Infliximab - Remicade; cA2; Avakine; tumor necrosis factor monoclonal antibody, recombinant
Status - approved; marketed
Organizations involved:
Centocor B.V. – Manuf.
Centocor, Inc. (Jannsen) – R&D; Tech.; USA mark.
Ortho-McNeil Pharmaceutical, Inc. – USA mark.
Johnson & Johnson Co. – Intl. mark.; Parent
Schering-Plough Corp. – Former
Merck & Co., Inc. – Intl. mark.;Parent.
Gallus Biopharmaceuticals, LLC – Manuf.
Mitsubishi Pharma . – Asia mark.; Japan mark.
Tanabe Seiyaku Co., Ltd. – Former
Domantis Ltd. – R&D; Tech
GlaxoSmithKline Ltd. - Parent
Peptech Ltd. – Patent dispute; Parent
Sandoz Inc. – Patent dispute
Novartis AG – Parent
Lonza Biologics plc – Tech.
Alusuise-Lonza Group – Parent
New York University – Tech.
Weizmann Institute of Science – Tech.
Genentech, Inc. – Tech.
Merck Serono S.A. – Tech.; Parent
University of Glasgow – Tech.
DRI Capital – Tech.
Royalty Pharma AG – Tech.
Inwest Investments Ltd. – Parent
New York Blood Center, Inc. – Tech.
Serono International S.A. – Former
Cross ref.: See the entry for Monoclonal Antibodies (#300). See also the entries for other tumor necrosis factor (TNF) inhibitors – etanercept (Enbrel); adalimumab (Humira), and anakinra (Kineret).
Description: Infliximab or Remicade (chimeric A2 or cA2 monoclonal antibody) is a lyophilized (freeze-dried) powder formulation of a recombinant chimeric (partially humanized) murine IgG1kappa monoclonal antibody glycoprotein having specificity for human tumor necrosis factor alpha (TNF-alpha) produced by a transformed murine SP2/0 cells (c168A; ATCC CRL 8287). Infliximab involves the variable or antigen-binding region of a murine immunoglobulin G1 (IgG1) monoclonal antibody (designated A2) with high-affinity and specificity for TNF-alpha, and the constant (Fc) or framework regions of human IgG1kappa immunoglobulin (i.e., murine variable region swapped with the human variable region). Infliximab is produced by the c168A cell line cultured by continuous perfusion, with viral inactivation by solvent detergent treatment (with tri-n-butyl phosphate and polysorbate 80) and steps for removal of viruses, e.g., nano- or ultrafiltration. Infliximab contains approximately 30% murine variable region amino acid sequence, which confers antigen-binding specificity to human TNF-alpha. The remaining 70% corresponds to a human IgG1 heavy chain constant region and a human kappa light chain constant region.
Infliximab binds specifically to human TNF-alpha with an association constant of 1010 M-1. From binding assays of infliximab and recombinant human TNF-alpha, the affinity constant was calculated to be 1.8 x 109 M-1. Infliximab has an a molecular weight of ~149,100 Daltons (149.1 kDa). The avidity and epitope specificity of infliximab are derived from the variable region of the A2 murine antibody. Infliximab binds to and neutralizes the cytotoxic effects of both natural and recombinant human TNF-alpha in a dose dependent manner. The use of the human IgG1 Fc region framework improves allogeneic antibody effector function; increases the circulating serum half-life of the antibody; and decreases the immunogenicity of the antibody (reducing human mouse antibody or HAMA rejection-like reactions).
Remicade is packaged in 20 ml vials, each containing 100 mg infliximab and excipients – 500 mg sucrose, 0.5 mg polysorbate 80 (Tween 80), 2.2 mg monobasic sodium phosphate, and 6.1 mg dibasic sodium phosphate. Remicade contains no preservatives. Following reconstitution with 10 mL of Sterile Water for Injection, USP, the resulting pH is ~7.2, and Remicade is administered by intravenous infusion. The dating period when stored at 2-8˚C (refrigerated) is 18 months from the date of manufacture,defined as the date of final sterile filtration of the final formulated product. The bulk product may be stored frozen for up to 12 months at -40˚C.
Nomenclature: TNF Mab, rDNA [BIO]; Remicade [TR]; infliximab [FDA]; tumor necrosis factor-alpha monoclonal antibody [SY]; chimeric IgG1 anti-human TNF MAb cA2 [SY]; cA2 [SY]; TNF-alpha MAb cA2 [SY]; Avakine [TR former; dropped because it suggested the product was a cytokine]; CentTNF [TR former foreign]; 57894-0030-01 [NDC]
Biological.: TNF (in its alpha and beta forms) is one of the dominant cytokine proteins that plays an important role in the cascade of reactions that cause the inflammatory process, including in rheumatoid arthritis. Tumor necrosis factor-alpha (TNF-alpha, also known as cachectin) and tumor necrosis factor-beta (TNF-beta, also known as lymphotoxin-alpha) are homologous mammalian endogenous secretory proteins capable of inducing a wide variety of effects on a large number of cell types. The similarities in the structural and functional characteristics of these two cytokines have resulted in their collective description as “TNF.”
Tumor necrosis factor-alpha (TNF-alpha) is a naturally occurring cytokine involved in normal inflammatory and immune responses. TNF-alpha is produced by numerous cell types, including monocytes and macrophages, and was originally identified based on its capacity to induce the necrosis of certain mouse tumors. Subsequently, a factor termed cachectin, associated with cachexia, was shown to be the same molecule as TNF-alpha. TNF-alpha has been implicated in mediating shock, sepsis, infections, autoimmune diseases, transplant rejection, and graft-versus-host disease. TNF-alpha exists as a 17 kDa secreted form and a 26 kDa membrane associated form, the biologically active form of which is composed of a trimer of noncovalently bound 17 kDa molecules.
Biological activities attributed to TNF-alpha include: induction of pro-inflammatory cytokines, such as IL-1 and IL-6; enhancement of leukocyte migration by increasing endothelial layer permeability and expression of adhesion molecules by endothelial cells and leukocytes; activation of neutrophil and eosinophil functional activity; and induction of acute phase and other liver proteins.
Two distinct TNF cellular receptors (TNFRs) exist naturally as monomeric molecules on cell surfaces and in soluble forms – Type I TNFR (TNFRI) and Type II TNFR (TNFRII). The mature full-length human TNFRI is a glycoprotein having a molecular weight of about 75-80 kDa. The mature full-length human TNFRII is a glycoprotein having a molecular weight of about 55-60 kDa) TNF-alpha was first shown to bind to a common receptor on the human cervical carcinoma cell line ME-180 (Aggarwal, et al., Nature 318:665, 1985). Hohmann et al. (J. Biol. Chem. 264:14927, 1989) reported that there are two different cell surface receptors (I and II) for TNF on different cell types. Two separate groups reported cloning and expression of a human 55 kDa TNFRII (Loetscher et al., Cell 61:351, 1990; Schall et al., Cell 61:361, 1990). TNFRI has also been cloned (Smith et al., Science 248:1019, 1990). Cloning enabled purification and study of soluble TNFR proteins. TNF antagonists, such as soluble TNF receptors, antibody-like TNF binding proteins (e.g., etanercept/Enbrel), and TNF monoclonal antibodies (e.g., infliximab/Remicade and adalimumab/Humira), bind to TNF and prevent TNF from binding to cell membrane TNF receptors. TNF-beta (lymphotoxin-alpha) uses the same cellular receptors as TNF-alpha. However, infliximab (unlike etanercept/Enbrel) is specific for TNF-alpha and does not bind or neutralize TNF-beta.
In rheumatoid arthritis, synovial membranes for unknown reasons start to express high levels of glucose-6-phosphate dehydrogenase, which breaks the disulfide bonds in cell membranes. Proteolytic enzymes leak from cellular lysosomes and cause damage to surrounding bone and cartilage. The body responds by producing TNF-alpha and other cytokines, which exacerbate the disease symptoms. Chronic rheumatoid joint inflammation associated with TNF-alpha frequently results in destructive lesions of cartilage and peratricular bone, leading to physical disability. TNF-alpha also stimulates production of other pro-inflammatory cytokines, e,g., interleukin-2.
TNF has been implicated in the progression of rheumatoid arthritis because it is present in the synovial membranes of patients with the disease. In patients with rheumatoid arthritis, joint damage is evident as narrowing of the joint space between bones and erosion of the bones at the joint space. Clinical data demonstrate that Remicade inhibits both joint erosions and joint space narrowing. This can provide considerable benefit to patients while also improving the pain and stiffness of rheumatoid arthritis.
TNF has been found in the mucosa and stools of patients with Crohn’s disease, and is thought to have an important role in this disease. Fecal excretion of TNF-alpha in the stool of Crohn’s disease patients correlates with increased disease activity (fistulas).
Infliximab binds with high affinity (10 x 10 M-1) to TNF-alpha in its soluble and transmembrane (cell membrane-associated) forms, resulting in neutralization of the activity of TNF-alpha. Binding of soluble TNF-alpha to infliximab prevents TNF-alpha from binding to TNF-alpha cellular receptors. In vitro, infliximab inhibits TNF-alpha activity in multiple bioassays and cell types, including B- and T-lymphocytes, fibroblasts, neutrophils, and endothelial cells. Binding of infliximab to TNF-alpha is highly specific and dose dependent. Cells expressing transmembrane TNF-alpha bound by infliximab can be lysed in vitro by complement or effector cells.
In the May 2002 issue of Pharmacology, Centocor researchers compared the mode of action of Remicade (infliximab) and Enbrel (etenercept), involving a p75 TNF receptor linked to the Fc portion of human IgG1 (TNFr:Fc) that binds TNF alpha and beta. Up to three infliximab molecules can bind one The relative instability and high disassociation rate of the p75 receptor-etanercept leads to the release of disassociated active TNF-alpha, which remains bioactive. Also, etenercept binding is restricted to the trimer form of soluble TNF alpha, while infliximab binds both monomer and trimer forms. These differences may explain some of the differences in activity and efficacy between Enbrel and Remicade, with Remicade showing signicantly improved efficacy for some indications:, e.g., psoriasis.
Companies.: Remicade was developed by Centocor, Inc. Centocor is now majority owned by Johnson & Johnson Co. (J&J). Remicade was originally manufactured by Centocor, Inc., CBER/FDA est. no. 1242, at company facilities in Leiden, the Netherlands. Subsequently, a second facility was apparently added at Centocor in Malvern, PA. Manufacture was also added at Centocor facilities in St. Louis, MO. This St. Louis facility was sold to
Gallus Biopharmaceuticals in March 2011, which continues manufacture as a CMO.
Remicade is co-promoted in the U.S. by Centocor and Ortho-McNeil Pharm., Inc. (both J&J companies) for rheumatoid arthritis indications:. Centocor/J&J has an option to grant U.S. co-promotion rights to Schering-Plough Corp. (but with its acquisition by J&J, this seems unlikely).
Schering-Plough Corp. (merged into Merck in 2009) has rights to market Remicade for all indications: in all international (non-U.S.) markets worldwide, except in Japan and parts of Asia. Schering-Plough paid Centocor $20 million up front and provided $30 million in milestone payments. Both Centocor and Schering-Plough share profits from non-U.S. sales, weighted in favor of Schering-Plough, and share certain development costs (weighted in favor of the company that benefits the most, e.g., Schering-Plough would pay for Phase IV trials in Europe). It has been reported that prior to concluding this license, with little historical data to work from, Centocor had projected ex-U.S. sales (for RA and Crohn’s) to be about $1 billion/year, which Schering-Plough estimated only ~$300 million/year. Rather than negotiating based on a compromised number, or walking away from the deal, Centocor took a lower percentage on sales up to the number Schering-Plough was predicting, with the percentage increasing after this. To support its projection, Centocor conducted a survey of 500 rheumatologist asking if they would prescribe a product meeting the profile for Remicade, what would be a fair price, etc. Centocor was proven correct, with $942 million sales by Schering-Plough in 2005.
Tanabe Seiyaku Co., Ltd., was granted certain Japanese co-marketing and other Asian marketing rights by Centocor in 1993. In Feb. 2005, the 2003 agreement was modified, with Tanabe Seiyaku receiving exclusive rights to develop and market Remicade for all indications: including ankylosing spondylitis, psoriasis and ulcerative colitis. In fall 2006, Tanabe Seiyaku was acquired by and merged into Mitsubishi Pharma.
In April 2001, Drug Royalty Corp. Inc. (DRC), now now DRI Capital, for $7 million acquired from an unspecified inventor an unspecified interest in royalty payments from sales of Remicade for 15 years (although, apparently effectively limited to 13 years due to patent expirations). DRC was acquired by Inwest Investments Ltd. in March 2002.
In May 2007, Royalty Pharma AG purchased all future royalties due to New York University from its licensing or Remicade-related technology to Centocor/J&J (see the Tech. transfer section below). Royalty Pharma paid NYU $650 million in cash, along with additional payments should yearly sales of Remicade exceed certain agreed sales levels.
In Dec. 2007, Centocor, Inc., revised its original 1998 development and marketing agreement with Schering-Plough Corp. (now part of Merck). Upon regulatory approval of golimumab (seee related entry) in the EU, the revised agreement will extend the duration of Schering-Plough's rights to exclusively market Remicade in its current marketing territories outside the U.S. beyond 2014 to match the current duration of its exclusive marketing rights for golimumab product, which will extend for 15 years after the first golimumab commercial sale. Centocor will receive a progressively increased share of profits on Schering-Plough's distribution of both products between 2010 and 2014, and remaining fixed thereafter for the remainder of the term. Centocor/J&J continues to exclusively market Remicade in the U.S.
In July 2008, Johnson & Johnson and Schering-Plough Corp. extended their distribution agreement for Remicade for another 15 years for 15 years after market launch of golimumab, another TNF inhibitor from Centocor/J&J (see related entry). Centocor will receive a progressively increased share of profits on Schering-Plough's distribution of both products in the Schering-Plough marketing territory between 2010 and 2014, and remaining fixed thereafter for the remainder of the term.
In May 2009, with Merck recently acquiring Schering-Plough, Johnson & Johnson notified Merck that it is seeking arbitration to end its partnership with Schering-Plough for Remicade.
In April 2011, Johnson & Johnson provided additional information on its amended agreement with Merck regarding distribution rights for Remicade (and Simponi) in markets outside the United States. The amended agreement concluded the arbitration, which had been filed by J&J in May 2009; and uncertainty related to Merck had tended to depress its share price in the prior year. The deal doesn’t affect the U.S., where J&J has exclusive rights to the two products. Merck will keep exclusive marketing rights in 70 percent of the areas where it now sells the Remicade while J&J’s share of profit from those sales rises to 50 percent. In areas where Merck is keeping rights, J&J will get an equal share of profits starting July 1, up from the 42 percent it previously received. Merck will relinquish exclusive marketing rights to the drugs in Canada, Central and South America, the Middle East, Africa and the Asia-Pacific area starting July 1, while keeping rights in Europe, Russia and Turkey. The division of contribution income on sales was amended to a 50 percent/50 percent split between Johnson & Johnson and Merck, from July 1, 2011, through Oct. 1, 2024. Johnson & Johnson will begin recording 2011 sales of product from the relinquished territories on July 1, 2011. Johnson & Johnson will receive a one-time, $500 million payment from Merck during the second quarter of 2011.
In Oct. 2012, J&J reported it was investing about $225 million in upgrading its manufacturing facilities in Puerto Rico. The Gurabo plant will manufacture Remicade. Current Remicade manufacturing facilities in Switzerland will then apparently be terminated.
Manufacture: The A2 murine hybridoma was initially prepared by repeated immunization of a BALB/c mouse with recombinant TNF-alpha, fusion of isolated spleen cells with murine myeloma SP2/0 cells in the presence of polyethylene glycol (PEG), culture of the resulting fused hybridoma cells, subcloning at limited dilution on mouse feeder cells, and isolation of the A2 hybridoma which expresses the murine A2 monoclonal antibody.
The recombinant human-murine chimeric A2 (cA2) monoclonal antibody was developed as described in Knight, E.M., et al., “Construction and Initial Characterization of a Mouse-Human Chimeric Anti-TNF Antibody,” Molecular Immunology, vol. 30, no. 16, p. 1443-53, 1993. Gene sequences for the variable (antigen-binding) portion of the murine A2 monoclonal antibody and sequences from constant or framework regions of human immune globulin G (IgG) were inserted into plasmids. Expression plasmids with appropriate chimeric heavy and light chains were transfected into the murine myeloma SP2/0 cell line. The resulting transformed cells express chimeric A2 monoclonal antibody (cA2; infliximab) with improved TNF-alpha binding and neutralization compared to the original A2 antibody.
Manufacturing begins with removal and thawing of a vial of plasmid-transformed murine SP2/0 cells (ATCC CRL 8287) from the manufacturer’s Working Cell Bank. With the exception of expected murine endogenous retroviruses, all cell banks are free of microbial contaminants (bacterial, fungal, mycoplasma), adventitious murine viruses, and human, bovine and caprine viruses. Two expression vectors are used carrying infliximab chimeric light chain or heavy chain genes. SP2/0 cell subclone C-168C was selected as the host cells. Transformed SP2/0 cells are cultured continuously in perfusion bioreactors (culture medium constantly removed and replaced by fresh medium) using a medium containing bovine-derived materials (sourced from BSE/TSE-free countries only). The transformed SP2/0 cells synthesize, assemble, glycosylate, and secrete immunoglobulin encoded by the transfected immunoglobulin genes. The culture fluid supernatant is clarified by filtration.
Bioprocessing has been reported to involve between 5-20 bioreactors each 500 L at Leiden operating in internal spin-filter mode, and 8 x 1,000 L bioreactors at Malvern, PA, operating in external spin-filter perfusion mode {Farid, S., Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production, presented at ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013].
Purification is performed by a combination (Protein A-Sepharose) of affinity and ion-exchange chromatography. The infliximab IgG is eluted with 0.1M citrate, pH 3.5, inhibited or neutralized with 1M Tris, and dialyzed into phosphate buffered saline (PBS). This is followed by two virus removal/inactivation steps – solvent-detergent treatment (with tri-n-butyl phosphate and polysorbate 80; see the Plasma SD entry for further information) and removal of viruses by nano- or ultrafiltration. The purified bulk contains 30-60 mg/mL of infliximab in a solution of 0.01 M sodium phosphate, 10% sucrose, and 0.01% polysorbate 80 (residual from virus inactivation), with a pH of 7.2. The bulk is diluted with formulation buffer, aseptically filtered, dispersed into vials, lyophilized, and sealed. Testing is performed throughout the manufacturing process to ensure the product meets specifications for identity, strength, quality, purity, and potency.
Remicade is manufactured in production batches of 10,000 to 63,000 vials. For finishing, frozen infliximab pre-formulated bulk (PFB) is thawed, formulated to the final batch size, sterilized by filtration, filled and dried by lyophilization to yield finished product, 100 mg/vial.
FDA class: Biologic BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19980824; first approval; accelerated approval; BLA (ref. no. 98-0012); orphan designation (expires 8/24/2005); Indication = treatment of moderately to severely active Crohn’s disease for the reduction of signs and symptoms, in patients who have had an inadequate response to conventional therapy; and for the treatment of patients with fistulizing Crohn’s disease for the reduction in the number of draining enterocutaneous fistula(s)..
Date = 19991110; BLA supplement; Indication = for reduction in signs and symptoms of rheumatoid arthritis in patients who have had an inadequate response to methotrexate
Date = 20001229; BLA supplement; Indication = inhibition of progression of structural damage in patients with rheumatoid arthritis with an inadequate response to methotrexate
Date = 20020227; BLA supplement; Indication = improving physical function in patients with moderately to severely active rheumatoid arthrits who have had an inadequate response to methotrexate
Date = 20020628; BLA supplement; Indication = reducing signs and symptoms, and inducing and maintaining clinical remission in patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy
Date = 20030401; BLA supplement; Indication = approval for reducing the number of draining enterocutaneous and rectovaginal fistulas and for maintaining fistula closure in patients with fistulizing Crohn’s disease using an 8-week maintenance dosing regimen
Date = 20041221; BLA supplement; Indication = treatment of active ankylosing spondylitis
Date = 20050516; BLA supplement; Indication = arthritis in patients with psoriatic arthritis
Date = 20050916; BLA supplement; Indication = treatment of ulcerative colitis
Date = 20050516; BLA supplement; Indication = second line pediatric moderate to severe Crohn’s disease in children resistant to other treatments, e.g., aminosalicylates, steroids, and immunomodulator drugs (e.g., azathioprine and 6-mercaptopurine)
Date = 20060814; BLA supplement; Indication = inhibiting progression of structural damage and improving physical function in patients with psoriatic arthritis, in addition to reducing signs and symptoms of active arthritis
Date = 20060926; BLA supplement; Indication = treatment of severe psoriasis
Date = 20061019; BLA supplement; Indication = for maintaining clinical remission and mucosal healing in patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response to conventional therapy
Date = 20090804; BLA supplement; Indication = addition of stronger warnings in the prescribing information for all TNF blockers, including a 'black box' warning
Date = 20110923; BLA supplement; Indication = treatment of ulcerative colitis in pediatric patients who have had an inadequate response to conventional therapy (with orphan designation granted for this indication)
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling, 6/25/2012]:
Crohn’s Disease:
Status: The original BLA was filed on Dec. 30, 1997, received priority review status; and was approved on Aug, 24, 1998, with orphan designation; review time = ~7.8 months (~.65 year). Remicade was launched on Sept. 24, 1998. As part of its initial approval, Centocor was required to conduct Phase IV studies to examine retreatment and maintenance in adults and conduct studies of Remicade in pediatric patients. Remicade is exempt from CBER/FDA lot release requirements.
The BLA supplement for treatment of rheumatoid arthritis was submitted on Jan. 26, 1999 and accepted for filing on March 26, 1999. The application included the pivotal Phase III ATTRACT trial, then the largest ever conducted with a biologic product for treatment of rheumatoid arthritis, with all patients then in their second year of treatment. The BLA supplement for Crohn’s disease was filed on Dec. 28, 2001 and received priority review.
As a result of post-approval Phase IV studies, in Nov. 1998 Centocor sent out a warning letter to U.S. physicians concerning delayed hypersensitivity observed in some Remicade patients treated long-term for Crohn’s disease. However, nearly all adverse effects occurred in patients having received an earlier liquid formulation in clinical trials. Delayed hypersensitivity has not been observed in patients treated with the marketed lyophilized formulation, and Centocor does not believe these adverse effects were relevant to the current formulation.
In Jan. 2003, Centocor, Inc./J&J received priority review (6 month approval target) for a BLA supplement for maintaining fistula closure in patients with fistulizing Crohn’s disease. Up to 30% of the estimated half-million in the U.S. with Crohn’s disease suffer from fistulas.
In April 2004, Ortho/J&J reported that Remicade is approved in 72 countries, indicating it is now approved in nearly all pharmaceutical markets worldwide.
In April 2004, FDA accepted filing of a BLA supplement for the treatment of ankylosing spondylitis (AS), a chronic, progressive and debilitating inflammatory disease that often leads to stiffening and subsequent fusion of the spine. This submission was based primarily on the results of the ASSERT (Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy) trial, which showed that patients with active AS treated with Remicade achieved improvement in signs and symptoms associated with their disease, including reduced spinal pain, increased physical function, and increased health-related quality of life.
On Sept. 30, 2004, FDA granted a supplemental BLA for approval of Remicade for first-line therapy in combination with methotrexate for the treatment of early rheumatoid arthritis (RA) patients with moderately-to- severely active disease. The prior RA indication was for patients having inadequate response to methotrexate monotherapy. The sBLA was filed in April 2004, and was based on results form the ASPIRE (Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset) trial.
In Oct. 2004, Centocor/J&J issued a warning letter to physicians that patients receiving Remicade for rheumatoid arthritis (RA) are at increased risk for lymphoma, and this warning was added to the product labeling. This essentially meant that Remicade has a safety profile similar to its main competitors for RA, Enbrel and Humira, with each of these having similar warnings.
On Dec. 1, 2004, FDA accepted a supplemental BLA for approval of Remicade for treatment of psoriatic arthritis in patients with active disease. This was based on results from two studies – IMPACT (Infliximab Multinational Psoriatic Arthritis Controlled Trial) and IMPACT 2.
Remicade received its first approval in the European Union (EU) on Aug. 13, 1999 for treatment of severe, active Crohn’s disease in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant, and for treatment of fistulizing Crohn’s disease in patients who have not responded despite a full and adequate course of therapy with conventional treatment. The application for EU approval for rheumatoid arthritis indications: was filed on Aug. 17, 1999, and approved in late June 2000. Remicade received EU approval in Feb. 2001 for use in combination with methotrexate for treatment of rheumatoid arthritis in patients with inadequate response to other drugs (e.g., methotrexate monotherapy). In May 2003, Remicade received EU approval for treatment of ankylosing spondylitis; and also approval of maintenance dosing to sustain clinical responses and remission in patients with severe active Crohn’s disease. In Oct. 2003, Remicade received EU approval for maintenance dosing to sustain clinical response in patients with active fistulizing Crohn’s disease responding to Remicade therapy. On June 21, 2004, Remicaid in combination with methotrexate received EU approval for first-line treatment of early rheumatoid arthritis. On Oct. 14, 2004, Remicade received supplemental EU approval for use in combination with methotrexate for the treatment of active and progressive psoriatic arthritis in patients who have responded inadequately to disease modifying anti-rheumatic drugs (DMARDs).
On May 17, 2005, FDA approved a supplemental BLA for use of Remicade to reduce the signs and symptoms of active arthritis in patients with psoriatic arthritis based largely on Induction and Maintenance of Psoriatic Arthritis Clinical Trial 2 (IMPACT 2). The application had received priority review, and Remicade has orphan designation for this indication. Along with this approval, Centocor, in consultation with FDA, added to the boxed warning in the labeling for Remicade a description of rare post- marketing cases of hepatosplenic T-cell lymphoma that have been reported in adolescents and young adults with Crohn’s disease.
In Sept. 2005, the European Union granted supplemental approval of Remicade for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or have a contraindication to, or are intolerant of other systemic therapy including cyclosporine, methotrexate or psoralen plus ultraviolet light A (PUVA).
On Sept. 16, 2005, FDA approved a supplemental BLA for Remicade for treatment of ulcerative colitis. Centocor had submitted the sBLA for REMICADE for UC to the FDA in March 2005, based on data from the ACT 1 and ACT 2 trials.
In Nov. 2005, FDA accepted a supplemental BLA for Remicade use in the treatment of moderate to severe plaque psoriasis. The application included data from two Phase III trials, EXPRESS and EXPRESS II.
In Feb. 2006, the European Union approved Remicade for a new indication – treatment of patients with inflammatory bowel disease.
On March 2, 2006, the European Union (EU) approved a label extension for Remicade allowing for greater dosing flexibility in the treatment of rheumatoid arthritis (RA). For patients with an incomplete response to initial combination treatment with methotrexate and Remicade 3 mg/kg, the dose titration label extension permits increasing the Remicade dose stepwise from 3 mg/kg up to 7.5 mg/kg every 8 weeks, or to treat patients with 3 mg/kg as often as every 4 weeks.
In March 2006, the European Union (EU) approved Remicade for the treatment of moderately to severely active ulcerative colitis (UC) in patients who have had an inadequate response to conventional therapy, including corticosteroids and 6-MP or AZA, or who are intolerant to or have medical contraindications: for such therapies. The approval made Remicade the first biologic therapy approved to treat moderately to severely active UC in the EU, addressing an unmet medical need for patients who previously had limited treatment options.
In early April 2006, FDA FDA accepted for filing and granted priority review to a supplemental BLA for Remicade to treat pediatric Crohn’s disease. Remicade has orphan designation for this indication.
On July 26, 2006, Remicade received European Union (EU) supplemental approval as monotherapy in the treatment of active and progressive psoriatic arthritis (PsA) in patients who show intolerance to methotrexate or for whom methotrexate is contraindicated. This was largely based on one-year data from Infliximab Multi-National Psoriatic Arthritis Controlled Trial 2 (IMPACT 2), a Phase III clinical study of 200 patients, with active PsA; and two-year data from the original IMPACT Trial, upon which the initial approval of REMICADE in PsA was based. See the Trials section below
On Oct. 9, 2006, Remicade received European Union supplemental approval as a second-line therapy for the treatment of severe, active Crohn’s disease (CD) in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and/or an immunosuppressant, or who are intolerant to or have medical contraindications: for such therapies.
On Jan. 26, 2007, Tanabe Seiyaku Co., Ltd. received approval in Japan for Remicade treatment of Behcet’s disease complicated with refractory uveoretinitis which does not respond to conventional therapies. This is the first approval anywhere for this indication.
On Aug. 6, 2007, Remicade received European Union supplemental approval for a revised label including a description of improvement in nail psoriasis, as measured by the Nail Psoriasis Severity Index (NAPSI), and improvement in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and the 36-item short form health survey (SF-36).
In Nov. 2007, Centocor reported that Remicade had received approval in 88 countries
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 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.
Tech. transfer: New York University and Centocor/J&J are coassignees on a large number of TNF antibody-related patents (over 30 in mid-2009). These cover various antibody constructs and their therapeutic use, and include: 7,744,885, Methods of treating vascular inflammatory pathology using anti-TNF antibodies and fragments thereof; 7,425,330, Methods of inhibiting TNF.alpha. activity in the blood of a patient; 7,416,729, Methods of treating rheumatoid arthritis with anti-TNF antibodies; 7,404,955, Methods of inhibiting or neutralizing TNF.alpha. in patients with tissue injury; 7,374,761, Recombinant A2-specific TNF.alpha.-specific antibodies; 7,335,358, Methods of treating psoriasis with anti-TNF antibodies; 7,276,239, Recombinant A2-specific TNF.alpha.-specific antibodies; 7,252,823, Recombinant A2-specific TNF.alpha.-specific antibodies; 7,227,003, Anti-TNF antibody fragments; 7,226,593, Methods of treating cachexia with chimeric anti-TNF antibodies; 7,223,396, Methods of treatment of fistulas in Crohn's disease with anti-TNF antibodies; 7,214,376, Methods of inhibiting TNF.alpha. in patients with neoplastic disease; 7,204,985, Methods of treating disseminated intravascular coagulation by multiple administration of anti-TNF antibodies; 7,192,584, Methods of treating psoriasis with anti-TNF antibodies; 7,179,893, Recombinant anti-TNF-.alpha. antibodies; 7,179,466, Methods of treating rheumatoid arthritis by multiple administration of anti-TNF antibodies; 7,169,388, Methods of inhibiting TNF.alpha. in patients with cancer; 7,169,386, Methods of treating inflammation associated with viral infection with anti-TNF antibodies; 7,166,284, Methods of treating joint inflammation with anti-TNF antibodies; 7,160,995, DNA encoding anti-TNF antibodies and peptides; 7,160,543, Methods of inhibiting TNF-.alpha. in patients with Crohn's disease; 7,160,542, Method of treating psoriasis using human anti-TNF antibodies and fragments; 7,138,118, Methods of treating rheumatoid arthritis with anti-TNF antibodies; 7,135,179, Methods for treating sarcoidosis using anti-TNF antibodies and fragments thereof; 7,135,178, Methods of treating disseminated intravascular coagulation using anti-TNF antibodies; 7,128,908, Methods for treating systemic lupus erythematosus using anti-TNF antibodies and fragments thereof; 7,128,907, Methods of treating crohn's disease with anti-TNF antibodies; 7,101,674, Anti-idiotypic anti-TNF antibodies and related immunoassay methods; 7,070,775, Recombinant A2-specific TNF.alpha. specific antibodies; 6,991,791, Anti-TNF antibodies and peptides of human tumor necrosis factor; 6,835,823, Anti-TNF antibodies and peptides of human tumor necrosis factor; 6,790,444, Anti-TNF antibodies and peptides of human necrosis factor; 6,284,471, Anti-TNFa antibodies and assays employing anti-TNFa antibodies; 6,277,969, Anti-TNF antibodies and peptides of human tumor necrosis factor; 5,919,452, Methods of treating TNF.alpha.-mediated disease using chimeric anti-TNF antibodies; 5,877,006, DNAs encoding chimeric immunoglobulin light or heavy chains and fragments thereof having variable regions derived from monoclonal antibody 7E3, and vectors and host cells comprising same; 5,770,198, Platelet-specific chimeric 7E3 immunoglobulin; 5,698,195, Methods of treating rheumatoid arthritis using chimeric anti-TNF antibodies; 5,656,272, Methods of treating TNF-.alpha.-mediated Crohn's disease using chimeric anti-TNF antibodies;
U.S. patent 5,919,452, issued July 6, 1999, coassigned to New York University (New York, NY; inventors, Drs. Jan T. Vilcek and Junming Le) and Centocor, Inc., covers use of infliximab for inhibition of TNF-related disease. The exemplary claim (no. 1) states, “A method of treating TNF-alpha-mediated disease, other than disease resulting from infection, in a human comprising administering to the human an effective TNF-inhibiting amount of an anti-TNF chimeric antibody, wherein said anti-TNF chimeric antibody competitively inhibits binding of TNF to monoclonal antibody cA2.” NYU and Abbott subsequently received a large number of patents related to TNF inhibitors and their uses.
Drug Royalty Corp. Inc. (DRG), now DRI Capital, has purchased a portion of patent royalties from sales of Remicade. See the Companies section above.
Serono International S.A. (now Merck Serono S.A.) in July 2000 granted Knoll AG (now a subsidiary of Abbott Labs.) and Centocor Inc. co-exclusive licenses to patents covering monoclonal antibodies to tumor necrosis factor (TNF). Centocor made undisclosed cash payments to Serono, but does not pay royalties on sales of Remicade. Knoll will pay an undisclosed license fee, milestone payments and royalties on sales of products covered by the patents. In Jan. 2007, Merck KGaA acquired Serono, and the new company was renamed Merck Serono S.A. Centocor was granted the license as part of a settlement of litigation filed by Serono against Centocor in the District Court of The Hague (World Court), the Netherlands. The licensed patents resulted from a research alliance between Serono and the Weizmann Institute of Science.
Centocor in the 2nd quarter of 1998 acquired from Celltech Biologics plc, now assigned to Lonza Biologics plc, a subsidiary of Alusuise-Lonza Group, a nonexclusive license for Celltech’s “Boss” patents covering the glutamine synthetase (GS) recombinant mammalian cell selection, amplification and expression system. GS technology involves dominant selectable markers for use in amplification of genes and transforming host cell lines to glutamine independence. See related patents including U.S. 5,770,359 and 5,747,308. The technology is coassigned to the University of Glasgow (which presumably shares in royalties). The GS gene is used in recombinant vectors as a marker along with other gene(s) for expression, with only successfully transformed murine SP2/0 cells (normally deficient in glutamine synthetase) being capable of producing their own GS and surviving in glutamine-deficient culture media. Over forty companies have licensed GS System technology for various uses.
The situation concerning recombinant chimeric/humanized monoclonal antibody patents, licensing, cross-licensing and disputes is very complex. Centocor/J&J has apparently licensed the “Cabilly” patents (4,816,567 and 6,113,415), assigned to Genentech, Inc., concerning recombinant monoclonal antibody design and expression. Genentech currently has a very strong patent position concerning chimeric/humanized monoclonal antibodies. The company recently prevailed in a lawsuit resulting in it receiving a new “Cabilly” patent (6,113,415) and revocation of a similar patent assigned to Celltech Group plc. See the Tech. transfer (rDNA) section of the Monoclonal Antibodies entry (#300) for further information.
Solvent detergent viral inactivation technology was developed by and nonexclusively licensed from the New York Blood Center. For example, see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma) for further information about solvent-detergent viral inactivation, useful primarily for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Centocor has licensed recombinant TNF monoclonal antibody technology from Peptech Ltd., including U.S. 6,498,237; 6,451,983; and 6,448,38, each entitled “Tumor necrosis factor antibodies,” and 6,593,458, “Tumor necrosis factor peptide binding antibodies,” assigned to Peptech. These patents claim TNF monoclonal antibodies and fragments that bind to mature human TNF and specific portions of TNF. Prior related/similar patents assigned to Peptide Technology, Ltd., now Peptech, include 5,644,034; 5,959,087; and 6,416,757. These invention originated from Domantis Ltd., 36.1% owned by Peptech. Domantis was acquired by GlaxoSmithKline (GSK) in Dec. 2006 for £230 million. Peptech started anti-TNF research in.1988, and holds TNF antibody patents in Europe, Canada, Australia and the U.S. In the U.K., Peptech received a Supplementary Protection Certificate (SPC; patent extension) for EP486526.
In Nov. 2002, J&J, parent of Centocor, decided it was not infringing Peptech’s patents. Until the matter is resolved, Centocor is refusing to pay Peptech royalties on Remicade sales. It had previously paid about $30 million in royalties to Peptech starting in 2001 for sales of Remicade in Europe, Canada and Australia. Abbott Labs. has similarly licensed TNF Mab technology from Peptech and refused to make royalty payments from its sales of Humira, but this dispute has been resolved largely in favor of Peptech. In Sept. 2003, Peptech initiated binding arbitration proceedings against Centocor/J&J concerning its U.S. and European patents and licensing royalties. A final decision was expected in mid-2004.
In Aug. 2005, Dr. Jan T. Vilcek, New York Univ., one of the inventors of infliximab, donated (pledged) $105 million to the New York University School of Medicine, from his share of patent royalties.
U.S. patent protection for Remicade was projected by Decision Resources to expire in 2014, and in European countries in 2014. However, with diverse entity/active agent, use, manufacturing process, formulation and other patents, this may well be an oversimplification of the patents that may be expected to be asserted against competitors.
Starting in late 2013, the first patent disputes related to eventual biosimilars launch in the U.S. were filed. A second biosimilars-related U.S. lawsuit was filed in April 2014, Celltrion Healthcare Co., Ltd. and Celltrion, Inc. (collectively “Celltrion”) filed a Complaint for Declaratory Judgment in the U.S. District Court for the District of Massachusetts seeking a judgment with respect to certain patents allegedly covering Janssen Biotech, Inc.’s (“Janssen’s”) biological product REMICADE. The Complaint marks the beginning of the second lawsuit that will undoubetedly bring into play the complex patent resolution provisions added to the PHS Act by the Biologics Price Competition and Innovation Act of 2009 (“BPCIA”). The BPCIA created a pathway for the submission and approval of biosimilar versions of brand-name reference products under a so-called Section 351(k) application.
Trials: In the pivotal Phase III trial for Crohn’s disease supporting original approval, improvement in patients having received Remicade was measured in terms of the number of liquid or soft stools, number and severity of abdominal cramps, and the overall sense of well-being. Patients benefited most from treatment within a two to four-week period following a single dose. The percentage of patients who maintained benefits decreased over the next few months. In another trial, Remicade reduced the number of draining fistulas in some cases of Crohn’s disease – a benefit that lasted five months at most.
The pivotal Phase III ATTRACT trial for rheumatoid arthritis (RA; supporting the Jan. 2001 approval for RA) showed that over a 30-week period Remicade reduced signs and symptoms of rheumatoid arthritis in 52% of patients vs. 20% of controls receiving placebo, with all patients continuing conventional methotrexate treatment. ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis with Concomitant Therapy) was a double-blind, placebo-controlled, randomized clinical trial in 428 patients at 34 clinical sites in N. America and Europe. It evaluated the efficacy and safety of Remicade in combination with methotrexate in patients with active rheumatoid arthritis despite treatment with methotrexate. Progression of joint damage was measured radiographically using the van der Heijde modified Sharp system, based on changes in joint-space narrowing and bone erosion, on a 5-point scale (higher score = more damage). Among all Remicade plus methotrexate treatment groups (n=285), an overall median change from baseline for radiographic scores of 0.0 (no progression) was reported, compared to a median change of 4.0 (significant progression) for patients (n=63) treated with methotrexate alone. A total of 53% of Remicade patients demonstrated 0% progression. Remicade was well tolerated and side effects were minimal.
The July 2002 approval of Remicade for long-term delay of remission in Crohn’s disease (CD) was based on 54-week data from the ACCENT I trial, the largest study of a biologic therapy ever conducted in this disease, involving 545 patients with moderate to severe CD at centers in N. America, Europe, and Israel. The trial evaluated Remicade as a maintenance therapy for CD, and the effect of a maintenance regimen on steroid use and health-related quality of life.
Results from a trial demonstrating the safety and efficacy of Remicade in maintaining fistula closure when administered every eight weeks in patients with fistulizing CD were reported in the New England Journal of Medicine, 350(9):876-85, Feb. 26, 2004. Nearly twice as many patients who received Remicade as a maintenance therapy every eight weeks had complete and durable fistula closure compared with patients who received placebo maintenance in the 54-week ACCENT II study (36% vs.19%, respectively). This was a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy of infliximab maintenance therapy in 306 adult patients with Crohn’s disease and one or more draining abdominal or perianal fistulas of at least three months’ duration. The primary endpoint was the time to the loss of response among patients who had a response at week 14 and underwent randomization. Time to loss of response was significantly longer for patients who received infliximab maintenance therapy than for those who received placebo maintenance (more than 40 weeks vs. 14 weeks, p <0.001). At week 54, 19% of patients in the placebo maintenance group had a complete absence of draining fistulas, compared with 36% of patients in the infliximab maintenance group (p = 0.009).
In May 2004, the SONIC (Study of Immunomodulator Naïve patients in Crohn’s Disease) trial was initiated to evaluate the efficacy of Remicade vs. azathioprine, a conventional immunosuppressive agent, alone and versus the combination of both drugs for the treatment of patients with Crohn’s disease. SONIC is the first ever trial to evaluate a biologic vs. a conventional therapy in Crohn’s disease.
In June 2004, results from the ASSERT (Ankylosing Spondylitis Study for the Evaluation of Recombinant Infliximab Therapy) trial were reported. Patients with active ankylosing spondylitis (AS) treated with Remicade achieved significant improvement in signs and symptoms, with over 60% of treated patients showing improvement in the AS assessment (ASAS 20) measure that includes spinal pain and function, vs.19% of patients receiving placebo. Treated patients also experienced improvement in spinal mobility. Two subanalyses of ASSERT showed that treated patients had improved productivity, including reduction in missed work days, and improved quality of life.
Results from two studies, IMPACT (Infliximab Multinational Psoriatic Arthritis Controlled Trial) and IMPACT 2, formed the basis for Centocor’s sBLA filing for psoriatic arthritis. The randomized, double-blind, placebo-controlled IMPACT trial evaluated Remicade in 104 patients with active psoriatic arthritis (affecting at least five joints). Patients received Remicade 5mg/kg or placebo at weeks 0, 2, 6, and 14. Patients initially receiving placebo were started on Remicade induction and maintenance treatment at week 16. Significant improvements in arthritis among patients receiving Remicade were seen based on ACR 20, 50, and 70 response criteria. Thirty-eight patients with active skin disease experienced significant improvement in their psoriasis. Remicade also reduced the progression of structural damage, as assessed by x-rays, in the 70 trial participants that had evaluable x-rays at baseline and week 50. A van der Heijde-Sharp scoring method was modified for psoriatic arthritis and used to determine bone erosion, joint space narrowing, and total radiographic scores. Based on this, mean annual progression was reduced from a predicted rate of 5.8 points per year to a rate of –1.8 points per year with Remicade. Almost 85% of patients in both treatment groups experienced no progression in structural damage, which was defined as an increase in score of 0.5 or less compared to baseline. The number of patients experiencing adverse events in IMPACT (and IMPACT 2) was similar between the Remicade and placebo groups.
IMPACT 2 was a multi-center, randomized, double-blind, placebo-controlled, Phase III trial of Remicade in patients with active psoriatic arthritis who had inadequately responded to disease-modifying anti-rheumatic drugs (DMARDs) or nonsteroidal anti-inflammatory drugs (NSAIDs). Patients who received Remicade 5mg/kg experienced improvements in joint and skin disease as early as week two of treatment. At week 14, ACR 20 responses were achieved in 58% of patients receiving Remicade and 11% of patients receiving placebo (p <0.001). ACR 70 responses were attained in 27% of patients in the Remicade group and 2% of patients in the placebo group (p <0.001). A 75% or greater improvement in Psoriasis Area and Severity Index (PASI) was seen in 63.9% of Remicade-treated patients and 2.3% of placebo-treated patients (p <0.001); and 39% of patients treated with Remicade developed at least a 90% improvement in PASI, while no patients in the placebo group achieved this level of improvement (p <0.001). A 100% improvement in PASI score was seen in 21% of patients in the Remicade group. Responses occurred regardless of the baseline level of joint involvement or methotrexate use.
In Nov. 2004, results were reported from a study based on nearly 30,000 Crohn’s disease cases derived from a nationwide reimbursement database (2002-2003). Crohn’s disease patients taking Remicade every eight weeks were found to have only marginally increased their doses over time. The annual costs of maintenance therapy also remained relatively stable, with little variability by site of infusion or payer status.
Approvals: for for the treatment of moderately to severely active ulcerative colitis (UC) in patients who have had an inadequate response to conventional therapy are primarily based on data from the ACT 1 and ACT 2 (Active Ulcerative Colitis Trial) trials. ACT 1 and ACT 2 were multicenter, randomized, double-blind, placebo-controlled, Phase III trials conducted to evaluate the safety and efficacy of Remicade for the treatment of adult patients with moderately to severely active UC who experienced an inadequate response to conventional therapy. UC patients treated with Remicade can achieve mucosal healing and disease remission after failing conventional therapies. Results from ACT 1 and 2 were published in the the New England Journal of Medicine, Dec. 7, 2005. At week 8, among the 728 patients in the 54-week ACT 1 trial and the 30-week ACT 2 trial, statistically significant differences in the proportion of patients in clinical response, clinical remission, and with mucosal healing were shown in UC patients treated with Remicade vs. those receiving placebo. In particular, about two-thirds of UC patients treated with Remicade achieved the primary endpoint of clinical response, defined as improvement in signs and symptoms. More than half had mucosal healing and more than one-third were in clinical remission. In both ACT 1 and ACT 2, nearly one-quarter of Remicade patients receiving corticosteroids at baseline were in remission and steroid-free by week 30. In both ACT 1 and 2, a significantly greater proportion of patients treated with REMICADE compared with placebo achieved clinical response, clinical remission, and mucosal healing from week 8 through the end of each trial (week 54 in ACT 1 and week 30 in ACT 2).
The May 2005 supplemental approval for second-line pediatric Crohn;s disease was largely based on REACH (Randomized, Multicenter, Open-label Study to Evaluate the Safety and Efficacy of Anti-TNF Monoclonal Antibody REMICADE in Pediatric Subjects with Moderate to Severe Crohn’s Disease), a Phase III trial in 112 children with moderate-to-severe active Crohn’s disease. Previously, there were no approved biologic therapies for the treatment of pediatric Crohn’s disease. REACH showed unprecedented efficacy of Remicade in the treatment of these patients. In the REACH trial, 112 patients aged 6 -17 years with moderately to severely active Crohn’s disease, despite treatments with an immunomodulator +/- corticosteroids, received REMICADE 5 mg/kg at weeks 0, 2 and 6. At week 10, 103 patients who had responded to Remicade therapy were randomized to receive Remicade maintenance treatments either every 8 weeks (n=52) or every 12 weeks (n=51) through week 46. Nearly 90% (88.4%) of pediatric patients treated with 5 mg/kg at 0, 2 and 6 weeks achieved clinical response at week 10 when treated with Remicade, the trial’s primary end point. Also, some patients in the trial were able to reduce their corticosteroid dose.
In March 2006, results were reported from EXPRESS II (European Infliximab for Psoriasis [Remicade] Efficacy and Safety Study), a placebo-controlled, dose-ranging Phase III study of Remicade 3 mg/kg and 5 mg/kg in patients with moderate to severe plaque psoriasis. Every eight-week maintenance therapy resulted in greater long-term skin clearance compared with “as-needed” therapy regimens within each dose. At week 10, after infusions at weeks 0, 2 and 6, 70% of patients treated with Remicade 3 mg/kg and 75% of patients receiving 5 mg/kg achieved at least 75% improvement in psoriasis as measured by Psoriasis Area Severity Index (PASI 75), compared with 2% of patients receiving placebo (p <0.001). At week 50, patients receiving Remicade 5 mg/kg achieved the highest level of sustained PASI improvement with the majority of the patients achieving PASI 75 versus the 3 mg/kg eight-week maintenance therapy and the 3 mg/kg and 5 mg/kg “as-needed” therapy regimens. The study showed that most patients receiving Remicade maintenance therapy achieve long-term clinical response in psoriasis. Remicade may be more than twice as effective for plaque psoriasis as other biopharmaceuticals (e.g., Enbrel, Raptiva and Amevive), other than Humira with similarly robust data.
Remicade was approved by the FDA for the treatment of ulcerative colitis (UC) in Sept. 2005 based on results from two randomized, placebo-controlled, pivotal Phase III trials – (Active Ulcerative Colitis Trial) ACT 1 and ACT 2. Fifty-four week results from the ACT 1 trial demonstrated the long-term safety and efficacy of Remicade in patients with moderately to severely active UC, and found that Remicade not only induces clinical remission, but also maintains remission of symptoms up to one year. In each trial, 364 patients with active UC who were unresponsive to at least one standard therapy- including corticosteroids, immunosuppressants or 5-ASAs, were enrolled. Patients in ACT 1 and ACT 2 had evidence of moderate or severe UC. Patients were randomized to one of three groups: continued conventional therapy plus placebo infusions, continued conventional therapy plus Remicade 5 mg/kg infusions, or continued conventional therapy plus Remicade 10 mg/kg infusions. ACT 1 patients received the study agent at weeks 0, 2 and 6 and then every 8 weeks through week 46 and had their last evaluations at week 54. ACT 2 patients received the study agent at weeks 0, 2 and 6 and then every 8 weeks through week 22 and had their last evaluations at week 30. In Nov. 2006, results were reported from the Phase III ACT trails. In ACT 1, significantly higher proportions of patients receiving Remicade 5 mg/kg (69 percent) and 10 mg/kg (62 percent) achieved clinical response at week 8 versus patients receiving placebo infusions (37%; P <0.001 for both). At week 30, 52% of patients in the 5 mg/kg and 51% in the 10 mg/kg Remicade group were in clinical response versus 30% of placebo infusion group (P <0.001 and P <0.01, respectively). Reduction of hospitalizations in Remicade recipients was sustained through one year with ~50% lower mean number of hospitalizations (12 per 100 patients) compared with placebo (22 per 100 patients, P = 0.061). However, the first hospitalization among Remicade patients was longer compared with patients who received placebo (P = 0.032). Patients who responded and those who were in remission at one year had lower mean number of hospitalizations (no hospitalizations) vs. non-responders (23 per 100 patients, p <0.001) through one year of treatment. In ACT 2, significantly higher proportions of patients receiving Remicade 5 mg/kg (65 percent) and 10 mg/kg (69 percent) were in clinical response at week 8 versus 29 percent who received placebo infusions (P <0.001 for both). At week 30, 47 percent of patients receiving REMICADE 5 mg/kg and 60 percent receiving 10 mg/kg were in clinical response versus 26 percent of patients receiving placebo infusions (P <0.001 for both). Combined long-term data from ACT 1 and ACT 2 indicate that at week 30, patients treated with Remicade experienced fewer hospitalizations requiring high-dose corticosteroids than those treated with placebo. Among 484 Remicade-treated patients, there were 13 hospitalizations, and among 244 patients in the placebo group there were 19 hospitalizations (p = 0.025).
Remicade’s Aug. 2006 U.S. approval for further psoriatic arthritis indications: was based on one-year data from the double-blind, placebo-controlled trial IMPACT 2 and two-year data from the double-blind, placebo-controlled trial IMPACT (see above). IMPACT 2 showed that at week 24, Remicade-treated patients had less structural damage as assessed radiographically compared with patients receiving placebo (mean change -0.70 vs. 0.82, p < 0.001), and Remicade-treated patients were more than twice as likely to achieve a clinically meaningful improvement in physical function compared with patients receiving placebo (54% vs. 22%, respectively). In terms of the skin component of the disease, 50% of treated patients in IMPACT 2 maintained at least 75% improvement from baseline, as assessed by Psoriasis Area Severity Index (PASI 75), in psoriasis at one year, and 64% maintained PASI 75 through two years. Also, 42% of treated patients in IMPACT 2 achieved PASI 90, or near total skin clearance, at one year, and 48% achieved PASI 90 through two years.
In Feb. 2007, findings were reported from an integrated analysis of data from three pivotal, randomized, placebo-controlled trials showing that at week 10 more than three-quarters of patients with severe psoriasis receiving Remicade 3 mg/kg or 5 mg/kg achieved a 75% improvement in the chronic, inflammatory skin disease as measured by the Psoriasis Area Severity Index (PASI 75). Out of the 991 patients with severe disease as defined by a body surface area of at least 20%, 73% and 69% had received previous phototherapy or systemic therapy, respectively. At week 10, among these previously-treated patients with severe psoriasis treated with Remicade, 79% of those who had received prior phototherapy and 76% who had been treated with one or more systemic agents achieved PASI 75, compared with 3% and 1%, respectively, of placebo patients (p < 0.001 for both). A separate analysis from the European Phase III Infliximab for Psoriasis [Remicade] Efficacy and Safety Study (EXPRESS) trial showed that among study patients with psoriasis affecting the nails at baseline who were treated with Remicade 5 mg/kg, 7%, 26% and 45% had clearance of nail psoriasis at weeks 10, 24 and 50, respectively, compared with 5% of patients in the placebo group at week 24 (P = 0.0002). Nail disease occurs in up to 50% of people with psoriasis.
Disease: There are an estimated >550,000 patients in major markets (U.S., France, Germany, Italy, Spain, United Kingdom, and Japan) diagnosed with Crohn’s disease. Crohn’s disease (CD) is a seriously debilitating inflammatory disease of the gastrointestinal tract. Patients commonly experience abdominal pain, diarrhea, fever, rectal bleeding and other symptoms. Patients with active disease experience periodic worsening of symptoms and, sometimes, fistulating disease involving formation of abnormal intestinal passages between the intestine and the skin or other organs.
In Crohn’s disease, treatment with Remicade reduces infiltration of inflammatory cells and TNF-alpha production in inflamed areas of the intestine, and reduces the proportion of mononuclear cells from the lamina propria able to express TNF-alpha and interferon gamma. After treatment, patients with Crohn’s disease have decreased levels of serum interleukin-6 and C-reactive protein, compared to baseline. Peripheral blood lymphocytes from treated patients show no decrease in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients.
Ulcerative colitis (UC) is a chronic disease affecting >1.2 million people in the U.S. and Europe for whom there is no medical cure. UC is characterized by inflammation and ulceration of the inner lining of the colon. Symptoms can often include weight loss, severe — sometimes uncontrollable — bloody diarrhea, fatigue, and frequent abdominal pain. Alternative treatments are limited and, if conventional treatments do not control the progression of the disease, many patients may have to face surgical removal of the colon. UC is characterized by high costs, and often results in extended hospitalization and surgery.
Behcet’s disease is a refractory systemic inflammatory disease characterized by repeated episodes of relapses and recoveries, such as oral ulcer on the mucous membrane, dermatitis, uveoretinitis, and ulcer on the vulva. It is sometimes associated with inflammatory symptoms in the intestines, nerve, and vessel. Vision loss due to repeated ocular attacks threatens quality of life-threatening. Suppression of frequency of ocular attacks is of primarily importance in treatment. TNF-alpha is involved deeply in ocular attacks in uveoretinitis, and clinical trials have shown Remicade suppressed the frequency of ocular attacks in Behcet’s disease patients with refractory uveoretinitis.
Medical: For Crohn’s disease, the usual dose is 5 mg/kg as a single intravenous infusion induction regimen at 0, 2, and 6 weeks, followed by a maintenance regimen at the same dose every eight weeks. For rheumatoid arthritis, Remicade (in a combination regimen with methotrexate) is administered intravenously in 3 mg/kg doses at 0, 2 and 6 weeks, followed by a maintenance regimen at the same dose every eight weeks. In the first year of treatment, patients generally receive eight infusions. In subsequent years, patients receive six infusions.
The most common side effects of Remicade are related to the intravenous infusion itself and include rash, low blood pressure, chills, and chest pain. These symptoms were generally temporary. Other common side effects included infections, some serious. These generally respond to antibiotics. In addition, patients occasionally develop antibodies to infliximab, which may be associated in rare cases with temporary symptoms similar to systemic lupus erythematosus (SLE).
Enbrel, unlike some other TNF inhibitors, e.g., Remicade, is not effective for treatment of Crohn’s disease, in addition to RA. Enbrel is associated with a lower incidence of tubererculosis (due to immune suppression) than Remicade. These differences have been attributed to the ability of Remicade (and also Humira), but not Enbrel, to fix complement and lyse cells expressing membrane—bound TNF-alpha, such as lymphocytes. Similarly, Enbrel, but neither Remicade or Humira, can bind and neutralize TNF-beta (lymphotoxin).
Remicade is infused in the physician’s office, clinic, hospital, etc., unlike other biopharmaceuticals approved or in late-stage development for RA, e.g., Humira which is self-administered by the patient. As such, Remicade meets criteria for Medicare reimbursement, which is an important consideration because as many as 50% of patients with RA are eligible to receive Medicare benefits.
Centocor/J&J claims, “The safety and efficacy of REMICADE have been well established in clinical trials over the past 14 years and with more than 770,000 patients treated worldwide through commercial experience.“ Also, “Remicade is unique among available anti-TNF biologic therapies. Unlike self-administered therapies that require patients to inject themselves frequently, Remicade is the only anti-TNF biologic administered directly by caregivers in the clinic or office setting. In RA (3 mg/kg), CD [Crohn’s disease] (5 mg/kg), PsA [psoriatic arthritis] (5 mg/kg), UC (5 mg/kg), PCD [pediatric Crohn’s disease] (5 mg/kg) and [psoriasis] PsO (5 mg/kg). Remicade is a two-hour infusion administered every 8 weeks, following a standard induction regimen that requires treatment at weeks 0, 2 and 6. As a result, Remicade patients may require as few as six treatments each year. In AS [ankylosing spondylitis] (5 mg/kg), Remicade is a 2-hour infusion administered every 6 weeks, following a standard induction regimen that requires treatment at weeks 0, 2 and 6.”
Market: Remicade is among the worldwide market share leader samong TNF-alpha inhibitor therapies.
Total sales were $7.56 billion in 2011; $6.52 billion in 2010; $6.52 billion in 2010; $5.93 billion in 2009; $5.33 billion in 2008; $4.220 billion in 2007; $3.76 billion in 2006; and 3.7 billion in 2005.
Total sales by J&J were $5.429 billion in 2011 and $4.611 billion in 2010.
Until Jan. 1, 2006, when the Medicare Prescription Drug, Improvement, and Modernization Act (MMA) went into effect, Remicade held a reimbursement advantage over other TNF-alpha inhibitors because, under previous Medicare regulations, self-administered injectable drugs were not reimbursable.
The Jan. 2001 approval of Remicade for inhibition or prevention of the progression of joint damage in patients with rheumatoid arthritis (RA) significantly expanded the product’s potential market to include the approximate 2.1 million Americans, mostly women, with RA. In these patients, Remicade can inhibit the progression of joint damage as well as control the pain and stiffness associated with rheumatoid arthritis.
Significant reimbursement limitations for Remicade,have constrained its use for treatment of Crohn’s disease. In Jan. 2007, a Pharmacor study reported that third-party payers in both the U.S. and Europe impose significant limitations on the use of biologics to treat Crohn’s disease. One of the limitations is that patients must fail to respond to at least two conventional therapies, such as corticosteroids and immunosuppressants, before receiving treatment with a biological agent. As a result, only a small percentage of Crohn’s disease patients are forecast to be treated with biologics during 2005-2015. In Europe, although approved for second-line use in Crohn’s disease, it remains to be seen whether national health care systems will alter reimbursement policies in response to the expanded labeling. In the U.S., most patients can receive Remicade because it is either mostly or fully covered by Medicare and private insurers, but co-payments have risen in recent years, leaving some unable to afford treatment with Remicade or other biopharmaceuticals. For Crohn’s there will also be increased competition from cheaper drugs. Many agents in the Crohn’s disease market now or going off-patent and are or will be available as relatively inexpensive generics, with the price of these therapies declining in coming years. These drugs include Imuran/Imurel/Imurek, Azanin, and Purinethol.
Remicade holds a marketing advantage over other marketed TNF inhibitor biologics for treatment of psoriasis largely because it is considered about twice as effective. The only competitor for which similarly robust data have been published is Humira. Other competitors for psoriasis include Cimzia and TNF inhibitor from UCB, and Amevive from Biogen Idec Inc. and Raptiva from Genentech, which are not TNF inhibitors (see related entries).
Total worldwide sales for Remicade were $5.934 billion on 2009, $5.335 billion in 2008, ~$4.220 billion in 2007 and ~$3.764 billion in 2006.
In Nov. 2007, "Centocor, Inc., Schering-Plough Corporation, and Mitsubishi Tanabe Pharma Corp. announced that an estimated one million patients had been treated with Remicade, with it the leading anti-tumor necrosis factor (TNF)-alpha therapy worldwide. In fact, Remicade has been used to treat more patients worldwide than all other anti-TNF-alpha agents combined."
Among the various TNF inhibitors in the U.S. market, Remicade originally was the only one currently reimbursed by Medicare (CMS), due to its need to be administered intravenously by a trained medical professional. However, Medicare reform legislation that went into effect in 2006 allow for the reimbursement of self-administered injectable drugs, including Enbrel and Humira.
The initial U.S. market for Remicade was the ~100,000 Crohn’s disease patients with active or fistulating disease, about 25% of the estimated 400,000 persons with the disease. Analysts originally projected (for original Crohn’s disease indication only; prior to approval for rheumatoid arthritis) eventual peak sales of $185 million/year.
The 2007 Average Wholesale Price (AWP) is $670.96/100 mg vial (Red Book, 2007). The AWP was $691.61/100 mg vial in 2005, and $591.61 in 2004.
At the 5 mg/kg i.v. dosage, the average Crohn’s patient requires 2 to 4 vials of Remicade per infusion. The average rheumatoid arthritis patient requires 2-3 vials per infusion. Presuming infusions require 3 vials, the cost for the first full year (8 infusions) at the current AWP would be ~$16,100 (24 vials total). For rheumatoid arthritis, Remicade has been reported to cost from $7,300-$14,700/year (several years ago), while Enbrel was reported to cost about $11,400/year. An older and commonly used rheumatoid arthritis drug, methotrexate, costs $1,000-$1,500 annually. A course of treatment for a nonfistulating U.S. Crohn’s patient has been estimated to cost from $900 to $1,800; and about $4,050 to $5,400 for those with fistulizing disease. [Note, end-user cost estimates reported for TNF inhibiting products (Remicade, Enbrel, Humira, etc.) vary greatly].
In Feb. 2007, Centocor/J&J disclosed that in Nov. 2006 the U.S. Attorney for the Central District of California had served a subpoena on the company in connection with an investigation into pricing of Remicade related to the average selling price calculations under the company’s contract purchase program.
In Feb. 2007, a class-action lawsuit was underway in federal court charging Centocor with deceptive drug pricing for Remicade. The suit was filed by federal government, and many state, local government, and employee health plans. Centocor/J&J has previously admitted that Remicade had been listed for reimbursement at prices 30% higher than the drug’s cost to the physicians who administer it, providing physicians the potential to profit from administering the drug and artificially raising the costs of the drugs to patients and insurance providers.
In Aug. 2008, National Institute for Health and Clinical Excellence (NICE), U.K., which rules on use (cost-benetifs) of products used by the National Health Service, published final guidance on the use of Remicade in patients with psoriasis, deeming it an effective use of NHS resources.
In March 2008, a study by Decision Resources reported that although gastroenterologists are increasingly prescribing Remicade and Humira for the treatment of Crohn's disease and ulcerative colitis, a high proportion of managed care organizations (MCOs) subject both of these to multiple cost-control strategies to keep costs down and limit the use of the two biologic therapies. Nearly one-third of the 20 MCOs surveyed levy coinsurance charges on Remicade and Humira and most plans require prior authorization for each product. More than half of the plans that cover both drugs also employ step-therapy protocols. Six of the 20 MCOs surveyed plan to extend their step therapy requirements during 2008 for Remicade, and five of 19 MCOs will do the same for Humira.
In Aug. 2008, National Institute for Health and Clinical Excellence (NICE), U.K., which rules on use (cost-benetifs) of products used by the National Health Service, published a draft guidance initially recommending drug Remicade use to treat acute exacerbations of ulcerative colitis, but only in patients in whom cyclosporin is contraindicated. Schering-Plough had estimated Remicade’s cost-effectiveness to be £11,589 ($21,865) per additional quality-assured life year (QALY) gained compared with standard care, £18,425 per additional QALY gained compared with cyclosporin, and £13,407 per additional QALY gained compared with surgery. These figures were adjusted by the NICE Evidence Review Group to £12,307, £19,922 and £14,427 respectively. NICE called for further research and directly comparion studies of Remicade and cyclosporin in ulcerative colitis.
On Oct. 24, 2008, National Institute for Health and Clinical Excellence (NICE), U.K., published final guidance on the use of the TNF alpha inhibitors Remicade, Enbrel and Humira for the treatment of rheumatoid arthritis (RA). These were recommended as options for the treatment of adults who have confirmed active RA, and who have tried two disease-modifying anti-rheumatic drugs, including methotrexate (unless contraindicated). Treatment should be continued only if there is an adequate response at 6 months following initiation of therapy, and treatment monitored at least every 6 months. Treatment should cease if an adequate response is not maintained. An alternative TNF inhibitor may be considered for patients in whom treatment is withdrawn due to an adverse event before the initial 6-month assessment of efficacy, provided the risks and benefits have been fully discussed with the patient and documented.
In May 2010, National Institute for Health and Clinical Excellence (NICE), U.K., issued final guidance endorsing Humira nd Remicade as options for the treatment of severe, active Crohn's disease, but only when patients are unable to take standard therapies such as immunosuppressants or corticosteroids. Remicade was reported to cost about £12,584/year, depending on the patient's body weight.
Competition: Enbrel was the first of anti-TNF agent approved for rheumatoid arthritis in 1998, but partners Amgen’s and Wyeth’s sales were hampered by manufacturing issues and product shortages (see the Enbrel entry). Remicade was able to grab a significant market share following its approval for Crohn’s disease in 1998 and for RA a year after.
Worldwide competition among TNF inhibitors is substantial and promotional spending is in the range typically associated with more highly prevalent conditions, e.g., dyslipidemia, asthma, and allergic rhinitis. A Dec. 2006 report from Decision Resources and Millennium Research Group found that six companies with approved rheumatoid arthritis (RA) biologics in 2005 (Amgen, Wyeth, Centocor, Schering-Plough, Abbott, and BMS) spent $195 million promoting their biologics approved for RA at the time (Enbrel, Remicade, Humira, Kineret, and Orencia). This includes expenses for the indications: for which these products are approved, including physician detailing and journal advertising in the U.S., France, and Germany, as well as direct-to-consumer (DTC) advertising in the U.S. For example, the total promotional spending for Enbrel covered not only RA but also psoriatic arthritis, ankylosing spondylitis, and psoriasis, and the total promotional spending for Remicade included Crohn’s disease, ulcerative colitis, ankylosing spondylitis, psoriatic arthritis, and psoriasis in addition to RA. One reason for this high promotional spending is that the market for RA biologics is highly competitive, with similar agents competing for the small number of patients eligible for treatment with a TNF inhibitor. Much of the marketing is driven by new trial results (and vice versa), in addition to cost, convenience and insurance reimbursement.
In Nov. 2006, Decision Resources projected that physicians will increase their usage of both Humira and Remicade over the next two years. Based on a survey, both primary care physicians and gastroenterologists project that they will double their first-line use of Remicade. Gastroenterologists also projected an increase in their use of Humira, from 9% for first- and second-line treatment combined in 2006 to 41% for both lines of therapy combined in 2008. Primary care physicians’ use of Humira in early-line therapy was found to be 44%, with this expected to reach 56% in 2008, However, lack of FDA approval for Humira in Crohn’s disease (at the time), coupled with its high price, made the current outlook for reimbursement very poor. These hurdles appeared to be an overwhelming limitation for Humira, with 55% of primary care physicians and 69% of gastroenterologists citing these disadvantages. The report also found that Crohn’s disease sufferers often need to visit their physician numerous times before getting treatment. Within one year of initial diagnosis, 54.5% of patients with Crohn’s disease did not receive any prescription drug therapy. Gastroenterologists and primary care physicians say that mild disease, patient refusal, and misdiagnosis or uncertain diagnosis are the primary culprits for this low treatment rate. Surveyed gastroenterologists reported they prefer to see a patient 3-4 times before initiating Crohn’s disease treatment, while primary care physicians prefer to wait to see a patient seven times.
Ongoing: Centocor/J&J and Genzyme Transgenics Corp. (GTC), Genzyme Corp., concluded an agreement in 2001 for GTC to develop a herd of transgenic goats expressing infliximab in their milk, potentially a more cost-effective source for manufacture of infliximab. Remicade is in advanced clinical trials for treatment of psoriasis. Other product are also approved or in advanced trials for psoriasis – Enbrel, Humira, Raptiva, and Amevive (see related entries) – and will likely compete with Remicade, if it is approved for this indication.
Centocor/J&J is developing a second-generation TNF monoclonal antibody, golimumab (see related entry).
R&D: Domantis Ltd., 36.1% owned by Peptech Ltd., is developing a recombinant human TNF monoclonal antibody using Domain Antibody (dAb) technology from the Medical Research Council (MRC).
Companies involvement:
Full monograph
264 TNF Mab, rDNA/J&J
• reducing signs and symptoms and inducing and maintaining clinical
remission in adult patients with moderately to severely active disease
who have had an inadequate response to conventional therapy.
• reducing the number of draining enterocutaneous and rectovaginal
fistulas and maintaining fistula closure in adult patients with fistulizing
disease.
Pediatric Crohn’s Disease:
• reducing signs and symptoms and inducing and maintaining clinical
remission in pediatric patients with moderately to severely active disease
who have had an inadequate response to conventional therapy.
Ulcerative Colitis:
• reducing signs and symptoms, inducing and maintaining clinical
remission and mucosal healing, and eliminating corticosteroid use in
adult patients with moderately to severely active disease who have had
an inadequate response to conventional therapy.
Pediatric Ulcerative Colitis:
• reducing signs and symptoms and inducing and maintaining clinical
remission in pediatric patients with moderately to severely active disease
who have had an inadequate response to conventional therapy.
Rheumatoid Arthritis in combination with methotrexate:
• reducing signs and symptoms, inhibiting the progression of structural
damage, and improving physical function in patients with moderately to
severely active disease.
Ankylosing Spondylitis:
• reducing signs and symptoms in patients with active disease.
Psoriatic Arthritis:
• reducing signs and symptoms of active arthritis, inhibiting the
progression of structural damage, and improving physical function.
Plaque Psoriasis:
• treatment of adult patients with chronic severe (i.e., extensive and /or
disabling) plaque psoriasis who are candidates for systemic therapy and
when other systemic therapies are medically less appropriate.
Nomenclature:
TNF Mab, rDNA/J&J [BIO]
Remicade [TR]
Infliximab [FDA USAN INN]
immunoglobulin G, anti-(human tumor necrosis factor) (human-mouse monoclonal cA2 heavy chain), disulfide with human-mouse monoclonal cA2 light chain, dimer [CAS]
57894-0030-01 [NDC]
cA2 [SY]
chimeric IgG1 anti-human TNF MAb cA2 [SY]
TNF-alpha MAb cA2 [SY]
tumor necrosis factor-alpha monoclonal antibody [SY]
Avakine [TR former [dropped because suggested product was a cytokine]]
CentTNF [TR former or non-U.S.]
molecular weight (kDa) = 149
FDA Class: Biologic BLA
Year of approval (FDA) = 1998
Date of 1st FDA approval = 19980824
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2012, reported by J&J and IMS
Most agent patents expired in 2011 Note, Centocor/J&J and New York University have received over 30 U.S patents, most for relevant uses. This includes 5,919,452 expiring in 2016. Thomson Reuters had reported 2018. Technology Catalysts Intl., affiliated with Harvest Moon Pharmaceuticals, had reported 2014. A Nature Rev. Drug. Disc. article reported 2014. ABN Ambro has reported 2013.
An article by Ohly and Patel reported 2015. |
U.S. Patent Expiration Year: | 2012 |
U.S. Biosimilars Data Exclusivity Expiration: | 2010 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2005 |
U.S. Biosimilars Launchability Year: | 2014 |
U.S. Biobetters Launchability Year: | 2014 |
Biosimilars/biobetters-related EU Patents: | 2012, based on EP 0610201 and EP 1097945 ; 2021, based on EP 1309691
IMS had reported 2014. |
EU Patent Expiration Year: | 2012 |
EU Biosimilars Data Exclusivity Expiration: | 2008 |
EU Biosimilars Orphan Exclusivity Expiration: | 2008 |
EU Biosimilars Launchability Year: | 2012 |
EU Biobetters Launchability Year: | 2012 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
biopharmaceutical products
blepharospasm
bovine materials used<!-- bovinesource -->
cytokine antagonists
exempt from CBER lot release requirements
monoclonal antibodies, recombinant
murine (mouse) materials used
recombinant DNA
tumor necrosis factor alpha (TNF-alpha)
A2 murine hybridoma cells
ATCC CRL 8287
BALB/c mice
bioreactors, 10,000 Liter
c168A, mammalian cell line
glutamine synthetase (GS) expression system
mammalian cell culture
mice
murine (mouse) hybridoma cells
murine feeder cells
murine myeloma cells
myeloma cells, murine
perfusion bioreactors
rodent cells <!-- rodentcells -->
Sp2/0 murine hybridoma/myeloma cells
cA2, chimeric tumor necrosis factor Mab
lyophilized (freeze-dried)
methotrexate
monoclonal antibody A2 (cA2)
phosphate buffered saline (PBS)
polyethylene glycol (PEG)
polysorbate 80 (Tween 80)
Protein A affinity chromatography
Sepharose
Sepharose-Protein A
sodium phosphate, dibasic
sodium phosphate, monobasic
Sterile Water for Injection
sucrose
tri-n-butyl phosphate (TNBP)
tris (tromethamine)
tumor necrosis factor alpha (TNF-alpha)
viral inactivation, solvent detergent
Absorbable Gelatin Sponge, USP
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
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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