Status: approved; marketed

Organizations involved:

Bristol-Myers Squibb Co. - Manuf.; R&D; Tech.; World mark.

Lonza Biologics plc. - Manuf.

Celltrion Ltd. - Manuf.

VaxGen, Inc. - Parent co.

Genzyme Transgenics Corp. - Manuf; R&D; Tech.; Former

Genzyme Corp. - Parent

Repligen Corp. - Patent dispute

ZymoGenetics, Inc. - Patent dispute

University of Michigan - R&D; Tech.

U.S. Navy - R&D; Tech.

Novartis AG - Former

Description: Orencia is a lyophilized (freeze-dried) formulation of abatacept, a glycosylated fusion protein composed of two homologous cytotoxic T-lymphocyte- associated antigen-4 (CTLA4) receptor extracellular domain polypeptide chains (two identical active portions of CTLA4) fused with a modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1 (human heavy chain fragment) chain expressed by transformed Chinese hamster ovary (CHO) cells. The two CTLA4-Ig chains form a homodimer (single protein composed of two identical CTLA4-Ig chains; ~92 kDa apparent m.w.), with each chain of about 46 kDa linked by one disulfide bond and non-covalent interactions. CTLA4-Ig is expressed by transformed CHO cells containing a gene sequence encoding the exocellular domains of human CTLA4 fused to a gene sequence encoding a Fc hinge and constant region fragment (without the variable antigen-binding region) of human immunoglobulin G1 (IgG1). The immunoglobulin constant region of Abatacept has been modified to reduce constant region-mediated biological effector function. The molecular formula is C1965H3080N479O695S16.

Orencia is supplied as a sterile, white, preservative-free, lyophilized powder in a 15 mL vial for parenteral administration. The powder is reconstituted with 10 mL of Sterile Water for Injection, USP, forming a clear, colorless to pale yellow, solution with a pH range of 7.0-8.0. Each single-use vial of Orencia contains 250 mg abatacept, 500 mg maltose, 17.2 mg monobasic sodium phosphate, and 14.6 mg sodium chloride for administration, with no preservatives. A disposable silicone-free syringe with an 18-21 gauge needle is included with each vial.

Abatacept is the first in a new class of agents called selective T-cell co-stimulation modulators (for treatment of autoimmune diseases). A variation of CTLA4-Ig with several changes in amino acid residues, LEA-29Y (BMS-224818), has been under development by BMS as an immune suppressant for transplantation use.

Nomenclature: CTLA4-Ig, rDNA [BIO]; Orencia [TR]; Abatacept [TR USAN INN]; 1-25-oncostatin M (human precursor) fusion protein with CTLA-4 (antigen) (human) fusion protein with immunoglobulin G1 (human heavy chain fragment), bimolecular (146->146')-disulfide [CAS]; 332348-12-6 [CAS RN]; cytotoxic T-lymphocyte-associated antigen 4-immunoglobulin G1 fragment fusion protein, recombinant [SY]; CD152 antigen-immunoglobulin G1 fragment fusion protein [SY]; BMS-188667 [SY]; RG2077 [SY for CTLA4-Ig from Repligen]; NDC 0003-2187-10 [NDC]

Note, Abatacept is pronounced aba ta' cept, with emphasis on the second portion.

Biological: Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) has also been referred to a CD152 antigen; cytotoxic T-lymphocyte-associated serine esterase-4; cytotoxic T-lymphocyte protein 4 precursor; and cytotoxic T-lymphocyte-associated granule serine protease 4. CTLA-4 is a T cell surface molecule that was originally identified by differential screening of a murine cytolytic T cell cDNA library. CTLA-4 is also a member of the immunoglobulin (Ig) superfamily. CTLA4 is a B7 negative regulatory T-cell-presenting co-stimulatory molecule member of the immunoglobulin superfamily. CD28 (CTLA4 ligand) is found on most mature human T-cells. The interaction between CD28/CTLA4 and B7 interaction is one of the ways that T-cells are activated, by sending a signal to T-cells in conjunction with T-cell receptor (TCR) antigen recognition. Efficient T-cell activation is dependent on the intimate contact between antigen-presenting cells (APCs) and T-cells. The engagement of the B7 family of molecules on APCs with CD28 and CD152 (CTLA4) receptors on T-cells delivers costimulatory signal(s) important in T cell activation. These simultaneous signals are required to initiate T-cell activation. This pathway in turn is regulated by the expression of cytotoxic T lymphocyte antigen 4 (CTLA-4).

CTLA-4 comprises a single extracellular Ig domain, and CTLA-4 transcripts are found in T-cell populations having cytotoxic activity, indicating that CTLA-4 functions in the cytolytic response. Sequence comparison between human CTLA-4 DNA and that encoding CD28 proteins reveals significant homology of sequence, with the greatest degree of homology in the juxtamembrane and cytoplasmic regions. Some studies have suggested that CTLA-4 has an analogous function as a secondary costimulator, while others have reported that CTLA-4 has an opposing role as a dampener of T cell activation. CTLA-4 blockade augments T-cell responses in vitro.

Abatacept utilizes a mechanism known as a costimulatory signal, also known as a "second signal." The second signal activates both T-cells and B-cells (T and B-lymphocytes) using an additional pathway beyond the original antigen-presenting cells, and is necessary for the T-cell to be fully activated. Inhibition of costimulatory signals may be useful for treatment of T-cell-related autoimmune diseases. To induce antigen-specific T-cell activation and clonal expansion, two signals provided by antigen-presenting cells (APCs) must be delivered to the surface of resting T lymphocytes. The first signal, which confers specificity to the immune response, is mediated via the T-cell receptor (TCR) following recognition of a foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T-cells to proliferate and become functional. Costimulation is neither antigen-specific, nor MHC restricted, and is thought to be provided by one or more distinct cell surface molecules expressed by APCs. The B7-1 protein (CD80; originally termed B7), expressed on APCs, is one these critical costimulatory molecules.

Abatacept (CTLA4-Ig) binds to both human and murine B7 with a 20-fold greater affinity than CD28, blocks the binding of CD28 to B7, inhibits T-cell activation, and induces T-cell unresponsiveness in vitro. Abatacept (CTLA4-Ig) binds to CTLA4 (CD80 and CD86), blocking interaction with CD28, and blocking its ability to relay the second signal. CD28 is a counter-receptor for B-cell activation antigen, B7/BB-1 (B7 antigen). This interaction blocks a costimulatory signal necessary for full activation of T lymphocytes, implicated in the pathogenesis of rheumatoid arthritis (RA). Activated T lymphocytes are found in the synovium of patients with RA. CTLA4-Ig protein contains in its CTLA4 CDR3-like domain the hexapeptide motif MYPPPY. This motif (sequence) is shared between CD28 and CTLA4, and is necessary for binding of CTLA4-Ig to B7 ligands.  

In vitro, abatacept decreases T-cell proliferation and inhibits the production of the cytokines tumor necrosis factor alpha (TNF-alpha), interferon-alpha, and interleukin-2 (IL-2). In a rat collagen-induced arthritis model, abatacept suppresses inflammation, decreases collagen-specific antibody production, and reduces antigen-specific production of interferon-alpha. The relationship of these biological response markers to the mechanisms by which abatacept exerts its effects in RA is unknown (i.e., there is uncertainty about the molecular mechanism of abatacept). In clinical trials at doses of about 10 mg/kg, decreases were observed in serum levels of soluble interleukin-2 receptor (sIL-2r), interleukin-6 (IL-6), rheumatoid factor (RF), C-reactive protein (CRP), matrix metalloproteinase-3 (MMP3), and tumor necrosis factor alpha (TNF-alpha). The relationship of these biological response markers to the mechanisms by which Orencia exerts its effects in RA is unknown.

Human B lymphocyte antigen B7-2 (CD86) is expressed by human B-cells at about 24 hours following stimulation with either anti-immunoglobulin or anti-MHC class II monoclonal antibody. At about 48-72 hours post activation, human B cells express both B7-1 and a third CTLA4 counter-receptor which is identified by monoclonal antibody BB-1, which also binds B7-1. The BB-1 antigen is also expressed on B7-1 negative activated B cells and can costimulate T cell proliferation without detectable interleukin-2 (IL-2) production, indicating that the B7-1 and BB-1 molecules are distinct. The presence of these costimulatory molecules on the surface of activated B lymphocytes indicates that T-cell costimulation is regulated, in part, by the temporal expression of these molecules following B-cell activation.

B7-1 is a counter-receptor for two ligands expressed on T lymphocytes. The first ligand, termed CD28, is constitutively expressed on resting T-cells and increases after activation. After signaling through the T-cell receptor, ligation of CD28 induces T-cells to proliferate and secrete IL-2. The second ligand, CTLA4, is homologous to CD28, but is not expressed on resting T-cells and appears following T-cell activation. Like B7-1, B7-2 is a counter-receptor for both CD28 and CTLA4.

Activated T-cells orchestrate the autoimmune response that leads to the joint inflammation and destruction as well as the disability often associated with auto-immune diseases, such as rheumatoid arthritis. Abatacept selectively modulates one of the two signals needed for full T cell activation, thereby interrupting the inflammatory process. Abatacept binds to CD80 and CD86 on APCs with its extracellular CTLA4 portion, preventing them from making contact with CD28 on T-cells. By blocking engagement of CD28, Abatacept, like CTLA4, prevents the positive costimulation signals required for optimal T-cell activation. In rheumatoid arthritis, this may prevent the stimulation of T-cell effector functions in response to autoantigen exposure and may suppress the proliferation of autoreactive T cells, restoring the balance between self-tolerance and autoimmunity. CTLA4-Ig may also directly affect dendritic cells by cross-linking their B7 molecules.

CTLA4-immunoglobulin fusion proteins, e.g., Abatacept, ipilimumab and tremelimumab, are useful for inhibiting the interaction of CTLA4 ligands (e.g., B7 family members such as B7-1 and B7-2) with receptors on T-cells (e.g., CD28 and/or CTLA4), inhibiting delivery of the costimulatory signal in the T-cells and downmodulating an immune response. Since T-cells activate and coordinate a number of biological pathways that cause synovial inflammation and joint destruction in patients with rheumatoid arthritis, therapeutic strategies, e.g., abatacept, that specifically modulate T-cell function may reduce the severity of symptoms or slow the progression of the disease more effectively than currently available treatment options. By preventing positive costimulation signals normally generated through engagement of CD28, abatacept can block the release of T-cell cytokines that stimulate other immune cells, while it simultaneously suppresses T-cell proliferation.

Cytokine release and T-cell proliferation are the hallmarks of optimal T-cell activation. This has been demonstrated in an in vitro lymphocyte activation model in which human T-cells were stimulated with APCs and antigen. Abatacept exposure produces a clear, dose-related inhibition of T-cell proliferation, attaining approximately 80% suppression of proliferation at concentrations of 10 µg/mL or higher. It also significantly reduces the release of IL-2, tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma from the T-cells during the 72 hours after antigen exposure. Thus, Abatacept suppresses T-cell responses (both release of inflammatory cytokines and cell proliferation) to stimulation by APCs and antigen, and does so at concentrations that are similar to the serum concentration produced by Abatacept doses evaluated in clinical trials (see Trials section below).

Because the sequence of the binding regions of CTLA4 and its ligands are highly conserved between mammalian species, human CTLA4-Ig binds and cross-reacts with B7 of rodents and other nonhuman primates. This allowed extensive preclinical studies of abatacept in animals, including rodent models of transplant rejection. No toxicity was observed in animal models.

Abatacept has also been shown to reduce serum markers of joint inflammation in patients with rheumatoid arthritis after 6 months of treatment. Blood samples obtained from patients treated with abatacept exhibited reductions from baseline levels of several inflammatory biomarkers, including C-reactive protein, E-selectin, soluble IL-2 receptor, and the macrophage-derived cytokine IL-6. Blood samples from treated patients treated also demonstrated reductions from baseline levels of autoantibodies produced by B-cells. Combined with Abatacept's direct inhibitory effect on dendritic cells, this suggests that Abatacept may act to decrease joint inflammation in rheumatoid arthritis.

Preclinical studies provided the proof of concept for Abatacept in rheumatoid arthritis (RA). Data from several animal model studies of T-cell-mediated disease showed that targeting T cells can decrease the severity of autoimmune diseases, including RA. In systemic lupus erythematosus-prone mice (NZBxW strain), Abatacept blocked the production of autoantibodies, inhibited T-cell-dependent B-cell maturation, and increased life span. In a mouse model of collagen-induced arthritis (in which exposure of genetically susceptible mice to type II collagen results in cell-mediated and humoral immune responses, synovial inflammation, infiltration of immune cells into the joint, and destruction of bone and cartilage), pretreatment with Abatacept markedly reduced the number of mice that developed arthritis following collagen exposure. When administered after arthritis was already established, Abatacept significantly reduced the number of arthritic joints and improved other clinical signs of arthritis over 10 days following treatment; and also significantly reduced lymphocyte proliferation in the lymph nodes.

Companies: Bristol-Myers Squibb Co. (BMS) discovered, developed, manufactures, and markets Orencia. BMS originally manufactured and now manufactures some abatacept commercial supplies at its facilities in Syracuse, NY; and Lonza manufactures the bulk of abatacept under contract (starting in May 2006; see below). Finishing and packaging is performed at BMS facilities in Puerto Rico. Orencia is BMS's first internally discovered and developed biopharmaceutical product. Orencia is generally considered to be the most important near-term product in BMS' pipeline. In March 2006, BMS invested $200m in its Puerto Rico to accommodate increased filling and finishing needs for Orancia and other products.

In 1997 or earlier, BMS contracted with Genzyme Transgenics Corp. (GTC) for development of transgenic goat expressed CTLA4-Ig. In Jan. 2001, BMS contracted with GTC for expansion of CTLA4-Ig manufacturing capacity to support clinical trials. However, the BMS later switched to using its own CHO cell manufactured product.

In Oct. 2000, Novartis AG signed an agreement with BMS for collaborative development of Abatacept. BMS was to develop the product for autoimmune indications, and Novartis was to develop it for transplant rejection indications. However, there have no been no substantive activities, e.g., trials reported, since then indicating that Novartis pursued this development, while BMS has actively pursued development and conducted trials for transplant rejection indications.

In Jan. 2005, BMS concluded a supply agreement with Lonza Biologics plc for contract manufacture of Abatacept at its Portsmouth, NH, facilities. Lonza had already manufactured abatacept for clinical studies, and is starting larger-scale manufacture of abatacept after receiving FDA approval of an supplemental BLA covering manufacture by Lonza (received in May 2006). BMS will initially rely primarily on Lonza to help meet commercial demand, with Celltrion (see next paragraph) later assuming a larger share of outsourced manufacturing. Lonza manufactures abatacept until the end of 2009, at which time BMS's manufacturing facility is expected to assume primary manufacturing responsibilities. Full commercial launch of Orencia was delayed until after BMS received FDA approval for manufacture by Lonza, with manufacture in its own facilities and by Lonza expected to fulfill near- to mid-term demand. In March 2007, BMS extended by four years its deal with Lonza for manufacture of abatacept.

In June 2005, BMS concluded another contract manufacturing supply agreement with Celltrion, Inc. (Incheon, S. Korea) for manufacture of Abatacept. This "is believed to represent the largest biologics manufacturing contract for an Asian biopharmaceutical contract manufacturer." Celltrion is a joint venture spun-off from VaxGen, Inc., with VaxGen the largest shareholder. In Jan. 2006, BMS concluded a new contract manufacturing agreement with Celltrion. FDA approval for manufacture of abatacept by Celltrion was granted in De. 2007. Abatacept is manufactured according to U.S. cGMP standards, and is expected to utilize a significant portion of Celltrion's 50,000 liters of bioreactor capacity. Tthis will eventually result in a reduction of the quantities Lonza supplies to BMS.

In Feb. 2007, BMS announced it was investing $660 million in a new facility in Devens, MA, for manufacture of abatacept and other biopharmaceuticals. Manufacture by BMS will be supplemented by that of several contract manufacturers, at least until BMS completes this facility. The plant is expected to come online in 2009 and receive FDA approval in 2011.

Manufacture: The need for gram doses to treat individual cases and the capital estimates to manufacture the hundreds of kilograms required initially led BMS to contract with Genzyme Transgenics Corp. for expression of CTLA4-Ig in transgenic goats. However, this was later dropped in favor of CHO cell culture manufacture performed by BMS. The Ig portion of CTLA4-Ig allows purification using Protein A-bound chromatography, with Protein A having affinity for Ig. See the Prosorba entry for further information about Protein A. As described in U.S. patents assigned to BMS, e.g., 6,641,809, a stable CHO line, designated Chinese Hamster Ovary Cell Line CTLA4Ig-24, is preferred for expression of CTLA4-Ig and has been deposited as ATCC 10762.

FDA class: Biologic BLA

Approvals: Date = 20051223; BLA; Indication = second-line treatment of rheumatoid arthritis

Date = 20060605; supplement BLA; Indication = approval of manufacture by Lonza

Date = 20070425; BLA supplement; Indication = approved indication strengthened from "slowing" to "inhibiting" the progression of structural damage in adult patients with moderately to severely active RA who have had an inadequate response to one or more disease-modifying, anti-rheumatic drugs (DMARDs), such as methotrexate (MTX) or tumor necrosis factor (TNF) antagonists.

Date = 20071218; BLA supplement; Indication = approval for manufacture by Celltrion, Inc.

Date = 20080407; BLA supplement; Indication = approval for juvenile rheumatoid arthritis (JRA)

Indications: [Full text of the "INDICATIONS AND USAGE" section of product insert/labeling; 9/8/2008]:

ORENCIA is a selective T cell costimulation modulator indicated for:

Adult Rheumatoid Arthritis (RA) (1.1)

„ moderately to severely active RA in adults. ORENCIA may be used as monotherapy or concomitantly with DMARDs other than TNF antagonists (1.1).

Juvenile Idiopathic Arthritis (1.2)

„ moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 6 years of age and older. ORENCIA may be used as monotherapy or

concomitantly with MTX (1.2).

Important Limitations of Use (1.3)

„ Should not be given concomitantly with TNF antagonists (1.3, 5.1)

Status: In Dec. 2004, BMS reported that its rolling submission of non-clinical and clinical sections of the Abatacept BLA for rheumatoid arthritis had been completed. The remaining sections were submitted March 2005, and the original action (PDUFA) date set by FDA was Oct. 1, 2005. However, FDA later informed BMS it would require up to 90 additional days to complete the review of the BLA, due to the complexity of the chemistry and manufacturing controls section of the application, with the action date reset to Dec. 31, 2005. Abatacept received Fast Track status for treatment of rheumatoid arthritis. In _Sept. 2005, the Arthritis Advisory Committee, FDA, voted unanimously (7:0) to recommend approval of Orencia. The panel concluded that Orencia is effective in adults patients with moderately to severely active RA having had an inadequate response to one or more DMARDs, including tumor necrosis factor (TNF) inhibitors.

Orencia was approved by FDA on Dec. 26, 2005. BMS sales representatives immediately began detailing the product, which become available in Feb. 2006 through a single distributor (to better monitor supply) using product manufactured by BMS at its Syracuse, NY, facilities. Full commercial launch has been postponed until after Lonza is approved for manufacture and product it has manufactured is released for marketing.

As part of the approval, BMS agreed rather intensive post-approval (Phase IV) pharmacovigilance studies. This invovles an enhanced adverse event reporting system, paying particular attention to tumors; an open-label trials of Orencia 1,000-2,000 patients for five years; a pregnancy registry; and two 5-year epidemiology studies, one following 1,200 patients and the other involving an independent registry of 5,000 Orencia patients and 15,000 patients taking comparator drugs. This intensive program is often cited as an example of the increased attention to pharmaceutical safety in recent years on the part of FDA, the medical community and general public.

On Jan. 3, 2006, BMS submitted a supplemental BLA (sBLA) seeking approval of abatacept manufacture at Lonza's facilities in Portmouth, NH.

On May 23, 2007, Orencia received European Union (EU) approval for treatment of rheumatoid arthritis in combinantion with methotrexate for the treatment of moderate to severe active rheumatoid arthritis in adult patients who have had an insufficient response or intolerance to other disease-modifying anti-rheumatic drugs including at least one anti-tumor necrosis factor (TNF) inhibitor.

On Aug. 7, 2007, FDA accepted for filing a sBLA for Orencia for the treatment of pediatric patients with juvenile idiopathic arthritis who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate (MTX) or tumor necrosis factor (TNF) antagonists.

Tech. transfer: Abatacept-related U.S. patents assigned to BMS include: 5,977,318; 5,968,510; and 5,885,579, "CTLA4 receptor and uses thereof;" 5,851,795, "Soluble CTLA4 molecules and uses thereof;" 5,844,095, "CTLA4 Ig fusion proteins;" 5,773,253, "MYPPPY variants of CTL A4 and uses thereof;" 5,637,481; 6,132,992; 6,482,919; and 6,623,940, "Expression vectors encoding bispecific fusion proteins and methods of producing biologically active bispecific fusion proteins in a mammalian cell;" 5,434,131, "Chimeric CTLA4 receptor and methods for its use;" and 6,641,809, "Method of regulating cellular processes mediated by B7 and CD28. BMS' 5,434,131 was filed in 1993 (predating Repligen's; see below) and appears to cover the use of CTLA-4 in immune diseases.

BMS has also received WO-09299992, with this including claims for fragments and derivatives of the B7 antigen and CD28 receptor, including fusion proteins. WO-093000431 includes claims for CTLA4 receptor as a ligand for B7 antigen; methods of manufacture of soluble CTLA-Ig fusion proteins; and use of these for regulation of T-cell interactions and associated immune responses. WO-03088991 claims use of soluble CTLA4 molecules that block B7 alone or in conjunction with other therapeutics, with coverage including Abatacept (and LEA-29Y).

Repligen has exclusively licensed CTLA-Ig use patents from the University of Michigan (and the coassignee, the U.S. Navy, based on work at the U.S. Navy Medical Research Institute, Bethesda, MD), including U.S. 6,685,941, "Methods of treating autoimmune disease via CTLA-4Ig," with claims for treatment of systemic lupus erythematosus, multiple sclerosis, rheumatoid arthritis and other autoimmune diseases using CTLA4-Ig. The patent was filed in 1995 and expires in 2021. U.S. patents assigned to Repligen include 6,750,334, "CTLA4-immunoglobulin fusion proteins having modified effector functions and uses therefor," June 15, 2004, and 6,444,792, "CTLA4-Cgamma4 fusion proteins," including claims for recombinant molecules substantially similar or perhaps identical to Abatacept. U.S. 5,770,197, "Methods for regulating the immune response using B7 binding molecules and IL4-binding molecules," and 5,844,095 and 5,885,796, "CTLA4 Ig fusion proteins" identify the CTLA4 receptor as a ligand for the B7 antigen and the complete amino acid sequence encoding human CTLA4 receptor gene is provided, along with CTLA4-Ig fusion proteins. Repligen's patents include WO-09614865 claiming methods for inhibition of antigen-specific T-cell responses using CTLA4-Ig fusion proteins, including for treatment of graft-vs.-host disease (transplant rejection). Repligen also has exclusive rights to a European patent with substantially similar claims that will remain in force until 2013.

In Aug. 2000, Repligen and the University of Michigan (UM) filed suit against BMS seeking to add a UM researcher as an inventor on multiple U.S. patents assigned to BMS. If granted, this would effectively give Repligen co-assignment (co-ownership) rights, which could be worth even more than if Repligen were to (cross)license its patents to BMS (with co-ownership likely being less restrictive and allowing Repligen to bring out its own product and/or further license its patents to other parties).

On Jan. 6, 2006, Repligen and UM jointly filed a suit against BMY in U.S. District Court alleging that BMS is infringing U.S. 6,685,941 covering the use of CTLA4-lg to treat autoimmune diseases, including rheumatoid arthritis. Repligen, with an exclusive license to this patent from the UM, seeks to force BMS into a royalty-bearing license. With this seemingly strong method of use patent and Orencia expected to potential be a blockbuster product (>$1 billion sales/year), the stakes for those involved are very high. BMS may be forced to settle and pay a significant royalty, rather than risk treble damages if found guilty of infringment in court. 

In Aug. 2006, ZymoGenetics, Inc. filed a patent infringement suit against BMS alleging that Orencia infringes its patents concerning recombinant fusion proteins. Immunoglobulin fusion proteins, as claimed by ZymoGenetics, involve a portion of an antibody (e.g., heavy chain constant domain) combined with the portion of a second protein. This likely involves U.S. patents 5,843,725; 6,018,026; 6,291,212; 6,291,646; 6,300,099; and 6,323,323 providing coverage for certain secreted recombinant ligand-binding dimerized immunoglobulin fusion proteins. Zymogenetics had also filed a similar infringement suit involving Enbrel (see related entry), and Amgen settled the dispute by taking a license

In April 2008, Repligen and Bristol-Myers Squibb settled Repligen's lawsuit alleging infringement of U.S 6,685,941 (see above). BMS made an initial payment to Repligen of $5,000,000 and pays royalties on the U.S. net sales of Orencia for any clinical indication at a rate of 1.8% for the first $500 million of annual sales, 2.0% for the next $500 million of annual sales and 4% of U.S. annual sales in excess of $1 billion for each year from Jan. 1, 2008 until Dec. 31, 2013. The settlement provides for the grant by Repligen and co-plaintiff the University of Michigan to BMS of an exclusive worldwide license under certain patent rights of Repligen and the University of Michigan.

Trials: The efficacy and safety of Orencia have been studied in more than 2,600 patients. The BLA filing including more than 3,800 person-years of experience across the placebo-controlled and open-label extension periods of the clinical trials. The efficacy and safety of Orencia were assessed in five randomized, double-blind, placebo-controlled studies in patients ³ age 18 with active RA diagnosed according to American College of Rheumatology (ACR) criteria. In both of its pivotal Phase III efficacy studies (AIM and ATTAIN), Orencia demonstrated significant and sustained improvement of the signs and symptoms of RA as measured by American College of Rheumatology (ACR) 20, 50, and 70 scores, with significant difference from placebo by day 15 for ACR 20 in some patients (the first follow-up visit after the first dose). In both trials, significant improvements in physical function were noted as compared to placebo. Health-related quality of life was assessed by the SF-36 questionnaire. Improvements were observed in the patients treated with Orencia as compared to placebo in all eight domains of the SF-36. A significant proportion of patients taking Orencia plus methotrexate achieved a major clinical response (an ACR 70 score for six consecutive months), compared to those treated with methotrexate alone in AIM.

In Oct. 2004, BMS reported results of two Phase III clinical trials showing Abatacept to have significant clinical activity in patients with rheumatoid arthritis (RA). The studies focused on two different RA patient populations - those who had not adequately responded to methotrexate and patients who did not adequately respond to tumor necrosis factor (TNF) inhibitors. As assessed by clinical measures, including disease progression, ACR response rate, physical function, and quality of life, patients in both studies given Abatacept in addition to therapy, such as methotrexate, showed improvements compared to those receiving placebo plus additional therapy. Abatacept was administered in a single 30-minute intravenous infusion on days 1, 15 and 29 of each study and every 28 days thereafter. A primary endpoint in each study was the proportion of patients achieving an ACR 20 response at six months. Patients recording an ACR 20 response have >20% improvement in signs and symptoms of RA.

The Abatacept in Inadequate Responders to Methotrexate (AIM) trial assessed efficacy and safety for 12 months in RA patients who inadequately responded to treatment with methotrexate. The progression of disease, an additional primary endpoint, was also assessed and documented by radiographic evaluation. In addition to methotrexate, a disease-modifying antirheumatic drug (DMARD), patients received either Abatacept at a fixed dose approximating 10 mg/kg of body weight (385 patients) or a placebo (162 patients). Through one year of treatment, 73.1% of patients on Abatacept achieved an ACR 20 response compared to 39.7% on placebo. ACR 50 and ACR 70 responses (even better improvement in symptoms) in the Abatacept group at one year (48.3% and 28.8%, respectively) exceeded what was observed in the placebo group (18.2% and 6.1%, respectively). The one-year results were statistically significant (p < 0.001). As a secondary endpoint, the signs and symptoms of rheumatoid arthritis were also assessed using the internationally recognized Disease Activity Score (DAS28). Among Abatacept patients, 23.8% were in remission after one year, as defined by the DAS28 criteria, compared to 1.9% in the placebo group - a statistically significant result (p < 0.001). Radiographic evaluation showed significant reductions in progression of joint erosions (p = 0.029), joint space narrowing (p = 0.009), and total score (p = 0.012). The responses seen with Abatacept increased through one year of treatment. The incidence of adverse events was slightly higher with Abatacept compared to placebo (87% vs. 84%, respectively). Abatacept had a low incidence of infusion reactions and serious infections, such as pneumonia (3.9% vs. 2.3% for placebo). The most common adverse events in the trial were headache, nasopharyngitis and nausea.

In June 2006, new data from the long-term extension of the AIM indicated that Abatacept sustains inhibition of radiographic progression over 2 years in rheumatoid arthritis patients with an inadequate response to methotrexate. Two years of abatacept slowed progression of structural damage in RA patients with an inadequate response to methotrexate, with the effect seen at year 2 significantly better than those in year 1. Abatacept for two years was significantly better than 1 year of placebo followed by 1 year of abatacept. Radiographic progression in the 2-years abatacept group slowed during year 2 vs. year 1.

Abatacept Trial in Treatment of Anti-TNF Inadequate Responders (ATTAIN) evaluated efficacy and safety of Abatacept for six months in patients (n = 1,441) with active rheumatoid arthritis and inadequate response to TNF inhibitors (e.g., Enbrel). Patients randomized in the trial had discontinued all TNF inhibitor therapy. In addition to at least one DMARD, patients received Abatacept at a fixed dose approximating 10 mg/kg (258 patients) or a placebo (133 patients). After six months of treatment, 50.4% of the patients on Abatacept achieved ACR 20 responses compared to 19.5% on placebo; and 20.3% of patients in the Abatacept group achieved ACR 50 and 10.2% achieved ACR 70. In contrast, 3.8% of the placebo group achieved ACR 50 and 1.5% reached ACR 70. The results observed in the Abatacept group were statistically significant (p < 0.001 for ACR 20 and 50; p < 0.03 for ACR 70). Using the DAS28 scale, 10% of Abatacept patients achieved remission compared to 0.8% receiving placebo after 24 weeks of therapy, with these results statistically significant (p < 0.001). Even in these patients who had already responded inadequately to a TNF therapy, half achieved an ACR 20 response with Abatacept therapy after six months. The incidence of adverse events was similar between Abatacept and placebo, 13% for abatacept and 12% for placebo recipients; and the incidence of serious infections was also similar (2.3% in each group). The most common adverse reactions were headache and nasopharyngitis.

Evidence suggests that the immunosuppressive effects of CTLA4-Ig may persist after discontinuation of treatment, indicating that CTLA4-Ig may provide a unique and potentially safer option than existing therapies.

In June 2005, BMS reported results from the one-year, randomized, double-blind, placebo-controlled, multicente Phase III AIM (Abatacept in Inadequate responders to Methotrexate) trial investigating the progression of joint damage in subjects (n = 652) with active rheumatoid arthritis (RA). Abatacept inhibited progression independent of baseline clinical, biochemical or radiographic characteristics. The rate of adverse events in both study groups was similar.

In Nov. 2005, BMS reported results from a one-year, double-blind, placebo-controlled Phase II trial in patients with rheumatoid arthritis not responding to methotrexate monotherapy. Abatacept improved quality of life, sleep, and reduced fatigue compared to placebo.

In Nov. 2006, BMS reported results from a trial further supporting the efficacy, safety and durability of response of Orencia through 12 months in adults with moderate to severe rheumatoid arthritis (RA). This double-blind, double-dummy, placebo-controlled trial enrolled patients with moderate to severe RA with inadequate response to methotrexate and no prior anti-TNF therapy. Participants were randomized to one of three treatment groups: ORENCIA (~0 mg/kg) every four weeks (n=156) for 12 months, Remicade (3 mg/kg) every eight weeks (n=165) for 12 months, or placebo every four weeks (n=110) for six months. The primary endpoint was mean reduction in DAS28 in the group receiving Orencia vs. placebo at six months. DAS28 is a standard score used to measure the disease activity of RA. The secondary objectives included mean reduction in DAS28 with Remicade vs. placebo at six months, mean reduction in DAS28 with Orencia and Remicade at one year and ACR 20, 50 and 70 scores through one year for Orencia and Remicade. At six months, the data demonstrated that the efficacy, as measured by DAS28, of Orencia or Remicade was superior to placebo. At 12 months, Orencia showed both a durable response as measured by DAS28 (mean change at six months: -2.53; mean change at twelve months: -2.88) and a more favorable safety profile as demonstrated by fewer serious infections, acute infusional events and discontinuations due to adverse events (AEs) than Remicade through 12 months.

In its controlled clinical trials, patients receiving concomitant Orencia and TNF antagonist (e.g, Enbrel) therapy experienced more infections (63%) and serious infections (4.4%) compared to patients treated with only TNF antagonists (43% and 0.8%, respectively), without an important enhancement of efficacy. Less than 1% of treated patients experienced hypersensitivity reactions, including two cases of anaphylaxis or anaphylactoid reactions. Infusion reactions were experienced in 9% of patients treated with Orencia and in 6% of patients treated with placebo. The most frequent adverse events occurring in ³10% of treated patients were headache, upper respiratory tract infection, nasopharyngitis, and nausea. Trials failed to demonstrate significant enhancement of efficacy with concomitant administration of Orencia with with TNF antagonists. Therefore, concurrent therapy with Orencia and a TNF antagonist is not recommended.

The pharmacokinetics of abatacept in RA patients and healthy subjects appears to be comparable. In RA patients, after multiple intravenous infusions, the pharmacokinetics of abatacept showed proportional increases of Cmax and AUC over the dose range of 2-10 mg/kg. At 10 mg/kg, serum concentration appeared to reach a steady-state by day 60 with a mean (range) trough concentration of 24 (1-66) mcg/mL. No systemic accumulation of abatacept occurred upon continued repeated treatment with 10 mg/kg at monthly intervals in RA patients.

In Nov. 2006, BMS reported 2-year results form three Phase III pivotal trials demonstrating the long-term efficacy of Orencia in adult patients with moderate to severe rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and TNF antagonists. Orencia provided clinically meaningful improvements in multiple aspects of health-related quality of life and physical function, sustained improvements in pain and had a consistent safety and tolerability profile through two years of treatment. The study included analyses of the ongoing open-label, long-term extension component of Orencia's Phase III pivotal trials, including the AIM (Abatacept in Inadequate responders to Methotrexate), ATTAIN (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders) and ASSURE (Abatacept Study of Safety in Use with other Rheumatoid Arthritis Therapies) trials

The April 2008 approval for juvenile rheumatoid arthritis (JRA) was primarily based on the AWAKEN trial. This three-part study evaluated the safety and effectiveness of Orencia in patients ages 6 to 17 who had moderately to severely active polyarticular JRA for an average of four years and whose symptoms did not subside when given one or more disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and anti-TNF therapeutics. The 190 patients enrolled in the first part of the study received Orencia every 14 days for the first month and then every month thereafter. Orencia consistently improved symptoms.

Medical: Orencia is administered as a 30-minute intravenous infusion at dose levels based on body weight, e.g., for persons 60-100 kg, 750 mg or 3 vials; 250 mg or 2 vials for those under 60 kg, and 1,000 mg or 4 vials for those over 100 kg. Orencia is administered by intravenous infusion on days 1, 15, 29 and then every 28 days (once per month). Orencia may be used as monotherapy or concomitantly with disease-modifying, anti-rheumatic drugs (DMARDs) other than TNF antagonists. Due to concerns about infections, live vaccines should not be given concurrently with Orencia or within three months of its discontinuation.

Orencia is the first therapeutic shown effective and safe in patients with an inadequate response to TNF antagonists, as well as those with an inadequate response to methotrexate monotherapy. Methotrexate is the most widely used non-biologic DMARD for rheumatoid arthritis (RA), and TNF antagonists are the most widely used biologic therapies for RA. Orencia is the first in its new class of RA treatments that selectively modulate a co-stimulatory signal required for T-cell activation.

Market.: Total worldwide sales of Orencia were $89 million in 2006 (presumably, the calendar year), with Orencia receiving FDA approval in June.

Merrill Lynch has projected worldwide Orencia sales of $225 million in 2006, $526 million in 2007, $797 million in 2008 and $1.094 billion in 2009. Credit Suisse First Boston has projected Orencia sales will top $1 billion by 2010. Friedman, Billing and Ramsey (FBR) projected $266 million total sales in 2006, $1.02 billion in 2008 (achieving blockbuster status), rising to $1.9 billion by 2010. As can be seen, analysts projections of initial uptake were too optimistic. Standard & Poor's named Orencia one of its top 10 drug products to watch in 2005, noting its sales are "critical in stemming the three-year slide in [BMS'] ratings."

The Average Wholesale Price (AWP) reported in the 2007 edition of the Red Book is $540.00/syringe with a Direct Price (DP; bulk discount price) of $450/syringe.

Depending on a number of factors, Abatacept could become a blockbuster (annual sales >$1 billion). Other RA therapeutics, e.g., Enbrel, have already attained blockbuster status. One percent of the world's population has RA, accounting for more than 9 million physician visits and 250,000 hospitalizations in the U.S. annually. Three out of four patients diagnosed with RA are women. In the U.S., about 2.8 million people have RA, with about 20% receiving TNF antagonist therapy. According to the American College of Physicians, roughly 70% of RA patients do not gain adequate relief from methotrexate monotherapy, and many experience severe side effects including liver toxicities, ulcers, and blood abnormalities, with these patients being candidates for adding a TNF antagonist (or Orencia) to methotrexate. Approximately 250,000 U.S. RA patients are treated with anti-TNF therapies, of which 15%-25% result in an inadequate response. This places the U.S. TNF antagonist non-responder market at up to 62,500 patients.

Most of the patients receiving Orencia will have already tried and not responded to treatment with methotrexate alone or in combination with tumor necrosis factor (TNF) inhibitors, including Enbrel (etanercept), Remicade (infliximab) and Humira (adalimum-ab). Orencia will compete directly with Humira, also approved for use in patients with inadequate response to one or more DMARDs. Orencia is expected to compete with Rituxan (rituximab) for use patients who have failed methotrexate plus a tumor necrosis factor (TNF) antagonist. Since it is approved for use after failure to respond to a DMARD, many patients will have the option of starting Orencia after trying methotrexate monotherapy. However, since Orencia is new and few physicians have experience with it, most patients will start methotrexate, perhaps, in combination with Enbrel or Humira, and only move on to Orencia after not responding to methotrexate plus a TNF antagonist. Rapid uptake of Orencia is expected in patients having tried and failed TNF antagonist(s). With rheumatologists generally having a reputation as being conservative, it will likely take one or more years to see how the market for Orencia develops. In several years, with the projected approval of Rituxan

Rituxan (rituximab) from Genentech (see related entry) is often cited as Orencia's primary competitor in the marketplace for treatment of RA patients not responding to TNF antogonists, Orencia will also compete against Rituxan, which has a different mechanism of action targeting B lymphocytes (B-cells). Rituxan's efficacy for refractory RA appears roughly comparable to Orencia when comparing ACR 20 response scores. Prudential Equity group analysts have projected peak sales of Orencia to be ~$1.8 billion, with Rituxan largely held back as a third-line agent, after Orencia, because of its long-term effects in depleting B cells

BMS has formed a new ImmunoScience business unit and developed a specialty sales force specializing in rheumatoid arthritis (RA) treatment sales and marketing. BMS will follow the voluntary guidelines issued by the Pharmaceutical Research and Manufacturers Association (PhRMA) and avoid direct-to-consumer advertising for a full year.

In Aug. 2007, the National Institute for Clinical Excellence (NICE), U.K., which decides on therapeutics use and reimbursement by the U.K. National Health Service (NHS) ruled against the use (cost-effectiveness) of Orencia for the treatment of moderate to severe rheumatoid arthritis. NICE reaffirned its decision (issued final draft guidance) in Oct. 2007. In contrast, NICE had recently recommended Rituxan for rheumatoid arthritis. Orencia reportedly cost Ū9,300 a year in the U.K.

The April 2008 approval for juvenile rheumatoid arthritis (JRA) may further expand the market for Orencia. JRA is the most common form of arthritis in children, according to the American College of Rheumatology, the disease affects only about one in every 1,000 children in the U.S. Symptoms range from mild to severe and may include chronic pain, joint swelling, stiffness, joint deformities, and soft tissue damage..

Ongoing: BMS is investigating Orencia for treatment of juvenile RA, RA prevention, early RA, psoriasis, lupus (SLE), Crohn's disease, ulcerative colitis, and multiple sclerosis.