Rebif [recombinant]
Status - approved; marketed
Organizations involved:
EMD Merck, Inc. – Manuf.; R&D; Tech.; USA mark.
Merck Serono S.A. – Intl. mark.; Parent
Merck KGaA – Parent
Pfizer, Inc. – USA mark.
Laboratoires Serono S.A. – Manuf. other
Interpharm Labs. Ltd. – R&D; Tech.; Manuf. other
Weizmann Institute of Science – R&D; Tech.
Yeda Research and Development Co. Ltd. – Tech.
Biogen Corp. – Patent dispute
Biogen Idec Corp. – Patent dispute
Columbia University – Tech.; Patent dispute
Serono, Inc. – Former
Serono International S.A. – Former
Cross ref.: See the Interferon Products entry (#793) and other interferon beta entries.
Description: Interferon beta-1a or Rebif is a liquid formulation of recombinant interferon beta-1a glycoprotein expressed by Chinese hamster ovary (CHO) cells transformed with the human interferon beta-1a gene. The amino acid sequence of Avonex is identical to that of natural human interferon beta-1a (the same a interferon beta-1a in Avonex). CHO-expressed interferon beta-1a is a 166 amino acid glycoprotein with a predicted molecular weight of ~22,500 Daltons (~22.5 kDa). Interferon beta-1a (like human fibroblast beta interferon) is glycosylated, with a single N-linked complex carbohydrate chain at Asn-80, and has a single disulfide bond between Cys31 and Cys141.
Using the World Health Organization (WHO) natural interferon beta standard [Second International Standard for Interferon, Human Fibroblast (Gb-23-902-531)], an in vitro cytopathic effect bioassay using WISH cells and vesicular stomatitis virus (VSV), Rebif has a specific activity of approximately 270 million international units (MIU) of antiviral activity per mg. Rebif ‘s standard 44 µg dose contains approximately 12 MIU of antiviral activity.
Rebif is packaged as a sterile preservative-free solution packaged in 0.5 mL pre-filled syringes containing 44 µg or 22 µg interferon beta-1a for subcutaneous injection. A Rebif “Starter Kit” with 0.5 mL pre-filled syringes containing 22 µg (half dose) interferon beta-1a is available for use during the first four weeks of treatment.
Rebif is substantially identical to other interferon beta products in many respects. The amino acid sequence of interferon beta-1a is identical to that of fibroblast-derived human interferon-beta-1a and interferon-beta-1a in Avonex from Biogen, but differs by a single amino acid substitution from interferon-beta-1b in Betaseron from Chiron/Berlex. Biological activities are very similar. Rebif is the only interferon beta available (outside the U.S. only) in a ready-to-use liquid prefilled autoinjector syringe.
Rebif is stored at 2-8°C (refrigerated ), with a dating period of 24 months from the date of manufacture, defined as the date of final sterile filtration of the formulated drug product. Rebif may be stored at room temperature for up to 30 days. The dating period for bulk drug product is 30 months when stored frozen at -70°C.
In 2007/8, a new formulation (Rebif New Formulation) was launched, with this formulated without human serum albumin, manufactured without use of fetal bovine serum, and with fewer adverse reactions.. With the original formulation, each 0.5 mL of Rebif contains 44 µg (or 22 µg) of interferon beta-1a, 4 (or 2) mg Albumin (Human) USP, 27.3 mg mannitol USP, 0.4 mg sodium acetate, and Water for Injection USP.
In Jan. 2013, FDA approved Rebif RebiDose.
In Jan. 2013, FDA approved and in Oct. 2010, Merck KGaA announced European introduction of the new device, Rebif RebiDose, a Rebif single use pre-filled pen, for the self-administration of Rebif. RebiDose is available in a monthly pack in two different doses (22 micrograms and 44 micrograms) and in a titration pack including two different doses (8.8 micrograms and 22 micrograms).
Nomenclature: Interferon beta-1a, rDNA/Serono [BIO]; Rebif [TR]; interferon beta-1a [FDA USAN INN BAN]; interferon beta1 (human fibroblast protein reduced) [CAS]; 145258-61-3 [CAS]; interferon beta-1a [SY]; recombinant beta interferon [SY]; rhIFN-beta1a [SY]; BG-9015 [SY]; Neoferon [TR foreign]; NDC 44087-0022-3; NDC 44087-0044-2; NDC 44087-0044-1 [NDC]
Companies.: Rebif was developed and is manufactured by Serono, Inc. (Rockland, MA), CBER/FDA est. no. 1574., a subsidiary Serono International S.A. In Jan. 2007, Merck KGaA acquired Serono, and the new parent company was renamed Merck Serono S.A., and the U.S subsidiary was renamed EMD Serono, Inc. Rebif was originally developed by the Weizmann Institute and Interpharm Laboratories Ltd., a subsidiary of Serono International S.A. (now Merck Seronoa S.A.), both located in Israel.
Rebif is co-marketed in the U.S. by EMD Merck and Pfizer. In July 2002, Pfizer Inc., the world’s largest pharmaceutical company, concluded an agreement with Serono for rights to co-promote Rebif in the U.S. Pfizer paid Serono an up-front fee of $200 million, the companies share all commercialization and development costs in the U.S., and Serono (Merck Serono) receives unspecified royalties based on U.S. sales (estimated at 20-30% of revenue). The dedicated sales forces of the two companies provide Rebif with greater reach than competitors (e.g., Biogen) in the U.S. MS market.
Interferon beta-1a for Rebif was originally manufactured for European and certain international (not U.S.) markets by Interpharm; and alternatively manufactured by Laboratoires Serono S.A./Serono Biotech Center (Corsier-sur-Vevey, Switzerland). In Sept. 2004, Serono announced it was closing its Interpharm facilities in Israel, and would rely on manufacture at its Swiss facilities for supply of the international market. Vetter Pharma-Fertigung GmbH & Co. (Ravensburg, Germany) handles all finishing, formulation, and packaging, with Merck Serono facilities in Bari, Italy approved by the EU as an alternative site.
Manufacture: As produced by Interpharm for international markets (and reported in the European Product Assessment Report), interferon beta-1a is typically manufactured at the 10-75 L scale using microcarriers for attachment of the anchorage-dependent CHO cells. All steps, except for final filling, are performed at 2-8˚C (refrigeration temperature). Dehydrofolate reductase (DHFR) deficient CHO cells are transfected with two plasmids – one carries the interferon beta-1a coding region and the other carrying the mouse DHFR gene. Both plasmids transfect CHO cells and are integrated into the host cell DNA. The DHFR gene acts as a marker for selection of transfected cells, with methotrexate, a drug normally toxic to cells not expressing DHFR, used to select successfully transfected cells. The DHFR gene also allows methotrexate amplification of the cloned sequences. Cell culture harvests are filtered, pooled, and purified by affinity chromatography, ion exchange chromatography, reverse-phase liquid chromatography, and size exclusion chromatography. Downstream processing also includes three ultrafiltration or microfiltration steps.
Interferon beta-1a is reported to be manufactured at Corsier-sur-Vevey using up to 22 x 75 L bioreactors operating in fixed bed perfusion mode [Farid, S., Operational & Economic Evaluation of Integrated Continuous Biomanufacturing Strategies for Clinical & Commercial mAb Production, presented at ECI Integrated Continuous Biomanufacturing, Barcelona, Spain, 20-24 October 2013].
Each production batch is tested for identity by SDS-PAGE, N-terminal amino acid sequence, peptide mapping, PR-HPLC, carbohydrate mapping and isoelectric point); purity by testing a) clarity, color and pH according to the European Pharmacopeia; b) degradation, aggregation and by-products (using RP-HPLC, SE-HPLC and SDS-PAGE); c) impurities, DNA, host cell proteins, residual solvents (using ELISA, GLC and IE-HPLC); and d) microbial contamination (Eur. Ph.) and endotoxins (LAL); potency by content of interferon beta (using RP-HPLC) and activity (cytopathic effects assay).
FDA class: Biologic BLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 20020307; BLA, first approval; orphan designation (expires 3/2009)
Date = 20030502; BLA supplement; Indication = insert/labeling change to include data from the EVIDENCE trial comparing Rebif and Avonex, including reporting that Rebif was superior to Avonex (i.e., Rebif-treated patients more likely to remain relapse-free at 24 and 48 weeks); and a change in storage to allow room temperature storage for up to 30 days.
Date = 20041220; BLA supplement; Indication = new Titration Pack for MS patients starting Rebif therapy
Date = 201230108; BLA supplement; Indication = approval of the single-use Rebif Rebidose auto-injector
Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling]:
Date = 20130108; BLA supplement; Indication = approval of Rebif Rebidose single-use auto-injector for self-administration
Rebif (interferon-beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to decrease the frequency of clinical exacerbations and delay the accumulation of physical disability. Efficacy of Rebif in chronic progressive multiple sclerosis has not been established.
Status: Serono filed a BLA on Feb. 27, 1998 for FDA approval of Rebif for relapsing-remitting and transitional multiple sclerosis. In March 1999, FDA found the product to be safe and effective (approvable), but refused to grant approval to Rebif while orphan drug exclusivity remained in effect for the interferon beta products already approved for similar MS indications: – Avonex from Biogen Idec Corp. and Betaseron from Berlex Labs. and Chiron Corp., with the seven year market exclusivity for these products expiring in 2003 and 2001, respectively. Avonex, with its substantial similarity to Rebif and its later exclusivity expiration date, was the primary product keeping Rebif from receiving FDA approval.
The BLA was granted to Serono, Inc., CBER/FDA est. no. 1574, on March 7, 2002 (approval time = ~3.1 years). The product was launched in the U.S. the same day. FDA approved Rebif under the terms of the Orphan Drug Act (ODA). Rebif was able to overcome the orphan drug exclusivity held by Avonex and gain FDA approval under the terms of the ODA by demonstrating that it was a different product by virtue of its clinical superiority to Avonex, as shown at 24 weeks in the head-to-head EVIDENCE study. Avonex had previously overcome orphan drug exclusivity granted to Betaseron by demonstrating an improved safety profile. In March 2002, FDA ruled that Rebif’s labeling does not permit Serono to claim clinical superiority of Rebif vs. Avonex. [Note, various trials have now shown superiority with each of the multiple interferon beta products relative to another for MS indications:, so it is difficult to make conclusions about clinical superiority].
Rebif is exempt from CBER/FDA lot release requirements.
European Union (EU) approval was granted on May 4, 1998 for treatment of relapsing-remitting multiple sclerosis (RRMS). EU approval was granted in Feb. 1999 to slow progression of disability in RRMS patents. Approval in Canada was granted in Feb. 1998.
In Nov. 2004, Serono launched the Rebiject II autoinjection device in the U.S., using a new 29-gauge needle, the thinnest needle available for any MS therapy and designed to reduce injection pain and injection site reactions.
The Titration Pack approved in late 2004 is designed for MS patients starting Rebif therapy. It includes a one month’s supply of Rebif therapy, including a two-week supply of 8.8 µg and a two-week supply of 22 µg pre-filled syringes. Rebif is the only therapy currently available in such a titration pack.
On April 10, 2006, Serono and Pfizer submitted a supplemental BLA (sBLA) and a MAA supplement for European Union (EU) approval of a new fetal bovine serum (FBS)-free and human serum albumin-free formulation of Rebif. Data from a Phase III clinical trial in patients with relapsing forms of MS showed that the new formulation results in a substantial improvement in overall tolerability, as measured by pre-specified parameters including injection site reactions, an important factor for patients choosing an MS therapy. The trial also showed that the incidence of antibody formation with the new formulation is reduced. A new Phase III trial with the new formulation was initiated in Dec. 2006 (see the Trials section below).
On July 10, 2006, the European Union (EU) granted supplemental approval for Rebif use after the diagnosis of multiple sclerosis (MS) has been confirmed based on one attack and subsequent positive magnetic resonance imaging (MRI) scans. This involved an update of the Summary of Product Characteristics (SPC) for Rebif to align it with current medical practice. The ‘therapeutic indication’ section of the SPC now takes into account the McDonald criteria, which are the current reference criteria for the diagnosis of MS. The SPC was previously based on the Poser criteria, which were in use at the time of Rebif approval in the EU in 1998, and Rebif was consequently indicated for MS patients who had experienced at least two attacks. Compared with the Poser criteria, the McDonald criteria utilize MRI evidence as an alternative to a second attack, and allow the same patients to be diagnosed with more sensitivity and specificity. Current understanding of the disease supports that it is critical to initiate treatment as soon as the diagnosis of MS is established to ensure the best possible outcome for the patients.
In Feb. 2007, FDA requested additional data concerning the sBLA for the new bovin serum- and albumin-free formulation, delaying the products approval.
On Aug. 30, 2007, the European Union granted supplemental approval to Rebif for the treatment of relapsing multiple sclerosis. Supplemental approval was also granted to a new formulation of Rebif with reduced immunogenicity. This is available in the same strengths and pharmaceutical forms as currently registered, i.e., 8.8, 22 and 44 µg, as a solution for injection in pre-filled syringes. This approval was based on a Phase III study which showed that the new formulation leads to a rate of injection-site reactions in MS patients treated with Rebif over one year that is three times lower, compared with historical data from previous trials. The Aug. 30, 2007 approval also provided for Rebif manufacture without human- or animal-derived serum albumin and is pH neutral. This product has improved tolerability and immunogenicity, with injection-site reactions three times less likely than with other treatments.
In May 2011, Merck KGaA agreed with the U.S. Dept. of Justice to pay $44.3 million to settle allegations the company submitted false claims to U.S. health-care programs and paid physicians to prescribe Rebif. The government accused Merck Serono Laboratories Inc. and EMD Serono Inc. of making payments to health-care providers for hundreds of meetings and programs at upscale resorts where Rebif was promoted. The settlement was filed in a whistleblower lawsuit in federal court in Greenbelt, MD. Serono’s actions resulted in the submission of false claims to programs including Medicare and Medicaid for the payment of Rebif, because the claims were tainted by kickbacks, the Justice Department said. Under the agreement, the federal government will receive $34.6 million while various states will split $9.7 million.
On Jan. 25, 2012, the European Commission (EC) approved extension of the indication of Rebif for relapsing forms of multiple sclerosis (MS). This EC approval is for the use of Rebif 44 micrograms three times weekly in patients who have experienced a single demyelinating event, an early sign of the disease, and who are at high risk of converting to MS. This approval was based on the results of the REFLEX study, which showed the safety and efficacy of Rebif in this patient population. Neurologists can now prescribe Rebif for patients with early signs of MS.
Tech. transfer: Dr. M. Revel, et al., Weizmann Institute, was the first to clone and produce recombinant interferon beta-1a. U.S. 4,808,523, assigned to Yeda Research and Development Co., Ltd., which handles licensing for the Weizman Inst., and later patents (including 5,468,609; 5,468,608; 5,468,607; and 5,541,312) claim aspects of interferon beta-1a cloning and recombinant expression.
Serono 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 Serono 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 its patent, and could against pursue infringement and royalties at a later date. See the “Tech. transfer” section of the Recombinant DNA Products entry (#100).
U.S. patent protection for Rebif is projected by Decision Resources to expire in 2013, and in most European countries in 2013. However, with diverse entity/active agent, use, manufacturing process, formulation and other patents, this may well be an oversimplification of the patents that may be expected to be asserted against competitors.
In June 2010, Biogen Idec filed patent infringement suits against Bayer Schering and other interferon beta manfacturers alleging violation of U.S. patent 7,588,755, a formulation patent, expiring in 2021, claiming certain interfeon beta gene sequences.
Trials: Rebif has been proven effective on the following three key measures of MS treatment effectiveness: MRI lesion area and activity, relapse rates, and disability progression. The safety and efficacy of Rebif are supported by eight-year follow-up data and 12 years of patient experience from around the world (as of 7/2006).
The pivotal, randomized, double-blind, placebo-controlled trial supporting original BLA approval (proving safety and efficacy) was a study in 560 RRMS patients of 22 mg Rebif vs. 44 mg Rebif vs. placebo subcutaneously 3-times/week for two years; plus open-label safety data.
In the randomized, open-label EVIDENCE comparison study, RRMS patients received either Rebif 44 mg SC three times per week or Avonex 30 mg IM once weekly. Although the duration of the study was to be 48 weeks, the trial was halted after the primary endpoint (superior proportion remaining relapse-free after 24 weeks of treatment) was reached. Secondary endpoints (comparisons of MRI abnormalities) were also attained. Rebif was shown to have improved efficacy compared to Avonex, with 75% of Rebif patients not experiencing a relapse after 24 weeks of treatment compared to 63% of patients treated with Avonex (p <0.001). The improvement was also sustained at 48 weeks, at which point 62% of Rebif patients were relapse free as compared to 52% of Avonex patients (p = 0.009). At 48 weeks, patients treated with Rebif had fewer active lesions per MRI scan for all activity measures than did Avonex patients, with effects seen within 2-3 months of starting treatment. Results at 12-months from EVIDENCE were published the Nov. 2002 issue of Neurology.
In June 2002, Serono halted development of Rebif (in combination with methotrexate) for treatment of rheumatoid arthritis after the combination failed in a Phase II trial to show benefit compared to methotrexate monotherapy.
In Jan. 2005, Serono announced that patient enrolment for a head-to-head study comparing Rebif with Copaxone in relapsing remitting MS had been completed. This trial is expected to provide comparative data that will support an evidence-based approach for rational treatment decisions in multiple sclerosis, and Serono (Merck Serono) expects the data to support Rebif as a foundation therapy for treatment of multiple sclerosis.
In Dec. 2006, Serono initiated a second Phase III trial with its new fetal bovine serum- and human albumin-free formulation of Rebif (see the Status section above). This involves testing two dosage regimens of the new formulation of Rebif, 44 µg either three times or once a week, on the time to progression to MS in patients with first clinical symptoms suggestive of the disease. The randomized, double-blind, placebo-controlled trial, REFLEX (REbif FLEXible dosing in early MS) study, involves 480 patients considered at risk of developing MS because of a recently-experienced isolated demyelinating event and atypical MRI brain scans. The study will also evaluate the effect of the new formulation on cognitive function, as measured by the Paced Auditory Serial Addition Test. A substudy will assess retinal nerve fiber thickness (a marker of axonal loss) by means of optical coherence tomography. REFLEX will also attempt to identify genetic/genomic profiles associated with disease and treatment outcomes.
Serono (Merck Serono) is conducting Phase III trials with Rebif for treatment of chronic hepatitis C virus (HCV) infection. Studies are ongoing for using Rebif monotherapy and in combination with ribavirin (Rebetol). In 2005, an ongoing Phase III trial in Asians receiving Rebif monotherapy for treatment of hepatitis C virus (HCV) infection met its primary endpoint. In Feb. 2006, a double-blind, placebo-controlled Phase III trial in HCV patients showed a sustained virological response (SVR) in 57.5% (n=127) in the interferon beta-1a plus ribavirin group after 24 weeks of treatment and 24 weeks follow-up (results comparable or better than with interferon alpha products).
Serono (Merck Serono) has been conducting further trials to expand the indications: and defend Rebif. This includes the multi-year REGARD (REbif vs Glatiramer Acetate in Relapsing MS Disease) study of Rebif(R) vs Copaxone.
Market: The average annual cost for Rebif has been reported to be $17,500.
The 2007 Average Wholesale Price (AWP) is $1,925.81 for either twelve 0.5 mL, 22 µg/0.5 prefilled syringes, twelve 0.5 mL, 44 µg/0.5 prefilled syringes, or for 4.2 mL titration packs (starter kits)(Red Book, 2007).
Worldwide 2007 sales of Rebif were $1.452 billion, according to IMS. Worldwide 2006 sales of Rebif were ~$1.418 billion; 2005 sales by Serono were Euro 1.066 billion ($1.269 billion); $1.0906 billion in 2004 (achieving blockbuster status); $819.4 million in 2003; $548.8 million in 2002; $379.6 in 2001 and $143 million in 1999. U.S. sales were $389.5 million in 2005; $295.6 million in 2004; $188.5 million in 2003, and $71.2 million in 2002. Sales outside the U.S. were $795.0 million in 2004, and $630.8 million in 2003; $477.6 million in 2002; and $379.6 million in 2001.
Recent sales of Rebif had been expected to be significantly lower, if Tysabri (see related entry) had not been taken off the market. Reentry of Tysabri into the marketplace, expected in mid-2006, will cut into Rebif sales, but much less than originally expected before Tysabri had safety-related problems and was taken off the market.
In 2005 and 2004, Rebif was the fastest growing MS therapy in the U.S. with a a sales increase of 31.8% and 56.8%, respectivelys. Serono reported that Rebif became the world’s leading treatment for MS outside of the U.S. in July 2001, with Rebif then registered in more than 70 countries and with a 38% market share among MS therapeutics. Rebif became Serono’s top selling product in 2002, with this primarily due to international, not U.S., sales. U.S. co-promotion of Rebif with Pfizer began in March 2002.
Analysts expect Rebif (monotherapy and/or in combination with ribavirin) may enter Asian markets for treatment of chronic hepatitis C. This will further expand the market, particularly, if Rebif is shown to have advantages over interferon alpha products for HCV indications:.
At the end of 2004, Avonex held 44% of the U.S. market for MS therapeutics, while Copaxone had 28%, Betaseron had 15%, and Rebif had 13%. In the week ending May 7, 2004, among the main products used in the U.S. for treatment of MS (Copaxone, Avonex, Betaseron, and Rebif), Rebif held a 14.4% market share, with 2,253 prescriptions filled, including 712 new prescriptions. Serono reported that as of March 31, 2003, Rebif held 11% of the U.S. market and 36.3% of the international (ex-U.S.) market for MS treatments.
Rebif was a late entrant into the U.S. interferon beta MS market. Avonex and Betaseron are by far the U.S. market leaders, while Rebif holds the leading market share in Europe and other areas. Serono reported in 2002 that it expected 25% penetration of the potential $1.3 billion U.S. market for interferon beta within 3-4 years. In June 2003, Serono reported that ~75% of new U.S. Rebif patients had switched from other marketed therapeutics to Rebif, with about half switching from Avonex from Biogen.
The National Institute of Clinical Excellence (NICE), which advises the U.K. National Health Service (NHS) on the cost-effectiveness of pharmaceuticals, in June 2000 recommended that beta interferon not be offered by the NHS to MS patients. NICE considered the £10,000 (approx. $15,000) annual cost per patient to be too expensive. In early 2002 (after much criticism), NICE recommended use of interferon beta for MS, and estimated the annual cost (as it had negotiated) for treatment of multiple sclerosis with Rebif (plus glaritamer acetate) to be $10,652 (22 mg dose) and $12,678 (44 mg dose).
In late 2004, Serono launched the MS LifeLines Nurses Educators program in the U.S., providing qualified MS nurses to help educate newly diagnosed MS patients about therapy with Rebif. The Titration Pack was launched in the U.S. in early 2005.
In July 2007, with many patients experiencing month or more delays before receiving insurance reimbursement approval for Rebif, Merck Serono started a program allowing patients with relapsing MS to immediately start on Rebif without waiting for decisions on insurance coverage and regardless of income level, with no more than a $50 co-payment required (with the company presuming that the great majority will receive insurance approvals). If patients who begin treatment later turn out to be unable to obtain full insurance coverage, they can apply to Serono’s MS LifeLines Patient Assistance Program (PAP).
Ongoing: In March 2005, Serono exclusively licensed technology from Syntonix Pharmaceuticals for development of recombiant interferon-beta:Fc fusion proteins, which may enable administration of interferon beta by inhalation, based on Fc constructs facilitating transport of therapeutic proteins across the lung epithelium.
Companies involvement:
Full monograph
211 Interferon beta-1a, rDNA/Merck Serono
Nomenclature:
Interferon beta-1a, rDNA/Merck Serono [BIO]
Rebif [TR]
Interferon beta-1a [FDA USAN INN BAN]
Interferon beta1 (human fibroblast protein reduced) [CAS]
145258-61-3 [NUM CAS]
BG-9015 [SY]
recombinant beta interferon [SY]
rhIFN-beta1a [SY]
Neoferon [TR foreign]
NDC 44087-0022-3; NDC 44087-0044-2; mmNDC 44087-0044-1 [NDC]
C908H1406N246O252S7 [MFUSAN]
molecular weight (kDa) = 22.5
FDA Class: Biologic BLA
Year of approval (FDA) = 2002
Date of 1st FDA approval = 20020307
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | mid-2015 (reported by Merck KGaA). Also, reported in an analysis by Ohly and Patel.
2013 (based on licensed 5,541,312). 2013 also reported by IMS and a Nature Rev. Drug. Disc. article. |
U.S. Patent Expiration Year: | 2015 |
U.S. Biosimilars Data Exclusivity Expiration: | 2014 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 2009 |
U.S. Biosimilars Launchability Year: | 2015 |
U.S. Biobetters Launchability Year: | 2015 |
Biosimilars/biobetters-related EU Patents: | 2016 (based on EP 0220574; EP 0835661; and EP 0536520) |
EU Patent Expiration Year: | 2016 |
EU Biosimilars Data Exclusivity Expiration: | 2008 |
EU Biosimilars Orphan Exclusivity Expiration: | 2008 |
EU Biosimilars Launchability Year: | 2016 |
EU Biobetters Launchability Year: | 2016 |
Index Terms:
biopharmaceutical products
blepharospasm
exempt from CBER lot release requirements
hamster source materials
Interferon, Human Fibroblast (Gb-23-902-531), Second International Standard
recombinant DNA
rodent source materials
Chinese hamster ovary (CHO) cells
mammalian cell culture
mice, Viral Antigen Free
perfusion bioreactors
rodent cells <!-- rodentcells -->
Vero cells
WI-38 human diploid fibroblasts
Albumin (Human)
Gb-23-902-531
Interferon, Human Fibroblast (Gb-23-902-531), Second International Standard
mannitol
sodium acetate
Sterile Water for Injection
accelerated approval (based on surrogate endpoints) (FDAapproved)
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
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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