arthritis and Crohn’s disease therapeutics (particularly, when UCB is compared to Pfizer, which originally held worldwide marketing rights). UCB always has the option of licensing Cimzia marketing.
Competition: See the other TNF monoclonal antibody entries, including the Remicade, Simponi, Humira and Enbrel entries, for further discussion of the competitive market for these products, each of which compete with one or more others for their approved indications:.
With its May 2009 FDA approval for rheumatoid arthritis, Cimzia competes for this indication with other TNF antibody blockbusters, including Johnson & Johnson/Schering-Plough's Remicade (infliximab), Abbott Labs.' Humira (adalimumab) and Amgen and Wyeth's Enbrel (etanercept). It will also compete with J&J/S-P’s Simponi (golimumab), which was approved by the FDA the month before
With Cimzia having to compete with well-established products for its RA indication and with others offering increased convenience, e.g, Simponi only requiring monthly use, many expect Cimzia to capture relatively small market share.for RA.
A Cimzia spokesperson, after U.S. approval for RA, projected peak sales of about $1 billion. The company expects to market Cimzia largely based on its efficacy -- providing quick and long-acting response -- attributable to it being the only pegylated TNF inhibitor. UCB has an ~150-person sales force it will dedicate to the Cimzia RA market.
Piper Jaffray analysts project that Cimzia might eventually attain a 5% share of the RA biologics market, or about €593 million (~$794 million) in peak sales for its RA indications:.
The once-monthly administration schedule for rheumatoid arthritis (RA) will give Cimzia an advantage relative to other TNF inhibitors, e.g., Enbrel, Remicade and Humira. Current RA therapies require daily or weekly administration. Also some patients quit responding to Remicade, and it is administered intravenously.
Cimzia's OXO-designed syringe is apparently targeted to compete with Humira, which has gained market share with many attributing this to its packaging in pre-filled syringes.
For Crohn’s disease treatment, Cimzia is expected to directly compete with Remicade (already approved for this indication) and, eventually, Humira.
UCB in its marketing will likely point out that Cimzia offers various advantages compared to other products (theoretically, until proven in trials). For example, Remicade (see related entry) is composed of 25% murine (mouse) monoclonal antibody, causing some patients to have allergic reactions, while 95% of Cimzia is of human origin and therefore is presumed to be less likely to induce allergic reactions. Available TNF-alpha monoclonal antibodies possess non-human variable domains and human constant regions. As a result, undesirable inflammatory responses and human-antimouse antibody (HAMA) responses may occur during treatment. For example, the human constant regions of IgG1 antibodies activate proinflammatory responses through FcR-mediated mechanisms and/or by activation of the complement cascade.
Cimzia may eventually be used for treatment of plaque psoriasis, for which it would likely compete with other biopharmaceuticals - Amevive, Raptiva, Enbrel, Remicade and Humira.
In April 2008, UCB launched the CIMplicity program in the U.S., providing Cimzia patients and their caregivers with comprehensive financial, administrative, compliance and treatment support..
In the U.S., Cimzia competes for its approved Crohn's indication against Remicade and Humira. Cimzia offers comparable efficacy, with the convenience of subcutaneous adminstration.
Companies involvement:
Full monograph
266 TNF Mab Fab', rDNA, PEG-
Nomenclature:
TNF Mab Fab', rDNA, PEG- [BIO]
Cimzia [TR]
certolizumab pegol [INN]
immunoglobulin, anti-(human tumor necrosis factor) Fab' fragment (human-mouse monoclonal CDP870 heavy chain), disulfide with human-mouse monoclonal CDP870 light chain, pegylated at Cys-221 [CAS]
428863-50-7 [CAS RN]
CDP-870 [SY]
CDP870 [SY]
peg-antiTNF alpha antibody [SY]
PHA-738144 [SY]
tumor necrosis factor monoclonal antibody Fab' fragment–polyethylene glycol (PEG) polymer conjugate [SY]
molecular weight (kDa) = 91
FDA Class: Biologic BLA
Year of approval (FDA) = 2008
Date of 1st FDA approval = 20080422
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2023, based on applications |
U.S. Patent Expiration Year: | 2023 |
U.S. Biosimilars Data Exclusivity Expiration: | 2020 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2015 |
U.S. Biosimilars Launchability Year: | 2023 |
U.S. Biobetters Launchability Year: | 2023 |
Biosimilars/biobetters-related EU Patents: | 2023, based on EP 1534753 and, less relevant, EP 1495056 |
EU Patent Expiration Year: | 2023 |
EU Biosimilars Data Exclusivity Expiration: | 2019 |
EU Biosimilars Orphan Exclusivity Expiration: | 2019 |
EU Biosimilars Launchability Year: | 2023 |
EU Biobetters Launchability Year: | 2023 |
Index Terms:
biopharmaceutical products
conjugates
monoclonal antibodies, recombinant
recombinant DNA
tumor necrosis factor alpha (TNF-alpha)
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
exempt from CBER lot release requirements
FDA application withdrawn
isopropyl-beta-D- thiogalactopyranoside (IPTG)
lacI9 gene (Amersham)
octoxynol (Triton X-100)
p-nitrophenyl-beta-D-glucopyranoside
plasmapheresis, therapeutic
plasmid pOA15
prothrombin, human
T-Flask culture
tetracycline
Tn5 (Pharmacia)
ceramide trihexoside
lactate dehydrogenases
lyophilized (freeze-dried)
methotrexate
polyethylene glycol (PEG)
polysiloxane
sucrose
apheresis (hemapheresis)
North American coral snake
North American coral snake
ribose
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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