ustekinumab - Stelara; CNTO 1275; interleukin-12 (IL-12) and interleukin-23 (IL-23) p40 subunit monoclonal antibody, human, recombinant
Status: BLA approved in Sept. 2009; EU approval in Jan. 2009
Organizations involved:
Centocor Ortho Biotech – Manuf.; R&D; Tech.; USA mark.
Gallus Biopharmaceuticals, LLC - Manuf.
Janssen-Cilag NV – Intl. mark.
Johnson & Johnson Co. (J&J) – Parent
Medarex, Inc. - Tech.
GenPharm - Tech.; Former
New York Blood Center – Tech.
Description: Stelara is an aquesous formulation of usetekinumab, a recombinant fully human (fully humanized; cloned from a mouse expressing a fully human antibody) IgG1kappa monoclonal antibody with binding specificity for the p40 subunit of both primate interleukin-12 (IL-12) and interleukin-23 (IL-23), with this antibody expressed by a Sp2/0 murine myeloma cell line. Usetekinumab is comprised of 1,326 amino acids and has an estimated molecular mass (weight) of 145.65 kDa, with multiple disulfide bridges.
Usetekinumab has two identical heavy and light chains linked by covalent disulfide bonds and non-covalent heavy-heavy and heavy-light chain interactions. Ustekinumab is N-glycosylated at a single site in each heavy chain at Asn299. The N-linked structures consist of biantennal, core-fucosylated species with galactose and sialic acid heterogeneity. Ustekinumab exists as a mixture of isoforms with variations in mass and charge. The microheterogeneity results primarily from the presence of multiple N-glycan structures at Asn299 and from partial removal of heavy chain C-terminal lysine. IEF and cIEF profiles revealed 5 isoforms after carboxypeptidase B treatment.
The major source of molecular weight and charge heterogeneity is due to post- translational modifications caused by different glycoforms and partial loss of the C-terminal lysine.
Stelara is available in two package sizes, 45 mg of ustekinumab in 0.5 mL and 90 mg of ustekinumab in 1 mL, in prefilled syringes and vials. Each 45 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), polysorbate 80 (Tween 80; 0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL. Each 90 mg ustekinumab prefilled syringe also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL. Each 45 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (0.5 mg), polysorbate 80 (0.02 mg), and sucrose (38 mg) to fill to a final volume of 0.5 mL. Each 90 mg ustekinumab vial also contains: L-histidine and L-histidine monohydrochloride monohydrate (1 mg), polysorbate 80 (0.04 mg), and sucrose (76 mg) to fill to a final volume of 1 mL. Vials and prefilled syringes must be refrigerated at 2-8˚C with a shelf-live of 12 months.
Stelara is supplied as a sterile solution with no preservatives in a single-use prefilled syringe with a 27 gauge fixed 1⁄2 inch needle, or a single-use 2 mL Type I glass vial with a coated stopper. The syringe is fitted with a passive needle guard and a needle cover that is manufactured using a dry natural rubber (a derivative of latex).
Nomenclature: IL-12/23 Mab, rDNA/J&J [BIO]; Stelara [TR]; ustekinumab [USAN; INN]; Immunoglobulin G1, anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer [CAS]; Immunoglobulin G1, anti-(human interleukin-12 subunit beta (IL-12B, CLMF p40, NKSF2)) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer [CAS]; 815610-63-0 [CAS RN]; CNTO 1275 [SY]; CNTO-1275 [SY]; anti-IL-12/IL-23 antibody [SY]; interleukin-12 (IL-12) and interleukin-23 (IL-23) p40 subunit monoclonal antibody, human, recombinant [SY]; 57894-060-03; 57894-061-03; 57894-060-02; 57894-061-02 [NDC]
Biological.: Ustekinumab is a human IgG1 monoclonal antibody that binds with high affinity and specificity to the p40 protein subunit used by both the interleukin (IL)-12 and IL-23 cytokines. By binding to IL-12/23p40 and preventing IL-12 and IL-23 binding to the IL-12R1 receptor protein expressed on the surface of natural killer (NK) or T cells, ustekinumab neutralizes IL-12 (Th1) and IL-23 (Th17) mediated cellular responses. Abnormal regulation of IL-12 and IL-23 has been associated with a variety of immune-mediated human diseases, including psoriasis, Crohn’s disease, rheumatoid arthritis, ulcerative colitis and others.
The human antibody was developed using UltiMAb technology from Medarex. HuMAb-Mouse transgenic mice can secrete antibodies that are fully human (100% human protein sequences), In these transgenic mice, mouse antibody gene expression is suppressed and effectively replaced with human antibody gene expression. HuMAb-Mouse transgenic mice can be inoculated with an antigen to develop fully-human, mouse-derived recombinant antibodies, with the murine antibody genes spliced into CHO or other cells for recombinant Mab manufacture. Because the human genes in the HuMAb-Mouse are stable, they are passed on to offspring of the mice. Mice secreting human antibodies can be bred indefinitely at relatively low cost and without additional genetic engineering. HuMAb-Mouse can generate fully human antibodies with affinities in the picomolar range, as high as 1012. Because these mice contain genes encoding human antibodies, the monoclonal antibodies generated are more likely to have favorable safety profiles and be eliminated less rapidly from the human body, potentially reducing the frequency and amount of dosing required.
Interleukin-23 (IL-23) is a cytokine composed of the p40 subunit of IL-12 (IL-12beta, IL-12-p40) and another protein of 19 kDa, designated p19. The p19 subunit is structurally related to IL-6, G-CSF, and the p35 subunit of IL-12. The p19 subunit by itself is biologically inactive while the complex of p19 with p40 is active. The active complex is secreted by antigen presenting cells (APCs) after cell activation. Mouse memory T-cells proliferate in response to IL-23 but not in response to IL-12. Human monocyte-derived macrophages produce IL-23 in response to virus infection (Sendai virus, but not influenza A virus).
The IL-23 receptor complex consists of a receptor chain, termed IL23R, and the beta-1 subunit of the IL-12 receptor. IL-23 does not bind to the beta-2 subunit of the IL-12 receptor. IL-23 activates the same signaling molecules as IL-12: JAK2, Tyk2, and STAT-1, STAT-3, STAT4, and STAT-5. STAT4 activation is substantially weaker, and different DNA-binding STAT complexes form in response to IL-23 as compared to IL-12. IL-23R associates constitutively with JAK2 and in a ligand-dependent manner with STAT-3.
Biologically active IL-12 exists as a heterodimer comprised of 2 covalently linked subunits of 35 (p35) and 40 (p40) kD. IL-12 acts by binding to both the IL-12beta 1 and beta 2 receptor proteins and thereby induces signaling in a cell presenting both of these receptors. Several lines of evidence have shown that IL-12 can induce robust Th1 immune responses that are characterized by production of IFN.gamma. and IL-2 from CD4+ T cells. Inappropriate Th1 responses, and thus IL-12 expression, are believed to correlate with many autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease, insulin-dependent diabetes mellitus, and uveitis. In animal models, IL-12 neutralization ameliorates autoimmune disease. However, these studies neutralized both IL-12 and IL-23 through the shared p40 subunit.
IL-12 is thought to be important in the development of Th1, or "type 1," CD4+ T cell responses, whereas IL-23 is thought to be important for the activation of memory CD4+ T cells. Several studies suggest that IL-12 is responsible for generating effective immune responses to intracellular pathogens and tumor cells, while the function of IL-23 in these types of immune responses has yet to be fully described. Therefore, while inhibition of both IL-12 and IL-23 should provide significant therapy for immune-mediated disease, inhibition of IL-12 pathways could limit immunity to pathogens or tumor cells and result in an unwanted risk profile. In contrast, inhibition of only IL-23 could provide therapeutic benefit while leaving IL-12 pathways intact. Thus, effective therapy would be achieved concomitant with a lowered risk profile.
Companies.: Centocor Ortho Biotech (Centocor; CBER/FDA est. no. 1821), a subsidiary of Johnson & Johnson Co. (J&J), commercially developed and manufactures ustekinumab, and markets the product in the U.S. Janssen-Cilag NV, another J&J subsidiary holds international marketing rights.
Medarex receives single-digit royalties from sales of ustekinumab, from use of its transgenic mice with human(ized) immune systems for generation and cloning of the human monoclonal antibody (HumAb).
Stelara drug substance (ustekinumab) is manufactured at Centocor Biologics, LLC, St. Louis, MO, with this facility sold to
Gallus Biopharmaceuticals in March 2011. Gallus continues manufacture as a CMO.
Manufacture of Stelara final vialed product (FVP) and prefilled syringes are performed at Baxter Pharmaceutical Solutions, Bloomington, IN, for the U.S. market and at Cilag AG, Schaffhausen, Germany, for European markets European release and stability testing of Stelara are performed at Centocor B.V. , Leiden, The Netherlands.
Manufacture: Ustekinumab is a human IgG1 kappa (κ) mAb originally generated by
Centocor Research & Development, a division of Johnson &
Johnson Pharmaceutical Research and Development, LLC, using
human Ig (hu-Ig) transgenic mice obtained from GenPharm,
which was subsequently acquired by Medarex, now part of
part of Bristol-Meyers Squibb. In these
mice, four distinct genetic modifications replaced the mouse Ig
loci with human antibody transgenes. The mouse antibody
heavy chain joining (J) coding sequences were deleted, thereby preventing the DNA rearrangement process that is required to
assemble a functional mouse antibody heavy chain gene. In addition,
the mouse antibody κ (kappa) light chain and constant region coding
sequences were deleted, preventing expression of mouse κ light
chains. The human heavy chain “minilocus” of DNA (~80,000
bases in length), which contained coding sequences for four variable
(V) regions, sixteen diversity segments, six J segments, IgM
constant regions and IgG1 constant regions, were cloned and
inserted into the mouse genome. In addition, a human κ light
chain “minilocus” of DNA (~450,000 bases in length), containing
the coding sequences for at least ten V regions, five J segments
and κ constant region, was inserted. These genetic modifications
resulted in a mouse strain capable of producing human antibodies
in response to immunizations to any antigen of interest. The human Ig transgenic mouse technology enabled
generation of diverse, high affinity, and highly specific mAbs
with lower deleterious immunogenicity responses than previously
developed rodent mAbs
To elicit human anti-human IL-12 therapeutic mAbs, the
transgenic mice were immunized with human IL-12 antigen.
Mice with positive serum titers for anti-IL-12 antibodies
were selected for hybridoma fusion. Splenocytes, which
contain antibody-producing B cells from IL-12 titer-positive
mice, were fused with an immortal cell line, and the resulting hybridoma cells were cultured under selection conditions that
allowed only hybridoma cells to grow. Growth-positive hybridomas
secreting IL-12-specific antibodies were selected for limited
dilution subcloning. Binding and cell-based functional
assays using human T cells were utilized to select antibodies that
specifically bound IL-12 and inhibited IL-12-mediated responses.
A monoclonal hybridoma clone that produced a human IgG1κ
antibody capable of binding to and neutralizing human and nonhuman
primate IL-12 was thus identified. The antibody, initially
named 12B75, then CNTO1275, and later ustekinumab, was
chosen for further development based on its superior IL-12 binding
and neutralization activity.
To prepare a stable cell line producing
high quantities of ustekinumab, DNA encoding the entire heavy
and light chain genes of the ustekinumab antibody was cloned
from the hybridoma cells. Sequencing of the cloned
DNA encoding ustekinumab and their subsequent translation
into amino acid sequences, followed by comparison to antibody
databases, confirmed that ustekinumab was a human antibody
with a human IgG1 heavy chain and a κ light chain. The heavy
chain IgG1 constant region sequence is of the G1m (1,3) allotype.
The cloned heavy and light chain genes were then introduced
into a host cell line by electroporation. Transfected cell
lines producing the highest titers of ustekinumab were selected
for subcloning and expansion. A single cell line was chosen to
support early development. Subsequently, further changes were
made to support production using perfusion bioreactors in
accordance with Good Manufacturing Practice guidelines, with
the resultant recombinant antibody retaining the same amino
acid sequence as found in the original hybridoma cell lines.
Ustekinumab is purified from the supernatant generated from
the bioreactor process.
Ustekinumab is expressed in Sp2/0 murine myeloma cell line by continuous perfusion cell culture using a protein-free, chemically defined cell culture medium and purified by a series of affinity and ion exchange chromatographic steps and viral inactivation steps. Jannsen is reported to use ATF perfusion equipment from Refine Technology with 500 L bioreactors, using 5-20 bioreactors at its Leiden, Germany, facility.
In the development of the host cell line, Sp2/0 host cell were transfected to express ustekinumab. These cells did not synthesize heavy or light chains proteins. The cells were seeded to adapt growth in protein free chemically defined media. Splenocytes from mice immunized with human Il-12 and Ag653 mouse myeloma cells were fused to create hybridomas using standard technology. The hybridoma cell line C340A expressing an anti human Il-12 was identified and subcloned. A library of DNA fragments was prepared from genomic DNA to clone ustekinumab heavy and light chain genes. The bacteriophage from the library were mixed with an E.coli strain and the pure bacterophage clones of interest were obtained by DNA hybridization. The DNA inserts were transferred from the bacteriophage vectors to a pSV2gpt-based expression vector suitable for transfection in mouse myeloma cells C463A cells. The transfection was performed by electroporation. After three rounds of subcloning, the line C743B showed better growth and IgG titre and was chosen as the candidate to establish a MCB.
For culture, one or more cryovials of C743B from the Working Cell Bank (WCB) are thawed and diluted with chemically-defined medium. The preculture is expanded sequentially in a series of culture flasks and culture bags to scale up for inoculation of the seed reactor. The content of the seed reactor is transferred into the production bioreactor. Continuous perfusion is initiated and culture is drawn from the bioreactor into a cell retention system to separate cells from the permeate. The permeate is filtered and collected as harvest in bioprocess containers. The continuous perfusion cell culture continues up to 60 days post-inoculation. Cell culture conditions and in-process controls are tested during the culture expansion and at the end of the production.
Purification process of the cell harvest involves multiple purification and virus removal/inactivation steps: Affinity chromatography (Protein A); solvent-detergent viral inactivation (S/D treatment); cation exchange chromatography; anion exchange chromatography; virus removal filtration; and concentration by ultrafiltration and diafiltration.. The formulated bulk is prepared by addition of polysorbate 80.
The drug product manufacturing process consists of a sterilization filtration and aseptic filling into vials and syringes.
Changes to the drug substance manufacturing process during development included change in the site of manufacture, scale-up, chromatographic resins and changes in the filters, elimination of animal derived raw materials and changes in the dosage form. Viral safety capacity was improved. The approaches used by Centocor to assess the comparability of Stelara after implementation of specific changes included a retrospective analysis of the structural integrity of the molecule, an evaluation of its biological functionality, and a comparison of the stability data and degradation profiles. Centocor also performed two separate comparability exercises in order to ensure that the changes made in the manufacturing process for the final bulk did not affect the structural and functional integrity of ustekinumab. The manufacturing process was validated through manufacturing scale validation batches and representative reduced-scale studies. Process validation studies included validation of the cell culture process, anion and cation exchange chromatographic steps, virus removal filtration in filters, concentration and diafiltration of the pre-formulated bulk, resin re-use studies for chromatographic steps, cleaning processes for protein A, anion and cation resins, transport and control of impurities and excipients.
Polysorbate 80 was considered important to the formulation to protect ustekinumab from unfolding and aggregate formation particularly due to physical agitation.
The cell bank (like most mammalian cell lines) contains retrovirus-like particles observed by transmission electron microscopy (TEM) that have been shown to be defective, and for which the purification processes have been shown to be effective in removing. These retrovirus-like particles are expected in murine Sp2/0 cells.
The overall viral clearance of the manufacturing process for Stelara includes S/D inactivation, nanofiltration and chromatographic steps.
FDA class: Biologic BLA
Approvals: Date = 20090925; BLA 125261
Date = 20091230; BLA supplement; Indication = new a pre-filled syringe, 45 mg/0.5 mL and 90 mg/1mL formulation
Date = 20101020; BLA supplement; Indication = “Prior Approval” labeling supplement adding language regarding hypersensitivity, anaphylaxis, allergic reactions, immunotherapy, to the labeling and a proposed modification to the approved REMS.
Date = 20120406; BLA supplement; Indication = not disclosed by FDA as of July 2012; apparently, a trivial labeling change
Date = 20120614; BLA supplement; Indication = addition of new safety information to the Contraindications, Warnings and Precautions, and Adverse Reactions sections of the labeling.
Indications: [full text of the " "Indications and USAGE" section of the product insert/labeling]:
STELARA is indicated for the treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
Status: In Nov. 2007, Centocor filed a BLA with FDA and also reported having filed an MAA with EMEA/European Union for the treatment of adult patients with chronic moderate to severe plaque psoriasis. The BLA was accepted for filing on Feb. 4, 2008, then with a PDUFA (target approval) date of Oct. 4, 2008.
On June 17, 2008, the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC), FDA, unanimously (11-0) recommended the approval of ustekinumab for subcutaneous treatment of adult patients with moderate to severe plaque psoriasis. The committee was concerned over potential long-term malignancy (based on a higher incidence seen in mice) and recommended that longer-term studies be done to gather more safety data on the drug.
J&J had hoped for FDA approval in Sept. 2008, and European Union approval in early 2009. However, in Aug. 2008, J&J reported that FDA had extended its review timeline to Dec. 2008. FDA has requested no additional clinical trials.
On Nov. 21, 2008, the EMEA (EU) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for ustekinumab for the treatment of moderate to severe plaque psoriasis in adult patients who failed to respond to other systemic therapies, followed later by formal EU approval. The approved indication was “treatment of adult patients with moderate to severe chronic plaque psoriasis who have failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA”.
On Dec. 12, 2008, the Canadian Health Authority approved the use of ustekinumab for the treatment of chronic moderate to severe plaque psoriasis in adult patients who are candidates for phototherapy or systemic therapy.
On May 26, 2009, FDA informed Centocor of extention of the BLA review timeline by three months to provide time for a full review of an amendment to the pending application. The amendment, submitted within three months of the user fee goal date, pertained to testing results to establish the product's shelf life. The FDA requested no additional clinical trials.
On Dec. 19, 2008, FDA sent Centocor a Complete Response letter for its BLA for ustekinumab. The letter requested Centocor provide a Risk Evaluation and Mitigation Strategy (REMS) to ensure that benefits outweigh the risks. The ustekinumab REMS must contain a Medication Guide and communication plan. It did not require restricted distribution. The FDA did not requested any new non-clinical or clinical studies. Centocor anticipated responding to the FDA in Jan. 2009.
On Jan. 22, 2009, Stelara received approval in the European Union "for the treatment of moderate to severe plaque psoriasis in adults who failed to respond to, or who have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA (psoralen plus ultraviolet A light)."
On Sept. 25, 2009, Stelara received BLA approval from FDA. FDA required a risk evaluation and mitigation strategy or REMS for Stelara that includes a communication plan targeted to healthcare providers and a medication guide for patients. The product insert includes a Medication Guide.
On Dec. 6, 2012, Janssen Biologics B.V. filed a sBLA with FDA and a Type II Variation to the European Medicines Agency (EMA) requesting the approval of Stelara for the treatment of adult patients with active psoriatic arthritis. Phase III trials showed efficacy and safety of subcutaneously administered Stelara at 45 milligrams or 90 milligrams at weeks zero, four, and then every 12 weeks.
Tech. transfer: Medarex receives development milestone payments and unspecified royalties on product sales from its use of UltiMAb technology for cloning of the human antibody.
U.S. patents covering aspects of usetekinumab include 6,914,128, "Human Antibodies that Bind Human IL-12 and Methods for Producing; expiring Mar 24, 2020;
7,504,485, "Human Antibodies That Bind Human IL-12," expiring Mar 24, 2020;
6,902,734, "Anti-IL-12 antibodies and compositions thereof," expiring Aug 1, 2021;
7,166,285, "Anti-IL-12 antibodies and composition," expiring Aug 1, 2021;
7,063,964, "Nucleic acids encoding IL-12 antibody," expiring Aug 1, 2021;
7,279,157, "Method for treating psoriasis by administering an anti-IL-12 antibody," expiring Aug. 1, 2021; and
7,250,165, "Anti-TNF antibodies, compositions, methods and uses," expiring Aug 1, 2021.
These are all assigned to Centocor. Other related patents include 7,252,971, "IL-23p40 specific immunoglobulin derived proteins," and 7,247,711, "IL-23p40 specific antibody," both assigned to Centocor.
EP 1309692, "ANTI-IL-12 ANTIBODIES, COMPOSITIONS, METHODS AND USES, assigned to Centocor, expires in 2021.
EP 1839120, "ANTI-IL-12 ANTIBODY BASED VECTORS, HOST CELLS, AND METHODS OF PRODUCTION AND USES, expires in 2025.
EP1836294, "ANTI-IL-12 ANTIBODIES, EPITOPES, COMPOSITIONS, METHODS AND USES," expires in 2025.
Centocor had filed an interference proceeding with the U.S. patent office, claiming that it had invented its TNF antibodies, including ustekinumab, prior to Abbott, seeking to stop issuance of U.S. 6,914,128. In Aug. 2009, the Patent and Trademark Office’s Board of Patent Appeals and Interferences (BPAI ) rejected Centocor’s claims and recognized that Abbott had not only conceived of the claimed anti-IL-12 antibodies, but had successfully reduced the claimed antibodies to practice before Centocor completed its development of ustekinumab. As a part of the interference proceeding, Centocor had also sought a ruling that the claims of the ‘128 patent were unpatentable for obviousness under 35 U.S.C. § 103. The BPAI ruled against Centocor and recognized that the claimed anti-IL-12 antibodies were not “obvious” and thus that Abbott’s anti-IL-12 antibodies were patentable under 35 U.S.C. § 103.
On July 30, 2009, Centocor/J&J won the biggest patent infringement verdict in U.S. history ($1.67 billion) against Abbott, in a Marshall, Texas, suit alleging that Abbott's blockbuster rheumatoid arthritis drug, Humira (see related entry), infringes a patent co-owned by Centocor. In May 2008, Abbott sued Centocor in Boston federal district court claiming that Centocor's Simponi infringes Abbott's patent on Humira. Abbott's Simponi case was stayed in July 2008, right around the time Centocor's Humira case went to trial in Texas. In Aug. 2009, Abbott further filed suit in Boston federal district court claiming that Centocor's Stelera infringes Abbott human antibody patents, U.S. 6,914,128 and 7,504,485. Wilmer Cutler Pickering Hale and Dorr--which was on the losing end of the $1.67 billion Humira verdict--filed the new suit for Abbott. The Stelara case is Abbott GmbH & Co. v. Centocor Ortho Biotech Inc., 09cv11340, U.S. District Court, District of Massachusetts (Boston).
On March 9, 2010 the U.S. District Court, District of Massachusetts (Boston) issued an order deciding multiple motions of summary judgment filed by both parties. Here is a quick summary of some of those decisions. Overall, the court ruled that some of Abbott's claims were infringed by Stelara. Based on interpretation of "human antibody" covering ustekinumab, the court held that Stelara infringes some of the asserted patent claims broadly directed towards pharmaceutical compositions comprising isolated human antibody capable of binding to an epitope on the P40 subunit of IL-12 (see for example claim 1 of patent 7,504,485). However, many of the asserted claims also include limitations that can only be ascertained by analytical testing, such as threshold Kd value or IC50. The District Court declined to determine the infringement of these claims on summary judgment, given the fact that the experts disputed the results of tests that had been performed, and disagreed as to the methodology to be employed in performing the tests
Solvent detergent viral inactivation technology was developed by and presumably nonexclusively licensed from the New York Blood Center, e.g., see U.S. patent 4,820,805. See the entry for Pooled Plasma, Solvent Detergent Treated (SD Plasma; #799) for further information about solvent detergent viral inactivation, used for inactivation of enveloped viruses (e.g., HIV, hepatitis B and C viruses).
Trials: The BLA filing included data from two large Phase III multicenter, randomized, double-blind, placebo-controlled trials involving nearly 2,000 patients that evaluated the safety and efficacy of ustekinumab in the treatment of moderate to severe plaque-type psoriasis. Usetekinumab has been tested in three Phase III studies, known as PHOENIX 1, 2, and 3. Data from PHOENIX 1 (n=766) and 2 (n=1,230) have been reported (mid-2008). The trials enrolled patients over the age of 18 who had psoriasis (plaque-type) for over six months. Patients had a baseline PASI (psoriasis area and severity index) of > 12, with psoriasis covering more than 10% of their bodies, and patients had to be candidates to receive either phototherapy or systemic therapy. Each study was a four-arm study randomizing patients to either 45 or 90 mg ustekinumab at weeks 0 and 4 (Arms 1 and 2) or placebo at weeks 0 and 4, and to ustekinumab at either 45 or 90 mg at Weeks 12 and 16 (Arms 3 and 4). The primary endpoint of both studies was the proportion of patients who achieved at least a 75% reduction in psoriasis as measured by the Psoriasis Area and Severity Index (PASI 75). In both trials, a majority of patients treated with ustekinumab experienced significant skin clearance by week 12 and sustained efficacy through at least week 76 with ustekinumab maintenance therapy every 12 weeks
In Dec. 2008, results were reported from the ACCEPT trial comparing ustekinumab against Enbrel for the treatment of moderate to severe psoriasis. The Phase III Randomized Study Evaluating the Efficacy and Safety of Ustekinumab Compared to Etanercept in the Treatment of Subjects with Moderate to Severe Plaque Psoriasis (ACCEPT) included 903 patients with chronic plaque psoriasis (etanercept=347; ustekinumab 45 mg=209, 90 mg=347). Patients receive subcutaneously administered ustekinumab or etanercept (Enbrel). The primary endpoint was the percentage of patients achieving >75% reduction in psoriasis at week 12 as measured by the Psoriasis Area and Severity Index (PASI 75). At week 12, after two subcutaneous injections at weeks 0 and 4, 68% and 74% of patients receiving ustekinumab 45 mg or 90 mg, respectively, achieved a PASI 75 compared with 57% of patients receiving Enbrel 50 mg subcutaneous injections twice weekly for twelve weeks (p = 0.012 for ustekinumab 45 mg; P < 0.001 for ustekinumab 90 mg, each compared with Enbrel). Ustekinumab also achieved higher marked improvements in psoriasis as assessed by PASI 90 improvement, or nearly complete clearance of psoriasis, and Physician Global Assessment (PGA) scores compared with patients receiving Enbrel -- the major secondary endpoints of the trial. Also, a greater proportion of patients in the ustekinumab groups achieved a PGA score of "cleared" or "minimal" (65% and 71%, respectively) compared with patients in the Enbrel treatment group (49%) (p < 0.001 for each comparison vs. Enbrel). The levels of relief and clearance reported were beyond any prior reports with any therapeutic. However, Wyeth, which markets Enbrel, noted, "This is a short-term study with no long-term efficacy conclusions" or long-term safety data.
Clinical trials' results with usetekinumab for psoriasis are considered superior to those of Enbrel, the most established biologic competitor for this indication, both in terms of efficacy and safety.
In June 2012, new efficacy and safety data from the Phase 3 PHOENIX 1 study, one of two pivotal registration trials, showed that maintenance treatment with STELARA for up to five years of follow up resulted in consistent, significant clinical response in adults with moderate to severe plaque psoriasis (i.e., apost-approval, essentially Phase IV study, confiemed long-term efficacy). The study tracked five years of continuous biologic treatment for over 500 psoriasis patients.
Medical: Stelera is self-injected subcutaneously every 12 weeks following two starter doses at weeks 0 and 4. For patients weighing <100 kg (220 lbs), the recommended dose is 45 mg initially and 4 weeks later, followed by 45 mg every 12 weeks. For patients weighing >100 kg (220 lbs), the recommended dose is 90 mg initially and 4 weeks later, followed by 90 mg every 12 weeks. In subjects weighing >100 kg, 45 mg was also shown to be efficacious. However, 90 mg resulted in greater efficacy in these subjects. Stelara may be used in adult patients who are candidates for phototherapy or systemic therapy.
Market: Stelera may become the new "gold standard' for psoriasis treatment; and is expected to signficantly cut into the estimated $1 billion market of Enbrel for psoriasis treatment. Factors contributing to this are its convenient subcutaneous adminstration (presumably, self-administrable) and 12 week dosing frequency, much less than the competition. Over the first 12 weeks of treatment, 24 injections of Enbrel are needed, but only two of ustekinumab.
Stelara's main marketing advantage is its more-convenient dosing, only once every three months, compared with every few weeks for other TNF blockers.
In 2009, the average wholesale price (AWP) of Stelara was $5,595.60 per 45mg/0.5 ml vial, according to CVS Caremark. This was competitive with the average annual budgets expended on each of the three most popular injectable TNF-alpha inhibitors.
Stelera has shown rapid uptake among dermatologists, despite its lack of long-term safety data. Sixty-four percent of dermatologists surveyed in Sept. 2010 indicated that they use Stelara in a higher percentage of patients than those surveyed who currently prescribe Remicade. Also, 55% of surveyed dermatologists expected to increase their use of Stelara over the next two years. Dermatologists who prescribe both Stelara and Humira generally score each agent's efficacy in clearing psoriatic plaques as nearly equivalent, and perceive Stelara to be inferior to Humira when considering long-term safety record and reimbursement/lower copay.
For psoriasis, usetekinumab is expected to provide serious competition for Humira from Abbott and Enbrel from Wyeth and Amgen (see related entries). It will also compete against Remicade, also from J&J, which is adminstered by intravenous infusion. Note, these other competing products are all tumor necrosis factor inhibitors, a different mechanism of action than that of usetekinumab. TNF inhibitors are highly effective, but raise the risk of infection, can reactivate tuberculosis, and may potentially increase the risk of cancer. Buth there does not appear to be any increased risk of infection with ustekinumab. Ustekinumab is also has the advantage of significantly less frequent administration.
In Sept. 2009, the National Institute for Health and Clinical Excellence (NICE), U.K., endorsed use of Stelara by the National Health Service (NHS) as a treatment option for adults with moderate to severe plaque psoriasis. NICE stated that treatment should be stopped in patients who have failed to show an adequate response to the drug - by showing a 75% reduction in the PASI score or 50% reduction alongside a five point cut in the DLQI rating - by week 16 of therapy. Stelara’s approval was conditional upon a pricing agreement under which Janssen-Cilag provides the 90 mg dose necessary for patients weighing more than 100 kg at the same total cost as for a single 45 mg vial, to help keep treatment costs at around £9,335 a year.
Upon approval, analysts with Wells Fargo projected Stelar will generate sales of $130 million in 2010, growing to more than $500 million in 2013. Earlier, in June 2008, prior to the delay of FDA approval, analysts with Friedman, Billings & Ramsey (FBR) had projected total 2008 sales of $120 million; $228 in 2009; $319.2 million in 2010; $383.0 million in 2011; and $402.2 in 2012.
Analysts with Cowan & Co. in Aug. 2007 projected sales of $15 million in 2009, increasing to $225 by 2012.
Competition: Abbott Labs. is developing ABT-874, a similar IL-12/23 human monoclonal antibody, in Phase III trials in 2009/10.
In Feb. 2008, a study by Decision Resources predicted "Ustekinumab will become the clinical gold standard for psoriasis by 2011... because of its competitive advantages in long-term efficacy over Centocor/Schering-Plough/Mitsubishi Tanabe's Remicade and due to its superior effect on plaque clearance when compared to Amgen/Wyeth/Takeda's Enbrel.
Companies involvement:
Full monograph
222.6 IL-12/23 Mab, rDNA/J&J
Nomenclature:
IL-12/23 Mab, rDNA/J&J [BIO]
Ustekinumab [USAN; INN]
Immunoglobulin G1, anti-(human interleukin 12 p40 subunit) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer [CAS]
Immunoglobulin G1, anti-(human interleukin-12 subunit beta (IL-12B, CLMF p40, NKSF2)) (human monoclonal CNTO 1275 gamma1-chain), disulfide with human monoclonal CNTO 1275 kappa-chain, dimer [CAS]
815610-63-0 [CAS RN]
12B75 [SY]
anti-IL-12/IL-23 antibody [SY]
CNTO 1275 [SY]
CNTO-1275 [SY]
interleukin-12 (IL-12) and interleukin-23 (IL-23) p40 subunit monoclonal antibody, human, recombinant [SY]
Stelara [TR in Europe]
57894-060-03; 57894-061-03; 57894-060-02; 57894-061-02 [NDC]
molecular weight (kDa) = 145.65
FDA Class: Biologic BLA
Year of approval (FDA) = 2009
Date of 1st FDA approval = 20090925
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2021, based on 7,166,285; 6,902,734; 7,279,157; and 7, 250,165 |
U.S. Patent Expiration Year: | 2021 |
U.S. Biosimilars Data Exclusivity Expiration: | 2021 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2016 |
U.S. Biosimilars Launchability Year: | 2021 |
U.S. Biobetters Launchability Year: | 2021 |
Biosimilars/biobetters-related EU Patents: | 2025, based on EP1836294 and EP1839120 |
EU Patent Expiration Year: | 2025 |
EU Biosimilars Data Exclusivity Expiration: | 2019 |
EU Biosimilars Orphan Exclusivity Expiration: | 2019 |
EU Biosimilars Launchability Year: | 2025 |
EU Biobetters Launchability Year: | 2025 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
monoclonal antibodies
recombinant DNA
African green monkey kidney cells
ATCC VR 2089, VR 2090, VR 2091, VR 2092, VR 2093
Bacteriostatic Water for Injection
c168A, mammalian cell line
Chinese hamster ovary (CHO) cells
hyaluronidase
interleukin-11/thioredoxin fusion protein
mammalian cell culture
Moraxella catarrhalis
Moraxella catarrhalis
murine myeloma cells
percutaneous transluminal coronary angioplasty (PTCA)
plasmid pOA15
prothrombin, human
Sp2/0 murine hybridoma/myeloma cells
histidine
histidine
luteinizing hormone
polysorbate 80 (Tween 80)
Protein A affinity chromatography
ribose
EU002 EU application pending
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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