Alefacept - Amevive; leukocyte function-associated antigen-3/immune globulin G1 (IgG1) fusion protein, recombinant
Status: marketed in U.S.; EU approval refused
Organizations involved:
Biogen Idec, Inc. – Manuf.; R&D; Tech.
Biogen Corp. – R&D; Tech.; Former
Astellas Pharma Inc. – World mark.
Genentech Inc. – Tech.
Columbia University – Tech.; Patent dispute
Description: Alefacept or Amevive is lyophilized (freeze-dried) formulations of a fully human recombinant glycosylated dimeric fusion protein expressed in Chinese hamster ovary (CHO) cells consisting of the first extracellular domain of human leukocyte function-associated antigen-3 (LFA-3) protein fused (by a disulfide bond) to the Fc (hinge, CH2 and CH3) regions of human immunoglobulin G1 (IgG1), i.e., portions of a human monoclonal antibody. The molecular weight of alefacept is 91.4 kDa. Amevive is used for treatment of moderate-to-severe chronic plaque psoriasis, an autoimmune skin disorder involving activated T-cells.
The LFA-3 portion of alefacept binds to the CD2 receptor on T lymphocytes (T-cells), resulting in alefacept blocking the interaction of LFA-3 and CD2, interfering with T-cell activation, and modulating the inflammation process. The IgG1 portion binds to T-cells, resulting in alefacept initiating apoptosis (programmed cell death).
Amevive is packaged as a sterile, preservative-free powder for in two formulations specifically for administration by either intramuscular or intravenous injection. After reconstitution of each of the formulations with 0.6 mL of the supplied Sterile Water for Injection, USP, the solution is clear, with a pH of ~6.9; with Amevive for intravenous injection containing 7.5 mg alefacept per 0.5 mL of reconstituted solution, and Amevive for intramuscular injection containing 15 mg of alefacept per 0.5 mL of reconstituted solution. Both formulations also contain per 0.5 mL: 12.5 mg sucrose, 5.0 mg glycine, 3.6 mg sodium citrate dihydrate, and 0.06 mg citric acid monohydrate.
Amevive for intravenous administration is supplied in cartons containing one or four dose packs, with each dose pack containing one 7.5 mg single-use vial of Amevive, one 10 mL diluent vial (Sterile Water for Injection, USP), one syringe, one 23 gauge, 3/4 inch winged infusion set, and two 23 gauge, 1 1/4 inch needles. Amevive for intramuscular administration is supplied in cartons containing one or four dose packs, with each dose pack containing one 15 mg single-use vial of Amevive, one 10 mL single-use diluent vial (Sterile Water for Injection, USP), one syringe, and two 23 gauge, 1 1/4 inch needles.
Amevive is stored at controlled room temperature (15-30°C; 59-86°F). The dating period is 24 months from the date of manufacture, defined as the date of final sterile filtration of the formulated drug product. The dating period for drug substance (bulk alefacept) frozen stored at -70° to +10°C is 24 months from the date of manufacture The expiration date for the packaged product, Alefacept plus the Sterile Water for Injection, is the earliest expiration date of either component.
Nomenclature: LFA-3/IgG1, rDNA [SY]; Alefacept [FDA]; Amevive [TR]; 1-92-LFA-3 (antigen) (human) fusion protein with immunoglobulin G1 (human hinge-CH2-Ch3 gamma1-chain), dimer [CAS]; 222535-22-0[CAS RN]; BG-9712 [SY]; BG-9273 [SY]; leukocyte function-associated antigen-3/immune globulin G1 (IgG1) fusion protein, recombinant [SY]; LFA-3/IgG1 fusion protein [SY]; LFA3TIP [SY]; LFA-3(92)IgG [SY]; NDC 59627-020-01; NDC 59627-020-02; NDC 59627-021-03; and NDC 59627-021-04 [NDC]
Biological.: Activation of T lymphocytes, involving the interaction between LFA-3 on antigen-presenting cells and CD2 on T lymphocytes, plays a role in the pathophysiology of chronic plaque psoriasis. The majority of T lymphocytes (T-cells) in psoriatic lesions are of the memory effector phenotype characterized by the presence of the CD45RO marker, express activation markers (e.g., CD25, CD69), and release inflammatory cytokines, e.g., interferon gamma. Expression of CD2 receptors (to which alefacept preferentially binds) on the surface of these psoriatic cells is upregulated.
CD2, expressed on all T-lymphocyte subgroups, interacts with LFA-3 receptors on antigen-presenting cells. The resulting LFA-3/CD2 signal is involved in the activation of T-cells, resulting in increased proliferation of T-cells and enhancement of T-cell effector functions. Alefacept blocks the interaction between CD2 and its ligand/receptor, leukocyte-function-associated antigen type 3 (LFA-3). The LFA-3 portion of alefacept binds to the CD2 receptor on T lymphocytes, interfering with the activation of T lymphocytes by blocking antigen-presenting T-cell LFA-3/CD2 interactions, and modifying the inflammation.
Alefacept also causes apoptosis (programmed cell death) of CD4+ and CD8+ memory T-cells (primarily CD45RO+ cells), presumably by forming a bridge between CD2 on target lymphocytes and immunoglobulin Fc receptors on cytotoxic cells, e.g., natural killer (NK) cells and macrophages. Memory T-cells have higher levels of CD2 expression, and are preferentially targeted by the alefacept pro-apoptotic mechanism. In vitro, T-cell apoptosis occurs when the LFA-3 portion of alefacept binds CD2 on T-cells and the IgG1 portion of alefacept binds to cellular immunoglobulin (Ig) receptors (Fc RIII or CD16) on cytotoxic cells, such as natural killer (NK) cells and macrophages. Binding of the alefacept IgG1 domain to Fc RIII/CD16 leads to the release of pro-apoptotic mediators such as granzyme, which leads to programmed cell death (apoptosis), i.e., it binds and results in death of Fc RIII/CD16 receptor-bearing cells.
Companies.: Amevive was developed and is manufactured and marketed by Biogen Corp., now Biogen Idec, Inc., CBER/FDA est. no. 1204. FDA approvals include manufacture at facilities in Cambridge, MA, and Research Triangle Park (RTP), NC, although Amevive is now exclusively manufactured at the RTP site. Final formulated drug product is filled at another facility [redacted/censored by FDA]. Unlabeled vials are shipped to another undisclosed company for labeling and packaging. Priority Healthcare Corp. (PHCC; Lake Mary, FL) has preferred partner status for U.S. pharmacy dispensing and patient assistance product fulfillment for Amevive.
Biogen received FDA approval for its $173 million RTP manufacturing facility and its manufacture of Amevive on Aug. 1, 2003. The facility has six 15,000-liter bioreactors, with two purification suites allowing commercial manufacture of two products. This approval raised Biogen’s total mammalian cell culture capacity to 106,000 liters, with this increasing to >200,000 liters with its merger with IDEC, including IDECs’ Oceanside, CA, 90,000-liter plant then under construction. Biogen Idec is further increasing its manufacturing capacity with construction of a 90,000 liter capacity plant in Hillerod, Denmark, expected to be completed in late 2005.
In Sept. 2005, Biogen Idec underwent a restructuring and announced it intended divest Amevive.
In April 2006, Biogen Idec granted exclusive worldwide marketing rights to Astellas Pharma Inc. for $60 million plus undisclosed royalty payments. Biogen Idec will continue to manufacture and supply the product to Astellas for a period of up to 11 years.
FDA class: Biologic BLA
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 20030130; BL 125036/0
Indications: [full text of the "INDICATIONS AND USAGE” section of product insert/labeling];
AMEVIVE is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.
Status: Biogen’s BLA was completed on Aug. 6, 2001 seeking approval for moderate-to-severe chronic plaque psoriasis. The BLA was granted priority (6 month) review status and Biogen received a Complete Response Letter (citing deficiencies) in Sept. 2001. In Sept. 2002, FDA determined the BLA was a class 2 resubmission with no new trials required, and committed to priority (6-month) review. Approval was granted on Jan. 30, 2003 (approval time = ~1.48 years). The approval letter specifies 17 post-marketing studies and other commitments by Biogen. Alefacept is exempt from CBER lot release requirements.
Biogen filed for European Union approval on Aug. 6, 2001. In Feb. 2003 the MAA was rejected and additional clinical data were requested, with this expected to take several years to develop. Biogen had expected European sales of Amevive would be $100-$150 million. This delay has allowed introduction and marketing of Raptiva (see related entry) in Europe without competition from Amevive. Amevive has not yet received centralized European Union approval.
On Oct. 13, 2004, Amevive received approval in Canada for treatment of patients with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy.
In Nov. 2005, Biogen Idec issued a letter to U.S. healthcare professionals and revised the label to warn that Amevive alefacept should not be administered to HIV-infected patients. Amevive reduces CD4 T-lymphocyte cell (T-cell) counts, which might accelerate disease progression or increase complications in these patients.
Tech. transfer: U.S. patents assigned to Biogen/Biogen Idec covering aspects of recombinant LFA-3 include 4,956,281; 5,185,441; 5,547,853; and 5,914,111. U.S. patents covering aspects of Amevive’s uses, e.g., psoriasis treatment, include 5,728,677 and 6,162,432. See also WO 092166622.
In June 2003, Biogen nonexclusively licensed immunoadhesin fusion protein technology from Genentech Inc., e.g., U.S. patents 5,116,964; 5,428,130; 5,455,165; 5,514,382 and/or 5,712,155, for Amevive and other products in development. Biogen Idec pays Genentech unspecified royalties on sales. These patents concern antibody-like fusion proteins (immunoadhesins; receptor affinity protein–immunoglobulin fusion proteins) combining structural features and activities of antibodies with those of high-affinity cell surface receptors.
Biogen was a licensee of Columbia University’s patents concerning cotransformation, a broadly-useful genetic engineering method allowing selection and isolation of transformed cells. The original patents and license expired in 2000, but Columbia received another patent in 2002 and was again seeking royalties, which Biogen Idec and other companies challenged in court. Recently, the University decided not to continue to press infringement suits and seek royalties, but the patent office is reexaming the relevant patent, and the university could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100) for further information.
Trials: Amevive was evaluated in two randomized, double-blind, placebo-controlled studies in adults with chronic (≥1 year) plaque psoriasis and a minimum body surface area involvement of 10% who were candidates for or had previously received systemic drug therapy or phototherapy. Each course consisted of once-weekly administration for 12 weeks (intravenous for Study 1, intramuscular for Study 2) of Amevive or placebo. Patients could receive concomitant low potency topical steroids, but not phototherapy or systemic therapy.
In Study 1, patients received one or two courses of Amevive 7.5 mg administered by intravenous (i.v.) bolus. A total of 553 patients were randomized into three cohorts. The first and second courses in the two-course cohort were separated by at least a 12-week post-dosing interval. Study 2 compared intramuscular (i.m.) administration of either 10 mg of Amevive i.m. (n = 173), 15 mg of Amevive IM (n = 163) or placebo (n = 68). In both studies, 77% of patients had previously received systemic therapy and/or phototherapy for psoriasis. Of these, 23% and 19%, respectively, had failed to respond to at least one of these prior therapies. Response to treatment in both studies was defined as the proportion of patients with a reduction in score on the Psoriasis Area and Severity Index (PASI) of at least 75% from baseline at two weeks following a 12-week treatment period. Other treatment responses included the proportion of patients who achieved a scoring of “almost clear” or “clear” by Physician Global Assessment (PGA), and the proportion of patients with a reduction in PASI of at least 50% from baseline two weeks after the 12-week treatment period.
In both studies, onset of response to Amevive treatment (at least a 50% reduction of baseline PASI) began 60 days after the start of therapy. In Study 2, the proportion of responders to the 10 mg i.m. dose was higher than placebo, but the difference was not statistically significant. In Studies 1 and 2, an additional 11% (42/367) and 7% (12/166), respectively, of patients treated with Amevive achieved the primary endpoint, a 75% reduction from baseline PASI score at one or more visits after the first 2 weeks of the follow-up period. With one course of therapy in Study 1 (i.v. route), the median duration of response (defined as maintenance of a 75% or greater reduction in PASI) was 3.5 months for Amevive-treated patients and 1 month for placebo-treated patients. In Study 2 (i.v. route), the median duration of response was approximately 2 months for both Amevive-treated patients and placebo-treated patients. Most patients who responded to either Amevive or placebo maintained a 50% or greater reduction in PASI through the 3-month observation period. Responders (n=52) in a subset of patients in Study 1 who crossed over to placebo for a second course maintained a 50% or greater reduction in PASI for a median of 7 months. Overall, the i.v. route provided better results.
Amevive reduced memory effector T-lymphocyte counts in peripheral blood, and the reduction correlated with the improvement in psoriasis. At doses tested, Amevive resulted in a dose-dependent decrease in circulating total lymphocytes, predominantly affecting the memory effector subset of CD4+ and CD8+ T-cell (CD4+CD45RO+ and CD8+CD45RO+), the predominant cell phenotype in psoriatic lesions. Circulating naive T lymphocyte and natural killer cell counts appeared to be only minimally affected, while circulating B lymphocyte (B-cell) counts appeared not to be affected at all. Historical data suggest that alefacept is more effective than either methotrexate or cyclosporine, two drugs commonly used or treatment of severe psoriasis. The rate of infections in the Amevive recipients did not differ significantly from that of the placebo recipients.
In Nov. 2005, Biogen reported results from a completed Phase II trial indicating that Amevive (plus methotrexate) provides clinical improvement for patients with active psoriatic arthritis, a condition that’s even more debilitating than psoriasis alone. Treated patients experienced clinical improvement in their psoriatic arthritis after a single 12-week course of therapy followed by a 12-week observation period. Patients treated with Amevive also experienced less progression of disease, as measured by radiographic assessment, than placebo-treated patients after 24 weeks. At week 24, 54% of patients treated with Amevive and methotrexate achieved an ACR 20 response, the study’s primary endpoint, in contrast to 23% in the methotrexate monotherapy group.
Disease: Psoriasis is primarily an autoimmune disorder. A subset of white blood cells (lymphocytes), memory T-cells, becomes overactive and invade the skin, resulting in inflammation and the growth of scaly patches. The cascade of events leading to psoriasis begins when specialized antigen presenting cells (APCs), dendritic cells (e.g., Langerhans’ cells), process antigen, and eventually migrate to the lymph nodes and the skin, where they present the antigen to naive CD45RA+ T-cells and activate them, resulting in inflammation and the growth of scaly patches.
T-cell activation involves two signals. The recognition of the antigen by the T-cell receptor on the naive CD45RA+ T-cell begins the activation process; followed by costimulatory signaling between cell-surface molecules on both the dendritic cells and CD45RA+ T-cells. The result is the proliferation of memory-effector CD45RO+ T-cells in the skin-draining lymph nodes, which enter the blood and eventually migrate to the skin. When memory-effector CD45RO+ T-cells encounter antigens in the skin, they become activated and begin releasing cytokines, which directly and indirectly stimulate hyperproliferation of keratinocytes. This ultimately leads to the development of psoriatic plaques.
Cell-surface CD2 is more highly expressed on memory-effector CD45RO+ T-cells than on naive CD45RA+ T cells. This increased expression of CD2 on the pathogenic memory-effector CD45RO+ T -cells provides a specific marker targeted by LFA-3/IgG1 (alefacept). Amevive’s ability to reduce the number of memory-effector T-cells explains why patients who respond to treatment experience relief for months at a time.
Treatment of psoriasis has commonly involved use of immunosuppressive therapies—specifically methotrexate and cyclosporine, and also phototherapy [ultraviolet B (UVB), and photo-reactive psoralens in conjunction with ultraviolet A (PUVA)]. These treatments generally involve cumulative toxicity, short duration of post-treatment remission, and inconvenient administration modalities/requirements. Methotrexate extended use is associated with hepatic fibrosis and cirrhosis. Long-term use of cyclosporine also entails serious adverse effects.
As many as 1.5 million Americans are estimated to have moderate-to-severe psoriasis.
Medical: The recommended dose is 7.5 mg once weekly as an intravenous bolus or 15 mg once weekly as an intramuscular injection. The recommended regimen is a course of 12 weekly injections. Retreatment with an additional 12-week course may be initiated, if CD4+ T lymphocyte counts are within the normal range and >12-weeks has passed since the previous course of treatment. The CD4+ T lymphocyte (T-cell) counts of patients receiving Amevive should be monitored weekly before initiating dosing and throughout the course of the 12-week dosing regimen. Dosing should be withheld, if CD4+ T-cell counts fall below 250 cells/mL. Treatment should be discontinued, if the counts remain below 250 cells/mL for one month. Amevive is not indicated for pediatric patients
Amevive results in a dose-dependent decrease in total circulating CD4+ and CD8+ lymphocyte counts. CD2 is also expressed at low levels on the surface of natural killer (NK) cells and certain bone marrow B lymphocytes. Thus, the potential exists for Amevive to affect the activation and numbers of immune system cells other than T lymphocytes. This has raised concerns that Amevive-associated immune suppression may involve increased risk of infection and/or increased susceptibility to cancer. However, the loss of lymphocytes predominantly affects the memory effector subset of the CD4+ and CD8+ T cells (CD4+CD45RO+ and CD8+CD45RO+ T-cells), the predominant phenotype in psoriatic lesions. Circulating naive T lymphocyte and natural killer cell counts appear to be only minimally susceptible to Amevive treatment, while circulating B lymphocyte counts appear not to be affected.
Amevive may have a marginal risk/benefit profile in less severely affected psoriasis patients, and its efficacy in moderately affected patients may be only marginally better than other therapeutics.
Market: Total sales were $48.5 million in 2005, $43 million in 2004, and $40 million in 2003 (with approval received at the end of January). U.S. 2005 sales were $34.9 million, and international sales were $13.6 million. The author’s estimate for 2006 sales is on the order of $32 million, based on Biogen Idec reporting 1st quarter sale of $8.28 million (with then turning the product over to Astellas).
Upon approval, Biogen reported that it expected 2003 sales of at least $85 million, growing to $500 million in the third year on the market. Several stock analysts had projected U.S. sales in 2005 to be $273 million, and $353 million worldwide. However, as discussed above, approval was initially rejected in the European Union and it will take Biogen several years to develop information to reapply and then it will have to harder to gain acceptance by the medical community. Also, Amevive had had to and will compete with other biopharmaceuticals approved and in development for psoriasis indications:, including Raptiva from Genentech, Enbrel from Amgen, and Humira from Abbott Labs.
The 2007 Average Wholesale Price (AWP) is $995.00/15 mg vial (intramuscular), $3,980.00 for four (Red Book, 2007). These prices are unchanged from 2004.
A 12-week course of Amevive treatment has been reported to cost about $8,000 for the intravenous formulation and $12,000 for the intramuscular formulation. Many patients require a second 12-week course of treatment, and many patients will likely receive continuous, twice-yearly courses of treatment.
Reimbursement for Amevive has been an issue for some insurers. With existing therapeutics much less expensive, e.g., methotrexate costing only about $1.50/pill with patients taking 6-10/week, many insurers would prefer to refuse to pay for Amevive and/or delay as long as possible before adding Amevive to their formularies or approving its use for patients. Biogen (as reported in spring 2003) has set aside 10% of Amevive sales as a reserve to provide the product to patients whose insurance coverage has been denied.
Competition: For psoriasis-related indications:, Amevive’s current and potential competition includes Enbrel from Wyeth, Raptiva from Genentech, Humira from Abbott Labs., and Remicade from Centocor/J&J. Another factor affecting the market for Amevive is that considering its costs, some dermatologists may wait to put their patients on Amevive until other therapies have been exhausted and/or it has been on the market for a while and more is known about its long-term adverse effects.
Companies involvement:
Full monograph
227 LFA-3/IgG1, rDNA
Nomenclature:
LFA-3/IgG1, rDNA [SY]
Alefacept [FDA]
Amevive [TR]
1-92-LFA-3 (antigen) (human) fusion protein with immunoglobulin G1 (human hinge-CH2-Ch3 gamma1-chain), dimer [CAS]
222535-22-0 [CAS RN]
BG-9273 [SY]
BG-9712 [SY]
leukocyte function-associated antigen-3/IgG1 fusion protein, recombinant [SY]
LFA-3 fusion protein [SY]
LFA-3(92)IgG [SY]
LFA-3/IgG1 fusion protein [SY]
LFA3TIP [SY]
NDC 59627-020-01; NDC 59627-020-02; NDC 59627-021-03; and NDC 59627-021-04 [NDC]
molecular weight (kDa) = 91
FDA Class: Biologic
Year of approval (FDA) = 2003
Date of 1st FDA approval = 20030130
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2017, based on extension of 5,547,853
Technology Catalysts Intl., affiliated with Harvest Moon Pharm., had reported 2011-2017 |
U.S. Patent Expiration Year: | 2017 |
U.S. Biosimilars Data Exclusivity Expiration: | 2015 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2010 |
U.S. Biosimilars Launchability Year: | 2017 |
U.S. Biobetters Launchability Year: | 2017 |
Biosimilars/biobetters-related EU Patents: | 2012, based on EP 0503648, "CD2-Binding domain of lymphocyte function associated antigen 3" |
EU Patent Expiration Year: | 2012 |
EU Biosimilars Data Exclusivity Expiration: | |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | |
EU Biobetters Launchability Year: | 2012 |
Index Terms:
antibodies (see also immune globulins; monoclonal antibodies)
apheresis (hemapheresis)
biopharmaceutical products
exempt from CBER lot release requirements
fusion proteins, recombinant
hamster source materials
immune modulator
monoclonal antibodies
monoclonal antibodies, recombinant
rattlesnakes
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
mammalian cell culture
rodent cells <!-- rodentcells -->
citric acid
Durapore membrane
glycine
lyophilized (freeze-dried)
receptors, interleukin-2
sodium citrate
Sterile Water for Injection
sucrose
U.S. Standard Rabies Vaccine
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
exempt from CBER lot release requirements
priority review status
EU031 EU application denied
UM001 Marketed Product in US
US200 Currently Approved in US
EM999 Not Available/Not Marketed in EU
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