Status - approved; marketed

Organizations involved:

Biogen Idec, Inc. – Manuf.; R&D; Tech.; USA mark.

Biogen Corp. – R&D; Tech.; Former

Ben Venue Laboratories – Manuf. other

Schering-Plough Corp. – Europe mark.

Merck & Co., Inc. – Parent.

Dompe Biotec – Europe mark.

Bioferon Biochemische Substanzen GmbH & Co. – R&D; Tech.; Former

Rentschler Biotechnologie GmbH – Tech.; Former; Patent dispute

Boehringer Ingelheim Pharma KG – Patent dispute; Parent

Hoffmann-La Roche Ltd. – Tech.

Japanese Foundation for Cancer Research – Tech.

Abbott Laboratories – Former

Abbbvie – Latin Amer. mark.

ASTA Medica GmbH – Patent dispute

Berlex Laboratories – Patent dispute

Schering AG – Parent

Stanford University – Tech.; Patent dispute

Chiron Corp. – Tech.; Patent dispute

Genzyme Corp. – Japan mark.

Packaging Coordinators, Inc. – Manuf. other

Cardinal Health, Inc. – Parent

Columbia University – Tech.; Patent dispute

Cetus Corp. – Patent dispute

Triton Biosciences Inc. – Patent dispute

Hoechst AG – Patent dispute

Boehringer Mannheim GmbH – Patent dispute

Cross ref.: See the Interferon Products entry (#793) and the other interferon beta entries below.

Description: Avonex refers to lyophilized (freeze-dried) and aqueous formulations 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 interferon beta-1a is identical to that of human fibroblast-derived interferon beta-1a (and identical to interferon beta-1a in Rebif from Merck Serono). CHO-expressed interferon beta-1a is a 166 amino acid glycoprotein with a predicted molecular weight of ~22,500 Daltons (~22.5 kDa). Its glycosylation is similar to that of human interferon beta-1a, and occurs at the asparagine (Asn) residue at position 80. The glycoprotein is ~89% protein and ~11% carbohydrate by weight, with an empirical formula of C908-H1406-N246-O252-S7.

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, interferon beta-1a has a specific activity of ~200 million international units (IU)/mg, with 30 µg of Avonex containing 6 million IU of antiviral activity.

Avonex is packaged in single-use vials for intramuscular injection after reconstitution with supplied diluent; and as an Albumin (Human)-free liquid formulation in prefilled syringes. Vials are packaged along with two alcohol wipes, one gauze pad, one 3 mL syringe, one Micro Pin vial access pin, one needle, and one adhesive bandage. Each vial contains 33 µg (6.6 million IU; for withdrawal of a 30 µg dose) of interferon beta-1a; 16.5 mg Albumin (Human), USP; 6.4 mg sodium chloride, USP; 6.3 mg dibasic sodium phosphate, USP; and 1.3 mg monobasic sodium phosphate, USP. Avonex contains no preservatives.

AVONEX PEN is a sterile liquid for intramuscular injection in a prefilled glass syringe surrounded by an autoinjector. Each 0.5 mL (30 microgram dose) in the AVONEX PEN contains 30 micrograms of interferon beta-1a, 0.79 mg Sodium Acetate Trihydrate, USP; 0.25 mg Glacial Acetic Acid, USP; 15.8 mg Arginine Hydrochloride, USP; and 0.025 mg Polysorbate 20 in Water for Injection, USP at a pH of approximately 4.8.

Avonex vials are reconstituted with Sterile Water for Injection, with 1.0 mL withdrawn for administration. Diluent is supplied in a single-use vial (Sterile Water for Injection, USP, preservative-free). The dating period is 15 months from the date of manufacture at 2-8˚C (refrigerated). The date of manufacture is the date of final sterile filtration of the formulated bulk. The dating period for bulk intermediate is 12 months from the date of filling of bulk intermediate containers. In June 2006, Biogen Idec introduced prefilled syringes with new needle 20% shorter and thinner than the previously approved needle.

Avonex used in preclinical studies and various clinical trials, including its pivotal Phase III trial (for relapsing multiple sclerosis), was manufactured in Germany by Bioferon, then a joint venture of Biogen Corp., now Biogen Idec) and Rentschler Arzneimittlel GmbH & Co.. This involved use of Rentschler’s BG9015 CHO cell line – cells which grew as an adherent (stick to surfaces) culture.

After the Bioferon joint venture disbanded and filed for bankruptcy, Biogen developed a new CHO cell line, BG9216, adapted to suspension culture (to more easily manufacture larger quantities). Various manufacturing-related changes to reduce immunogenicity were implemented by Biogen as it established its own cell line and manufacturing, including changes in oxidation, protein aggregation, and removal of moisture from vials. Subsequent pharmacokinetic bioequivalence trials showed that BG9015 product was not comparable to the BG9216 product. Biogen then developed yet another suspension culture interferon beta-1a expressing CHO cell line, BG9418. The purification process (extraction methods and column chromatography) for the BG9418 product also differed from that of BG9015. BG9418 has been extensively tested by biological, biochemical, and biophysical studies, and in human pharmacokinetic studies, and has been accepted by FDA as equivalent to the BG9015 product [allowing acceptance of the studies and trials using the BG9015 product for approval of BG9418-expressed interferon beta-1a (Avonex)]. Note, this change in cell line during development is often cited in discussions of follow-on biologics/biogenerics.

All AVONEX dosage forms are single-use (injection of reconstituted solution, prefilled syringe, and prefilled autoinjector). Dosage forms and strengths are: for injection: 30 micrograms lyophilized powder in a single-use vial; for injection: 30 micrograms per 0.5 mL solution in a single-use prefilled syringe and for injection: 30 micrograms per 0.5 mL solution in a single-use prefilled autoinjector

The AVONEX PEN (AVONEX 30mcg/0.5mL solution for injection) approved in 2012 is an automated injection device designed to be easier to use than the currently available AVONEX Prefilled Syringe - "the first single-use, once-a-week, fully integrated IM autoinjector for MS." AVONEX PEN also incorporates a substantially smaller needle, which may reduce injection anxiety and pain. AVONEX PEN was approved based on data from a Phase IIIb study in which approximately nine out of 10 patients used the device successfully. Ninety-four percent of patients in the study also expressed a preference for AVONEX PEN over the AVONEX Prefilled Syringe. AVONEX PEN was approved in the European Union and Canada in 2011.

Nomenclature: Interferon beta-1a, rDNA/Biogen Idec [BIO]; Avonex [TR]; Interferon beta-1a [FDA]; interferon beta-1a [USAN INN BAN]; interferon beta1 (human fibroblast protein reduced) [CAS]; 145258-61-3 [CAS]; BG9418 [SY]; BG-9418 [SY]; BG-9015 [SY]; BG9015[SY]; BG9216[SY]; Dompe (beta) [TR foreign]; Neoferon [TR foreign]

Biological.: Interferon beta-1a (Avonex) and other interferon beta products have both antiviral and immunoregulatory activities comparable to those of native human interferon beta species. The mechanisms by which interferon beta exerts its actions in multiple sclerosis (MS) are not clearly understood. Interferon beta exerts its biological effects upon binding to specific cell surface receptors. Binding initiates a complex cascade of intracellular events that leads to the expression of numerous interferon-induced gene products and markers. These include MHC Class I, Mx protein, 2’,5’-oligoadenylate synthetase, beta2-microglobulin, neopterin, protein kinase, and indoleamine 2,3-dioxygenase, some of which are mediators of the biological actions of interferon beta. Some of these products have been measured in the serum and cellular fractions of blood collected from patients treated with Avonex. After a single intramuscular dose of Avonex, serum levels some of these products remain elevated for at least 4 days to 1 week.

The are no in vitro models for MS and no accepted animal model for MS in a species responsive to interferon beta. The activities of interferon beta-1b are highly species specific, and most preclinical pharmacologic information of Avonex was derived from studies in cultured human cells and, to a lesser extent, in rhesus monkeys.

In Oct. 2000, Biogen reported that an in vitro assay (developed by Dr. J. Oger, et al., Univ. of British Columbia) showed that Avonex is the most potent of the three available interferon beta products on a mass basis. This was the first in vitro assay for comparison of potency of interferon beta products based on mechanisms relevant to multiple sclerosis. Previously, the only potency assay was for antiviral effects. The assay is based on suppression of secretion of immunoglobulin G (IgG) antibodies, which are increased in MS patients. However, when potency of the three interferon beta products was expressed as a proportion of their weekly-injected dose, the overall effects were comparable. Since there have been no clinical trials comparing the interferon beta products, this is one of the few comparison studies of these products.

Companies.: Avonex was originally developed and manufactured by Bioferon Biochemische Substanzen GmbH & Co. (Germany), a former joint venture between Biogen Corp. (now Biogen Idec) and Rentschler Arzneimittlel GmbH & Co., now part of Boehringer Ingelheim Pharma KG. During late development, this collaboration was terminated, with Rentschler retaining the original cell line and manufacturing rights for product expressed by the BG9015 cell line and Biogen retaining clinical data.

Avonex is manufactured and marketed in the U.S. by Biogen Idec. It was originally commercially manufactured at Biogen facilities in Cambridge, MA, CBER/FDA est. lic. no. 1204. The FDA granted an establishment license to Biogen’s large-scale Avonex manufacturing facility in Research Triangle Park, NC, on March 2, 1998. Cambridge facilities now produce products for clinical trials.

Formulation of the bulk and filling of Avonex for the U.S. market are performed by Ben Venue Labs., Inc., now a subsidiary of Boehringer Ingelheim Pharma KG. The product is labeled and packaged at Packaging Coordinators, Inc. and is distributed by Amgen Inc. Distribution Center (Louisville, KY).

In June 2000, Biogen opened a packaging facility in Hoofddorp, The Netherlands, initially for packaging of Avonex for distribution to all markets outside of the U.S. and Canada. This establishment is the manufacturer of record for Avonex for all international markets.

Marketing rights for certain central and eastern European countries are held by Schering-Plough Corp. (acquired by Merck in 2009). Marketing rights for South Africa are held by Pharmaplan. Rights for Turkey are held by GenIlac. Rights for the Middle East are held by Algorithm. Rights in Latin America and the Caribbean are held by Abbott Labs. Rights in Italy are held by Dompe Biotec in Italy. Rights in Greece are held by Genesys Pharma. Rights in Israel licensed are held by Medixon. Rights in India are held by Nicholas Piramal (NPIL), which launched Avonex in Nov. 2003.

In Sept. 1998, Biogen granted Genzyme General, a subsidiary of Genzyme Corp., rights to commercialize and exclusively distribute Avonex in Japan. Genzyme is responsible for clinical development, product registration, and reimbursement approvals for the product. Genzyme estimates that there are at least 5,000 multiple sclerosis patients in Japan.

Manufacture: The human interferon beta-1a gene was cloned by polymerase chain reaction (PCR) from human genomic DNA isolated from a human leukocyte cell line. The BG9015, BG9016 and BG9418 Chinese hamster ovary (CHO) cell lines were plasmid transformed to express interferon beta-1a. All tests of the BG9418 cell line, used for commercial production, for the presence of infectious agents were negative except for intracytoplasmic A-type retrovirus particles (common in CHO cells). Large scale suspension culture for product for the U.S. market is now performed at Biogen’s dedicated large-scale facilities in Research Triangle Park, NC.

Following fermentation, cells and cell debris are removed, and the supernatant fluid is purified by a series of chromatographic separations. An unspecified viral inactivation step is performed (perhaps, nanofiltration). The purified product (bulk intermediate) is filtered, bottled and stored. This is shipped to Ben Venue Lab. in shipping containers packed in dry ice for final formulation and filling. Bulk intermediate is formulated with Albumin (Human), USP (for lyophilzed product packaged in vials) and diluent and sterilized by filtration. Vials are filled, lyophilized, and sealed. Labeling and packaging are performed by Packaging Coordinators, Inc., with distribution handled by the Amgen Inc. Distribution Center.

FDA class: Biologic PLA

CBER class: Biological Response Modifiers

CBER to CDER: Among the products transferred within FDA on June 30, 2003

Approvals: Date = 19960517; first approval, PLA no. 95-0979/ELA no. 95-0975 granted to Biogen; orphan designation (expired 5/2003); Indication = treatment of multiple sclerosis

Date = 19980302; supplemental PLA/ELA; Indication = new manufacturing site in Research Triangle Park, NC

Date = 20021112; Indication = labeling change to indicate a 5% rate of developing neutralizing antibodies (from previously reported 24% rate)

Date = 20030131; BLA supplement (after conversion to BLA 103628); Indication = revised package insert to include safety and efficacy data from a study of patients who experienced a single clinical exacerbation of multiple sclerosis, and to provide a Medication Guide

Date = 20030528; BLA supplement; Indication = new Albumin (Human)-free liquid formulation of Avonex in pre-filled syringe

Date = 20070202; BLA supplement; Indication = additional intramuscular needle size Date = 20120228; BLA supplements (nos. 5189 and 5191); Indication = two separate dosing regimens/devices for once-a-week treatment of relapsing forms of multiple sclerosis

[full text of "INDICATIONS AND USAGE” section of product insert/labeling]: Indications: [full text of the "Indications and Usage” section of product insert/labeling; 6/2012]:

AVONEX (interferon beta-1a) is indicated for the treatment of patients with relapsing forms of multiple sclerosis to slow the accumulation of physical disability and decrease the frequency of clinical exacerbations. Patients with multiple sclerosis in whom efficacy has been demonstrated include patients who have experienced a first clinical episode and have MRI features consistent with multiple sclerosis.

Status: The PLA was filed on May 22, 1995, received priority review (6 month target), and was approved on May 17, 1996; approval time of ~1 year. U.S. Orphan drug exclusivity for multiple sclerosis expired in May 2003.

Betaseron, a similar recombinant interferon beta from Chiron Corp./Berlex Labs., was approved with orphan status prior to the approval of Avonex (see entry below), and Berlex pressed for denial of FDA approval for Avonex for much the same multiple sclerosis indication based on substantial molecular and indication similarity. The interferon beta-2a in Betaseron has the same amino acid sequence as interferon beta-2a in Avonex, except for a single amino acid substitution. Despite this, under the regulations of the Orphan Drug Act, Avonex was essentially ruled to be a different and, thus, approvable product primarily based on it behaving differently in clinical trials, offering an improved safety profile relative to Betaseron. Specifically, Avonex “was determined by FDA to be a different product from Chiron’s interferon beta-1a, because of a difference in safety profile involving the occurrence of injection site skin necrosis with the Chiron product, but not the Biogen product.” No injection site necrosis was reported in the Avonex (BG9015 product) Phase III study in 158 patients, while an incidence rate of 5% was reported among 124 patients in Betaseron’s Phase III study. The incidence of injection site reactions was 85% in the Betaseron’s Phase III study, and only 4% in the Biogen Phase III study. Biogen’s open label safety study of Avonex in 274 MS patients using BG9418 product reported zero injection site necrosis and 4% injection site reactions, consistent with results with earlier BG9015 product trials. Thus, although not identical in amino acid sequence, orphan drug exclusivity for Avonex was granted on the basis of its improved safety profile (indicative of the two being a different product). FDA approval of Avonex was conditioned on satisfactory completion of multiple Phase IV trials.

Avonex is exempt from CBER/FDA lot release requirements.

In “The FDA’s assessment of follow-on protein products: a historical perspective,” Nature Reviews Drug Discovery (published online April 13, 2007), FDA rationalized its prior approvals of biogeneric/follow-on products, including those with major manufacturing changes. FDA noted that Avonex “illustrates the major challenge associated with approvals of follow-on recombinant versions of approved recombinant products — that is, the amount and type of data needed to demonstrate that a product produced after major changes (for example, use of a new cell line) in the manufacturing process has safety and effectiveness that are comparable with the product manufactured before the change….To obtain approval for Avonex, Biogen had to develop its own manufacturing process for Avonex and demonstrate that the version of interferon beta-1a produced by that process was sufficiently similar to the Bioferon product that the data from the clinical studies using the Bioferon product could be relied on to support approval of the Biogen version…Biogen’s initial effort to develop a new cell line and produce an interferon beta-1a that was comparable with the Bioferon product was unsuccessful. A subsequent effort using another new cell line was successful. Physicochemical testing (for example, peptide maps and glycoform characterizations) indicated that the structures were similar. Multiple bioassays (for example, antiproliferation and enhancement of major histocompatibility complex (MHC) class I expression) indicated that the products had comparable bioactivity, and pharmacokinetic data indicated that distribution and clearance of the products were comparable. On the basis of these data, the FDA concluded that the totality of the evidence indicated that the Bioferon product and Avonex were sufficiently comparable to rely on data from the major efficacy study using Bioferon’s product to support licensure of Avonex. In a subsequent immunogenicity study, the Avonex product demonstrated decreased immunogenicity. Although decreased immunogenicity is advantageous, the fact that there were differences in immunogenicity between the two products highlights the importance of immunogenicity to product evaluations.”

Despite having received full approval in the U.K., the National Institute of Clinical Excellence (NICE), which advises the National Health Service (NHS) on the cost-effectiveness of pharmaceuticals, originally (in June 2000) recommended that beta interferon not be offered by the NHS to MS patients in the UK. NICE considered the £10,000 annual cost per patient too high.

With the product’s launch in France in Jan. 1998, Avonex became available in all major European markets.

Avonex received supplemental European Union (EU) approval on May 20, 2002 for use in the treatment of patients at high risk of developing Clinically Definite Multiple Sclerosis (CDMS). Avonex can be prescribed after a patient has a single MS attack and when alternative diagnoses have been excluded. The standard practice had previously been to start treatment only after patients had experienced two separate and distinct attacks or demyelinating events. This decision made Avonex the only MS treatment approved for earlier use, after the first attack, when patients are considered at high risk for developing MS. This indication is not approved in the U.S., but a supplemental BLA is pending with the FDA. This EU approval was based on Biogen’s long-term clinical study, CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study), which showed a 66% reduction in the risk of developing CDMS based on clinical measures and brain MRI scans in a high-risk subgroup of patients.

In May 2004, Biogen Idec reported potential shortages of Avonex, due to manufacturing problems with some prefilled syringes (formation of aggregates). This led to a $2.1 million inventory write-down (loss). Biogen Idec did not foresee supply problems, but requested that physicians prescribe the lyophilized powdered form to new patients until problems are resolved.

In June 2011, the EU approved Avonex Pen for patients with relapsing multiple sclerosis (MS) and patients who have had a single demyelinating event..

The Feb. 28, 2012 sBLA approval included AVONEX PEN, the first intramuscular (IM) autoinjector approved for MS. AVONEX PEN incorporates a smaller needle and easier administration to help patients reduce anxiety about AVONEX self-injection. A new dose titration regimen was also approved, which gradually escalates the dose of AVONEX at treatment initiation, reducing the incidence and severity of flu-like symptoms that can occur at the beginning of therapy..

In May 2012, Biogen-Idec launched 2 new Avonex delivery systems/methods in the U.S. -- AVONEX PEN (AVONEX 30mcg/0.5mL solution for injection), the first intramuscular (IM) autoinjector for chronic use, designed to enhance the self-injection process; and a new dose titration regimen, facilitated by the AVOSTARTGRIP titration devices, providing patients with the option to gradually increase the dose of AVONEX at treatment initiation to reduce the incidence and severity of flu-like symptoms that patients may experience with therapy. AVONEX PEN is the first IM autoinjector approved in MS treatment.

Tech. transfer: U.S. patent 4,530,901, Weissmann, C., assigned to Biogen N.V., filed Feb. 4, 1980, granted July 23, 1985, covers recombinant interferon beta-1a. Biogen has claimed that patent U.S. patent protection for Avonex extends for at least another decade, e.g., 5,326,859 (expires in 2011) and 5,514,567 (expires in 2013).

The Aug. 26, 2002 Wall Street Journal incorrectly stated the patent expiration date for Avonex is in 2003 (when orphan exclusivity expires). Also, DataMonitor and ABN Amro have reported that U.S. patent protection for Avonex expires in 2003.

The Juridical Foundation, Japanese Foundation for Cancer Research (JFCR), has received U.S. and foreign patents, the “Taniguchi patents,” claiming the gene sequence of interferon beta. Taniguchi, et al., was the first to clone interferon beta. Biogen has nonexclusively licensed this technology, including 5,326,859 and 5,514,567, expiring in 2011 and 2013, respectively. The last of the Taniguchi patents expires in the U.S. in May, 2013, and related patents have expired already in other countries.

Berlex Labs., Inc., then a subsidiary of Schering AG, now Bayer Schering Pharma AG, manufacturer of a competing interferon beta product (Betaseron), filed suit against Biogen on July 3, 1996 alleging infringement of its “McCormick” U.S. patents concerning production of recombinant interferon beta in Chinese hamster ovary (CHO) cells, including 5,376,567 and a later continuation, 5,795,779. Biogen had previously filed suit against Berlex, Schering AG, and Stanford University seeking a judgement that it was not infringing 5,376,567 and that the patent was invalid. Biogen and Stanford University subsequently entered into an agreement voluntarily dismissing the university from the suit. In Sept. 2000, a U.S. District Court ruled in favor of Biogen, i.e., that Avonex does not infringe Berlex’s patents (covering Betaseron), and Berlex appealed.

Final settlement of the “McCormick” dispute between the companies was announced in Jan. 2002. Biogen received a fully paid up, royalty-free, non-exclusive license to 5,376,567 in return for a payment to Berlex of $20 million. A second/final payment from Biogen to Berlex would be due, if the Court of Appeals for the Federal Circuit (CAFC) were to reverse the District Court’s previous ruling granting summary judgment in favor of Biogen. The companies agreed not to pursue further litigation concerning these patents.

In Jan. 2003, the CAFC partially reversed the District Court’s ruling concerning the “McCormick” patents. This included remanding the case to the District Court to decide whether Berlex patents were infringed under a redefinition of the “doctrine of equivalents.” The District Court found in favor of Berlex (i.e., that Biogen was infringing). As stipulated in their prior settlement agreement, Schering AG received $55 million from Biogen, with this considered as nonexclusive licensing fees payable by Biogen Idec until 2007. Schering AG (keeping ~2/3rds) shared this with Stanford University and Chiron Corp. This payment was in addition to the $20 million received by Berlex from Biogen in Jan. 2002. In the worse case for Biogen, the final payment could have been ~$230 million.

In Oct. 1992, the European Patent Office (EPO) Boards of Appeal issued a final ruling in an oppostion filing against EPO patent application EP81300050 (EPO patent no. 32 134, granted Aug. 15, 1984), “DNA sequences, recombinant DNA molecules and processes for producing human interferon-alpha like polypeptides,” concerning interferon beta, assigned to Biogen Corp. The opposition had been filed by . Hoffmann-La Roche AG; Upjohn Company (now Pfizer); Bender & Co. GmbH; Cetus Corp. (now Chiron Corp.) and Triton Biosciences Inc., a subsidiary of Schering AG; Hoechst AG (now Sanofi Aventis); and Boehringer Mannheim GmbH (merged into Hoffmann-La Roche); and Boehringer Ingelheim Zentrale GmbH and Boehringer Ingelheim Pharma KG. The EPO ruled in favor of the challengers, including that the patent “did not even disclose the successful preparation of beta-interferon from plasmids containing DNA-sequences coding for this protein.”

In Oct. 1998, Biogen filed an opposition against then recently issued European Patent 529300 B1 (“Rentschler II Patent”) assigned to Rentschler Biotechnologie GmbH (now part of Boehringer Ingelheim ) challenging the validity of this composition-of-matter patent concerning recombinant glycosylated beta-interferon. This patent covers a certain group of beta interferons with specific glycosylations resulting from genetic engineering. In Nov. 2002, the European Patent Office ruled in favor of Rentschler (upheld validity of its European patent). Rentschler filed an infringement suit against Biogen in Germany, and Biogen appealed.

Biogen has nonexclusively licensed interferon-beta technology from Hoffmann-La Roche Ltd., apparently including U.S. 4,921,699, granted May 1, 1990, and 4,816,566, with these patents expiring in May 2009, and having generally expired elsewhere in the world. These patents claim interferons, including interferon beta, with one cysteine replaced by another amino acid to prevent formation of intermolecular disulfide bonds.

In April 2003, Rentschler and Biogen settled their European patent disputes, with Rentschler granting Biogen a nonexclusive European license to EP 529300 for current and future interferon beta products, and Biogen paying Rentschler an initial $13.1 million payment and unspecified future royalties on sales. [Also in April 2003, BioPartners GmbH, a company developing a biogeneric human albumin-free version of interferon beta, nonexclusively licensed worldwide rights to EP 529300 and associated trade secrets and CMC information from Rentschler, and has contracted with Rentschler for manufacture of its interferon beta product]. Biogen reports that the Rentschler EU patent expires in July, 2012.

In Dec. 1998, Biogen settled a dispute with ASTA Medica GmbH relating to a terminated 1989 agreement between Biogen, ASTA and Bioferon under which ASTA had obtained a license to certain Biogen’s patents related to recombinant beta interferon for a number of European countries. Under the terms of the settlement, ASTA dismissed its lawsuit against Biogen in the U.S. and released Biogen from all claims related to the 1989 agreement; and Biogen paid an undisclosed amount to ASTA.

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 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.

U.S. patent protection for Betaseron/Betaferon was projected by Decision Resources to expire in 2007, and in most European countries in 2008. 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 Sept. 2010, Biogen Idec received U.S. 7,588,755, "DNA sequences, recombinant DNA molecules and processes for producing human fibroblast interferon-like polypeptides," claiming certain interferon beta gene sequences (and later also 7,635,466). The company promptly filed patent infringement suits against Betaferon, Rebif and Extavia. This patent expires on Sept. 15, 2026, well after expiration of other patents in May 2013. Some might consider this a submarine patent, but the delay in obtaining the patent appears to lie with the USPTO, not Biogen Idec. The '755 patent claims priority to a first application filed in 1981 and a divisional application filed in 1989, both abandoned. The application that resulted in the '755 patent was filed on May 25, 1995, and thus has a patent term of 17 years from issue, determined by U.S. law prior to the adoption of the GATT provision limiting U.S. patent term to 20 years from the earliest priority date. During prosecution, there was a delay from March 12, 1998 to Jan. 15, 2003 -- almost five years -- while prosecution was suspended because of a potential interference. But no interference was declared. A second extensive period of delay involved the appeal of an asserted anticipation rejection, which was complicated by new rules for appeal briefs promulgated (and strictly enforced) by the USPTO. This delayed prosecution of the application to allowance by another 3 years, from June 24, 2005 to May 29, 2008. In addition to USPTO delays, the extended term of this patent is an artifact of the change in patent term in the U.S. The reason the term seems so long is that everyone has become accustomed to a 20-year maximum from the earliest priority date, with the prior norm of 17 years from grant date seeming anomalous, especially when the term is as extended as it is in this case (31 years from the application filing date, and 45 years from the earliest priority date). Something like this could not occur today. The ability of this patent to protect against biogeneric/biosimilar competition may depend in future understanding of the cause of MS, with claim no. 1 citing, "A method for immunomodulation or treating a viral conditions, a viral disease, cancers or tumors..." If MS treatment is not linked to viral infection or immune modulation, the patent may not apply

Trials: The CHAMPS study has shown that early treatment with Avonex significantly reduces the rate at which individuals at high-risk for MS developed clinically definite multiple sclerosis (CDMS). CHAMPS (Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study) was a longitudinal follow-up of the patient groups enrolled in an earlier Biogen MS treatment study conducted between April 1996 and April 1998. CHAMPS followed 383 patients given weekly injections of Avonex or placebo after experiencing a first MS-like symptom. CHAMPS was planned to last three years, but was stopped in Feb. 2000 after a pre-planned interim efficacy analysis found that the benefit of Avonex treatment was significant enough to halt the trial. Treatment with Avonex reduced the rate of development of CDMS by 44% versus placebo. Avonex also showed a highly significant positive impact on reducing the rate at which patients developed brain abnormalities or lesions visible on MRI scans. The increase in brain MRI T2 lesion volume (which reflects cumulative scarring) was 91% lower in the Avonex patients compared to the placebo group. CHAMPS results were published in the Sept. 2000 New England Journal of Medicine.

In early 2002, a Biogen-sponsored trial with Avonex in 795 relapse remitting MS patients treated for four years found that patients with interferon beta-neutralizing antibodies had a 34% higher annual relapse rate compared to patients without antibodies. This was the first demonstration of the effects of antibodies in MS clinical outcomes.

In Sept. 2005, Biogen Idec initiated GAP, an international, cross-sectional study of adherence to long-term MS treatment regimens in 1,800 patients. Patients taking Avonex, copaxone glatiramer from Teva, and Rebif from Serono were included.

In April 2007, one-year data were presented from the retrospective, claims-based, observational Multiple Sclerosis Benchmarks study in 10,000+-patients. Using a comprehensive analysis of medical and pharmacy costs, the study concluded that patients treated with Avonex have the lowest total one-year cost to a health plan when compared to other interferon beta treatments. Researchers analyzed 10,622 patients over one year to assess how demographic, administrative and clinical variables affect MS costs and utilization patterns and to examine the economic impact of treating MS. Avonex had the lowest average one-year cost compared to other interferon beta treatments. The total costs over one-year to MS patients on interferon beta therapy were: Avonex, $19,896.15; Rebif, $22,207.85; and Betaseron, $21,073.33. Avonex patients were also more likely to refill their prescriptions (average of 9.6/year vs. 8.1 and 8.2/year for the other interferon beta therapies) and were less likely to use certain concomitant medications. Use of disease-modifying therapies (interferon beta and glatiramer acetate) was almost always observed as monotherapy, reflecting little evidence of combination use or switching between products. In a separate study, Quality Assessment of Multiple Sclerosis Therapy (QUASIMS), reported at the same conference, it was shown that MS patients do not derive additional clinical benefit from switching among interferon beta therapies. QUASIMS was an open-label, retrospective, observational study conducted in 14 countries in 7,156 MS patients who had received two years of uninterrupted therapy with interferon beta as initial therapy or follow-up therapy.

In April 2008, results were published in Current Medical Research and Opinion from a Phase IV (post-marketing), open label, head-to-head study of intramuscular Avonex and high-dose, high-frequency subcutaneous Rebif (interferon beta-1a; see related entry) in patients with relapsing-remitting multiple sclerosis (RRMS). The two products showed similar efficacy over 18 to 30 months of continued therapy. The Prospective and Retrospective Long-Term Observational Study of Avonex and Rebif (PROOF), involved 217 patients with 136 completing a median of 25.9 months of AVONEX 30 µg once weekly (n=69) and a median of 22.2 months Rebif 44 µg three times weekly (n=67). T he study provides further clinical evidence that the dose and frequency of treatment shows no advantage on delivering better efficacy. So, with safety and efficacy being comparable, Biogen Idec expects Avonex, with its more convenient dosing, to have marketing advantage over Rebif.

Medical: The generally recommended dosage (for relapsing MS) is 30 µg (1.0 ml of reconstituted product) administered by intramuscular injection once weekly. (This compares to 250 µg every other day by subcutaneous injection for Betaseron).

AVONEX is administered intramuscularly. The recommended dose is 30 micrograms once a week. To reduce the incidence and severity of flu-like symptoms that may occur when initiating AVONEX therapy at a dose of 30 micrograms, AVONEX may be started at a dose of 7.5 micrograms and the dose may be increased by 7.5 micrograms each week for the next three weeks until the recommended dose of 30 micrograms is achieved . The AVOSTARTGRIP kit containing 3 titration devices can be used for titration and is to be used only with AVONEX Prefilled Syringes.

As discussed in the Interferon Products entry (in the Blood Products, Human section), administration of interferon products can result in induction of associated neutralizing antibodies which can reduce or even eliminate the activity and efficacy of the product. This is a particularly serious problem with interferon beta products used for treatment of multiple sclerosis. These patients must receive treatment for long periods, e.g., 10-30 years, often starting at an early age, so loss of the major treatment option (interferon beta) to induction of antibodies can be serious. Manufacturing-related changes can affect the development of neutralizing antibodies in the bulk and final products. The incidence of neutralizing antibodies due to Avonex (Manufactured by Biogen) is reported in the 2-6% range, is lower than for other interferon beta products, and is lower (~24%) than that for Avonex originally manufactured in Germany by Rentschler. FDA approved a label change reporting this lower incidence in Nov. 2002.

Market: Total worldwide sales of Avonex were $2.518 billion in 2010; $2.323 billion in 2009 and 2.226 billion in 2008.      In 2008, U.S. sales of increased 18% to $1.3 billion and international sales increased 18% to $926 million..

Total worldwide sales of Avonex were $1,857 billion in 2007; $1.794 billion in 2006; $1.54 billion in 2005; $1.417 billion in 2004; $1.168 billion in 2003; and $1.3 billion in 2002 (achieving blockbuster status), $970.5 million in 2001, $761 million in 2000, $621 million in 1999, $395 million in 1998, and $240 million in 1997. In 2004, U.S. sales were $922 million and international sales were $495 million; and in 2003, were $800 million and $368 million, respectively.

The 2007 Average Wholesale Price (AWP) is $1,672.20 for four 30 µg/0.5 mL syringes, and also for four 33 µg vials (Red Book, 2007).

In April 2008, Biogen Idec reported that Avonex had become, "the number one most prescribed treatment for relapsing forms of MS worldwide, with more than 130,000 patients on therapy." Also, Avonex was "the number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is effective after the first attack....The number one prescribed treatment for relapsing forms of multiple sclerosis (MS) worldwide, and is the only once-a-week MS therapy that is effective after the first attack."

In 2002, Avonex became the first multiple sclerosis treatment to attain $1 billion annual sales and with a market share above 50% in the U.S market (now down to about 31%). Avonex was reported in early 2002 to be the U.S. market leader, with a 56% U.S. market share among MS therapeutics, and 35% market share outside the U.S.

In June 2000, the National Institute of Clinical Excellence (NICE), which advices the U.K. National Health Service (NHS) on the cost-effectiveness of pharmaceuticals, recommended that beta interferon, including Avonex, not be offered by the NHS to MS patients. NICE considered the £10,000 (~$15,000) annual cost per patient to be too expensive. In early 2002 (after much criticism), NICE recommended use of beta interferon for MS, and estimated the annual cost (at the cost it had negotiated) for treatment of MS with Avonex (plus glaritamer acetate) to be $12,054.

Sales of Avonex are expected to increase as Biogen Idec promotes it as superior to Betaseron and as new MS patients begin interferon beta therapy, with increasing acceptance of the need to ‘treat early’ and treat all persons with MS, and with growing patient awareness of Avonex. Biogen Idec estimates that there are about 330,000 persons in the U.S. and Europe with relapsing forms of MS, with only about one-third receiving drug treatment (suggesting there may be a large potential for increased sales).

Avonex received approval in May 2002 from the Center for Medicare and Medicaid Services (CMS) for Medicare coverage for multiple sclerosis patients. In Dec. 2000, Congress clarified and expanded Medicare coverage of drugs and biologics by adding a provision (Section 112) to the Benefits Improvement and Protection Act of 2000 (BIPA). This reversed an August 1997 program memorandum by CMS, which had resulted in the termination of Medicare coverage for Avonex. Medicare had covered Avonex upon approval in the U.S. in 1996 until the 1997 program memorandum.

Avonex has been reported to be the most cost-effective of available interferon beta products for MS treatment, as discussed in the Trials section above.

Competition: In the MS therapeutics market, for comparison in 2003 Avonex total sales were $1.17 billion, Betaseron/Betaferon sales were ~$924 million (~$1 billion in 2004), Rebif sales were ~$819 million, and Copaxone (glutiramer acetate) sales by Teva (copromoted by Sanofi Aventis in the U.S) were $720 million.

Ongoing: Biogen (now Biogen Idec) has linked with Inhale Therapeutic Systems, Inc. for development of a dry powder formulation of Avonex for pulmonary (inhalation) delivery for treatment of multiple sclerosis. Inhale Therapeutic Systems received an upfront payment and may receive up to $25 million in R&D funding and milestone fees. Phase I trials began in April 2000. Biogen provides bulk interferon beta-1a for formulation by Inhale Therapeutic Systems. Biogen Idec retains full marketing rights, but has halted active development for MS and is exploring development for other indications:.

Aegis Therapeutics LLC (San Diego, CA) is in the early stages of developing intranasal formulations of interferon beta. Therapeutic Proteins Ltd. has reported it is developing a biogeneric interferon beta product. Nautilus Biotech S.A. is in preclinical development with a long-acting interferon beta mutein.

A generic (biogeneric, biosimilar, follow-on biologic, etc.) version of mammalian cell-expressed, glycosylated interferon beta-1a product developed and manufactured by the Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB (Stuttgart), Germany, in collaboration with CinnaGen (Tehran, Iran) is the first product from Fraunhofer to receive approval (as a biogeneric) – in Iran where it is marketed as CinnoVex by CinnaGen. A more soluble variant of interferon-beta also engineered by Fraunhofer is being developed by Vakzine Projekt Management (VPM) GmbH (Braunschweig, Germany).

In Nov. 2006, Stada Arzneimittel AG (Germany) abandoned its development of a biogeneric version of interferon-beta for multiple sclerosis, citing limited marketing opportunities.

Therapeutic Proteins, Ltd. (U.K.) is developing a biosimilar/biogeneric, Chinese hamster ovary (CHO) cell expressed interferon beta-1a (and also interferon beta-1b; similar to Avonex) for treatment of multiple sclerosis.