Status - approved; marketed

Organizations involved:

Bayer HealthCare Pharmaceuticals – Manuf.; R&D; Tech.; USA Mark.

Bayer Schering Pharma AG – Intl. mark.; Parent

Biogen Idec – Patent dispute

Boehringer Ingelheim Pharma KG – Manuf.

Chiron Corp. – Manuf.; R&D; Tech.; Former

Berlex Laboratories – Former

Triton BioSciences, Inc. – Former

Shell Oil – Parent; Former

Cetus Corp. – Former

Schering AG – Former

Biogen Corp. – Patent dispute

Cross ref.: See the Interferon Products entry in the Blood Products, Human section and the other interferon beta product entries above.

See also the entry for Extavia from Bayer Schering, which is Betaseron from Bayer Schering relabeled for distribution by Novartis AG.

Description: Interferon beta-1b, interferon betaser or Betaseron is a lyophilized (freeze-dried) formulation of a recombinant non-glycosylated mutein (variant form) of human interferon beta-1b protein produced by Escherichia coli (E. coli) transformed with a plasmid containing the gene for human interferon beta obtained from human fibroblasts altered to substitute serine for the cysteine residue at position 17. Interferon betaser is composed of 165 amino acids, has a molecular weight of ~18,500 Daltons (~18.5 kDa) and a molecular formula of C903-H1399-N245-O252-S5. Betaseron is the only high-dose interferon beta approved to be taken every other day, and is the most frequently dosed high-dose interferon beta therapy.

Betaferon is the trade name for Bayer Schering product in Europe. Extavia is an identical (relabeled) product, obtained from Bayer Schering, marketed by Novartis AG. Thus, both Bayer Schering and Novartis AG now market the same inteterferon betaser in Europe.

Interferon beta-1b is not glycosylated with carbohydrate side chains as is native human interferon beta and the other marketed versions of recombinant interferon beta (Avonex from Biogen Idec and Rebif from Merck Serono) produced in mammalian cells. The lack of carbohydrate side chains attached to non-glycosylated interferon beta-1b does not significantly affect its antigenicity, biological or therapeutic activity.

The interferon betaser mutein was designed by Cetus Corp. (now Chiron Corp.) to provide functional advantages over non-modified human recombinant interferon beta. A cysteine residue that is not essential to biological activity was replaced with another amino acid, serine, to eliminate sites for potential intermolecular crosslinking and incorrect intramolecular disulfide bridge formation. The TGT codon at position 17 of the coding sequence for the mature interferon beta was modified to an AGT codon, thereby replacing the cysteine (cys) at position 17 with a serine. This modification eliminates a free sulfhydryl (-SH) group which contributes to the formation of oligomers and/or to the formation of random, incorrect disulfide links which can alter the protein's conformation and specific activity.

The mutein is produced by bacterial expression of genes synthesized by oligonucleotide-directed mutagenesis. Interferon beta without the betaser17 modification can be manufactured by E. coli rDNA techniques. However, the product contains dimers and oligomers which form in E. coli extracts containing high concentrations of interferon beta. Multimer formation makes purification and separation of the desired monomeric protein difficult, requiring several additional laborious steps in the purification and isolation procedures, e.g., reducing the protein during purification and reoxidizing it to restore its conformation. Also, E. coli-expressed interferon beta, unlike E. coli-expressed interferon betaser, exhibits low specific activity (low potency). The betaser17 mutein can be manufactured in a monomeric form, facilitating isolation and purification, and retains the specific activity of native interferon beta.

The specific activity of interferon beta-1b in Betaseron is approximately 3.2 x 106 (3.2 million) International units (IU)/mg, providing approximately 9.6 x 106 or 9.6 million IU/0.3 mg dose. The IU unit of measurement is derived by comparing the antiviral activity of the product to the World Health Organization (WHO) reference standard for recombinant human interferon beta. Prior to 1993, a different analytical standard based on native human interferon alpha was used to determine potency. This method assigned a potency of 5.4 x 106 (5.4 million) IU to a single dose of 0.3 mg.

Betaseron is packaged as lyophilized powder in vials for subcutaneous injection after reconstitution with the diluent supplied (Sodium Chloride, 0.54% Solution). Each vial contains 0.3 mg of interferon beta-1b, 15 mg Albumin (Human), USP, and 15 mg Mannitol, USP. Mannitol (formerly Dextrose USP) and Albumin (Human), USP (15 mg each/vial) are added as stabilizers. The reconstituted product contains no preservative. Betaseron should be stored at room temperature 25°C (77°F), but may be stored between 15 to 30°C (59 to 86°F). Betaseron is the only available refrigeration-free MS therapy that can be stored at room temperature for longer than 30 days. Expiration dates are printed on the blister packs that each hold 15 vials.

In June 2006, Berlex launched Betaject 3, a new autoinjection device for Betaseron as an optional injection method for patients with relapsing forms of MS. Betaject 3 automatically delivers subcutaneous injections at a standard preset needle depth, eliminating a calibration step prior to each injection.

Nomenclature: Interferon betaser, rDNA/Bayer [BIO]; interferon beta-1b [FDA USAN INN BAN]; Betaseron [TR reg. to Bayer Schering]; Betaferon [TR used in Europe; reg. to Bayer Schering]; 2-166-interferon b1 (human fibroblast reduced), 17-L-serine- [CAS]; 145155-23-3 [CAS RN]; 96778-78-8 [CAS RN]; Interferon beta1, 17-L-serine-, (2S-(2R*,5R*))- [SY]; NVF233 [SY]; Human Recombinant Betaser17 Interferon [SY]; 50419-523-25 [NDC]

Biological.: Interferon beta-1b has been shown to possess both antiviral and immunoregulatory activities comparable to that of native human interferon beta species. The mechanisms by which Betaseron exerts its actions in multiple sclerosis (MS) are not clearly understood. However, it is known that the biologic response-modifying properties of interferon beta-1b and other beta interferons are mediated through its interactions with specific cell receptors found on the surface of human cells. The binding of interferon beta-1b to these receptors induces expression of a number of interferon-induced gene products (e.g., 2’,5’-oligoadenylate synthetase, protein kinase, and indoleamine 2,3-dioxygenase) that are believed to be the mediators of the biological actions of interferon beta-1b. A number of these interferon-induced products have been readily measured in the serum and cellular fractions of blood collected from patients treated with interferon beta-1b.

The is no in vitro model for MS and no generally accepted animal model of MS in a species responsive to interferon beta. The activities of interferon beta are highly species specific, and most preclinical pharmacologic information for development of Betaseron was derived from studies in cultured human cell and, to a lesser extent, in non-human primates.

Companies.: Betaseron was originally (until late 2008) nanufactured by Chiron Corp. (Emeryville, CA) now merged into Novartis AG, CBER/FDA biologics est. lic. no. 1106, originally for U.S. marketing by Berlex. formerly a subsidiary of Schering AG (now Bayer Schering AG), now a subsidiary of Bayer Schering Pharma AG, and renamed Bayer HealthCare Pharmaceuticals. As discussed below and in the Extavia entry, Novartis has obtained rights to market the same product, and received approvalsa for Extavia, identical to Betaseron/Betaferon and obtained from Bayer Schering.

Interferon betaser for the U.S. market (Betaseron and Extavia) is manufactured at former Chiron/Novartis facilities, now owned by Bayer Schering, in Emeryville, CA. Interferon betaser for both Betaferon and Extavia for European marketing was formerly manufactured for Schering, now Bayer Schering, under contract by Boehringer Ingelheim, with Bayer Schering now providing finished product (identical to Betaferon) to Novartis for its marketing as Extavia.

Initial development of Betaseron was performed by Cetus Corp. (later merged into Chiron) through a joint venture with Triton BioSciences, Inc., then a subsidiary of Shell Oil. Cetus formed a new alliance with Triton in Feb. 1986 and licensed Betaseron to Triton Biosciences, which was acquired in Nov. 1990 and merged into Berlex Laboratories, a subsidiary of Schering AG, later acquired by Bayer AG, now Bayer Schering Pharma AG. Schering AG and Bayer Schering Pharma AG are not related to the American company Schering-Plough Corp. Chiron merged into Novartis AG in Oct. 2005. In Spring 2006, Bayer AG acquired Schering AG, with the company renamed Bayer Schering Pharma AG.

Betaseron was exclusively marketed in the U.S. by Berlex Labs., now as subsidiary of Bayer Schering Pharma, and recently renamed Bayer HealthCare Pharmaceuticals. Chiron received 30% royalty on sales of Betaseron by Berlex/Bayer Schering, with this changing after finalization of the sale of Betaseron by Chiron/Novartis to Bayer Schering (see below). In Jan. 2006, it was reported that Schering AG received 22% royalty on worldwide sales of Betaseron (suggesting that the 30% royalty reported is for product manufactured by Chiron and sold primarily in the U.S.). Schering was reported in Dec. 2005 to pay Chiron about $180 million a year in royalties.

Betaferon, the same identical product as Betaseron is manufactured by Boehringer Ingelheim Pharma KG (BI) under contract to Bayer Schering. This is marketed by Bayer Schering as Betefaron in Europe and other countries worldwide. Betaferon has been reported to be BI’s largest manufacturing contract.

In Feb. 2006, Schering AG (now Bayer Schering Pharma AG) acquired all rights to Betaseron held by Chiron. The acquisition of Chiron by Novartis AG had triggered a clause in the agreement between Schering and Chiron which would have provided Novartis with rights to produce and market the drug in parallel with Schering starting in 2008, had Schering had not exercised its option to purchase exclusive rights. Schering AG purchased or leased all assets used by Chiron in the manufacture for Betaseron and all contractual rights at their fair market or lease value. The agreement required that the value be determined by an independent third party mutually agreed upon by both parties. The collaboration between Chiron and Bayer Schering was set to expire in Oct. 2008. The product insert and other FDA documentation as of 3/2007 reported Chiron as manufacturer of Betaseron.

In March 2007, the deal between Novartis and Bayer Schering was finalized. Bayer received a license for all intellectual property rights from Novartis, including allowing Bayer Schering to establish its own brand of interferon beta-1b from 2009 forward. Bayer Schering acquired an Emeryville, CA, Chiron (Novartis) Betaseron manufacturing facility, and will continue to manufacture Betaseron for the U.S. market at this site. Bayer Schering Pharma paid a total of ~$110 million as a one-off payment for the related equipment and lease, and $90 for acquisition of Betaseron manufacturing-related assets. After six years all land and buildings leased to Bayer Schering Pharma for the production of Betaseron will revert back to Novartis, which will continue operations at the Emeryville site. Novartis is assisting Bayer Schering in assuming Betaseron manufacturing, and will also help Bayer Schering qualify another possible supplier of the product. Bayer Schering will continue to pay Novartis royalties equivalent to those being paid currently on net sales of Betaseron until expiration of their original regulatory filing, development and supply agreement in Oct. 2008. Also, Bayer Schering supported Novartis in the regulatory filing process of a Novartis brand (Extavia) of interferon beta-1b, and Bayer Schering manufactures and supply Extavia to Novartis from 2009 forward and receives in return a double digit royalty payment from Novartis.

As of 2008, Chiron/Novaris continued to manufacture Betaseron for the U.S. market for Bayer Schering, while Bayer Schering has assumed the Boehringer Ingelheim contract for Betaferon manufacture for the European/foreign market, and has assumed Betaseron manufacture from Chiron/Novartis.

In May 2011, Bayer Schering reported it was outsourcing Betaferon manufacture to Boehringer Ingelheim. With this Bayer continued to phase out operations in Emeryville, CA, leased in 2007 from Novartis (formerly Chiron facilities), with the facilities to be returned to Novartis in 2013.

Manufacture: Recovery, purification and formulation processes involve fermenting the host organisms transformed to express interferon beta-1b, disrupting the E. coli cell membranes, separating the refractile bodies containing the recombinant interferon from the rest of the cellular debris, solubilizing the refractile material in an aqueous buffer under reducing conditions, extracting the interferon with 2-butanol or 2-methyl-2-butanol, subjecting the extracted interferon to chromatographic purification, diafiltering or desalting (preferably) the interferon to remove the solubilizing agent, and formulating the purified interferon beta-1b stabilized with Albumin (Human).

FDA class: Biologic PLA

CBER class: Biological Response Modifiers

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

Approvals: Date = 19930723, first approval, PLA/ELA; orphan designation (expired 7/2000)

Date = 20020100; BLA supplement; Indications: = room temperature stable formulation for subcutaneous injection

Date = 20030314; indications: = revised the Clinical Studies section, Adverse Reactions and Warnings sections of the package insert, and provided a Medication Guide

Date = 20030328; BLA supplement; Indications: = approval for treatment of relapsing-remitting MS (RRMS) [revisions to insert/labeling include data from two studies in patients with secondary progressive (relapsing forms) multiple sclerosis; indication section revised to include “for the treatment of relapsing forms of MS to reduce the frequency of clinical exacerbation”; updated safety information; and a new patient Medication Guide]

Date = 20031013; BLA supplement; Indications: = new pre-filled diluent syringe system

Date = 20060700 (launch, not approval, date); BLA supplement; Indications: = new autoinjection device, Betaject 3, specifically designed to work with Betaseron as an optional injection method for patients with relapsing forms of MS

Date = 20061023; BLA supplement; Indications: = MS treatment in patients having experienced a first clinical episode and with MRI features consistent with MS (earliest stage of MS)

Date = 20080915; announcement (not approval) of upcoming availability of new 30-gauge needle, the thinnest needle of any injectable disease- modifying therapy for people with MS.

Indications: [full text of the "INDICATIONS AND USAGE” section from product insert/labeling, 10/4/2009]:

Betaseron (Interferon beta-1b) is indicated for the treatment of relapsing forms of multiple sclerosis to reduce 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 with FDA in June 1992, received priority review, and received accelerated approved on July 23, 1993 (approval time of ~1.1 year) with orphan drug exclusivity (now expired). Betaseron was launched in the U.S. on Oct. 1, 1993. A supplemental BLA for treatment of secondary progressive multiple sclerosis was filed on June 30, 1998. A room temperature (non-refrigerated) formulation was approved by FDA in Jan. 2002 and launched in May.

Betaseron was the first biologic and biopharmaceutical product and the second therapeutic of any type to be licensed under FDA’s accelerated approval regulations. Accelerated approvals are granted on the basis of improvements in surrogate endpoints, rather than traditional clinical efficacy (e.g., disease progression, survival). In the case of Betaseron, a double-blind, randomized, placebo-controlled trial, showed indications: of efficacy, including decreases in clinical exacerbations and the area of lesions as determined by magnetic resonance imaging (MRI) of the brain. These initial studies did not demonstrate a correlation between changes in lesion size and slowing of disease progression. It has been estimated that accelerated approval based on surrogate markers made Betaseron available 48 or more months earlier than would have been required for traditional, full, clinical endpoint based approval. Berlex/Bayer Schering is not actively developing Betaseron for indications: other than multiple sclerosis.

European Union (EU) approval was granted on Nov. 30, 1995 for relapsing remitting MS (RRMS) in patients with two or more relapses within the last 2 years and to treat secondary progressive MS with active disease evidenced by relapses.. Room temperature formulation was approved in the EU in Dec. 2002.

On Feb. 23, 2006, a BLA supplement was accepted for filing by FDA seeking approval of Betaseron for multiple sclerosis treatment to delay a second exacerbation in patients having experienced a first clinical monofocal or multifocal demyelinating event, either monofocal (i.e., clinical evidence of a single lesion) or multifocal (i.e., clinical evidence of more than one lesion). This was supported by the results of BENEFIT, the largest study of patients with the first clinical signs of MS. The trial showed that Betaseron treatment reduced the risk of developing clinically definite MS (CDMS) by 50% compared with placebo. Patients in the Betaseron group were two times better protected against developing MS, as defined by the McDonald diagnostic criteria. The sBLA was approved in Oct. 2006. With this Betaseron became the only interferon-beta approved for use after the first event suggestive of MS. Betaseron is the only high-dose, high-frequency interferon beta indicated for patients at the earliest stage of MS.

On May 26, 2006, the European Union granted Betaferon supplemental approval for early and relapsing forms MS, i..e,. for patients with a first clinical event suggestive of multiple sclerosis, with Betaferon becoming the only high-dose high-frequency therapy approved for the earliest stages of MS, and allowing treatment of the majority of patients at risk for MS.

In Aug. 2006, Betaferon received European Union supplemental approval for treatment of early stage MS.

On May 26, 2008, Novartis AG received European Union (EU) approval for Extavia, i.e., Betaferon provided by Bayer Schering (Manufactured under contract by Boehringer Ingelheim) and relabelled as Extavia, for the same MS indications: as Betaferon. See the related entry.

In Sept. 2008, Bayer Schering announced impending U.S. launch of a new 30-gauge needle for use with Betaseron. This is the thinnest needle of any injectable disease- modifying therapy for people with MS, and is as thin as the needle commonly used for insulin and pediatric injections. Issues around injections, such as injection anxiety, injection fatigue and injection site pain, are among the top reasons MS patients cite for not starting or continuing an injectable medication.

Tech. transfer: The product insert/labeling cites U.S. patents 4,588,585; 4,959,314; 4,737,462; and 4,450,103.

U.S. patent 4,959,314, “Cysteine-depleted muteins of biologically active proteins,” Mark, D.F, et al., Sept. 25, 1990, assigned to Cetus (now Chiron), describes, “Muteins of biologically active proteins such as IFN-beta and IL-2 in which cysteine residues that are not essential to biological activity have been deleted or replaced with other amino acids to eliminate sites for intermolecular crosslinking or incorrect intramolecular disulfide bridge formation. These muteins are made via bacterial expression of mutant genes that encode the muteins that have been synthesized from the genes for the parent proteins by oligonucleotide-directed mutagenesis.”

U.S. 4,737,462, “Structural genes, plasmids and transformed cells for producing cysteine depleted muteins of interferon-beta,” April 12, 1988, assigned to Berlex Labs., describes recombinant betaser17 mutein. The native gene was obtained from human fibroblasts and altered to substitute serine for the cysteine at position 17. See also U.S. 4,588,585, “Human recombinant cysteine depleted interferon-beta muteins,” May 13, 1986, assigned to Cetus Corp. (now Chiron)

U.S. 4,450,103, Konrad, et al., “Process for recovering human IFN-beta from transformed microorganism,” May 22, 1984, assigned to Cetus Corp. (now Chiron), describes a process for recovering unglycosylated interferon beta from transformed E. coli by disrupting the cell membranes of the bacteria; solubilizing the interferon beta from the disruptate into an aqueous medium with a solubilizing agent such as sodium dodecyl sulfate (SDS); extracting the interferon beta from the aqueous medium with 2-butanol, 2-methyl-butanol, or mixtures under conditions that maintain phase separation between the aqueous medium and the extractant; and isolating the interferon beta from the extractant, e.g., by precipitating it from an aqueous buffer mixture of the extractant by lowering the pH.

Other patents assigned to Cetus/Chiron concerning purification of interferon beta include 4,462,940; 4,894,330; and 4,961,969. U.S. 4,894,330, “Purification of recombinant beta-interferon incorporating RP-HPLC,” Jan. 16, 1990, assigned to Cetus Corp., describes reverse phase-high pressure liquid chromatography (RP-HPLC) methods for purifying recombinant interferon beta using wide pore silica gel reverse-phase columns and solvent systems. U.S. 4,894,330, e.g., its Protocol 1, describes manufacture of interferon beta (but apparently not the more streamlined manufacture of interferon betaser), including repeated cycles of reduction and oxidation steps during purification.

Based on time during FDA regulatory review (under 35 USC §156), the expiration date of U.S. 4,588,585 was extended 1,516 days to July 7, 2007.

Berlex Laboratories, Inc. initiated a U.S. patent infringement suit against Biogen, Inc. in 1996 alleging that Avonex (another marketed recombinant interferon beta product) from Biogen (now Biogen Idec) violated Berlex’s “McCormick” patents (U.S. 5,376,567 and 5,795,779). Biogen countersued/appealed. The suit was substantially settled in Jan. 2002, with Biogen paying $20 million for nonexclusive licenses for these patents. See the Avonex entry for further information, including patent challenges to Avonex by Berlex and other European companies.

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: The pivotal trial with Betaseron was the first large, randomized, placebo-controlled study of any therapy in MS. This groundbreaking study was conducted in North America and led to the approval of Betaseron, the first disease-modifying agent for MS, in 1993. Patients received Betaseron 50 µg, Betaseron 250 µg or placebo, with a median duration of 45 months. After two years, significantly more patients receiving Betaseron were relapse-free, and those relapses that occurred were less severe and hospitalizations for MS were cut nearly in half compared to placebo. These results were confirmed at five years.

In Sept. 2005, interim results were reported from the completed 16-Year Long-Term Follow-up (16-Year LTF) Study of Betaseron in MS patients. When completed, the study will provide assessment of the patients who have been identified from the original 372 patients who enrolled in the Betaseron pivotal trial between 1988 and 1990. This is the longest follow-up for any disease-modifying therapy in MS. Patients in the pivotal trial received Betaseron 50 µg, Betaseron 250 µg (currently approved dose) or placebo. Betaseron was made available to all patients after completion of the pivotal study. The trial included 331 of the 372 original patients (89%) in the pivotal trial. Among these, 51% of the MS-patients originally assigned to the 250 µg group can still walk with or without assistance, compared with 45% originally assigned to the placebo group; and 95 percent of the original 250 µg group are still alive, as compared with 83% of the placebo group. Among a subset of 210 patients studies, half have been on Betaseron 250 µg for 10 years or longer (median nearly 14 years).

In July 2005, Schering and Chiron reported completion of enrollment with over 2,100 patients for the double-blind, international Phase III BEYOND study comparing 500 µg Betaferon vs. the marketed 250 µg dose vs. glatiramer acetate (Copaxone from Teva).

In Sept. 2005, results were reported from the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) 2-year, Phase III study of Betaferon (250 µg) in 487 MS patients having experienced a single clinical episode suggestive of multiple sclerosis. A 50% reduced risk of developing clinically definite multiple sclerosis (CDMS) compared to placebo was reported. Over the 24-month observation period, the risk to develop CDMS was 45% in the placebo group compared to 28% in the Betaferon group. In patients with only one symptom of the disease, the effects of Betaferon were even more pronounced, with a 58% reduction in conversion to CDMS.

In Oct. 2005, results were reported from the double-blind, international Phase III BENEFIT (BEtaseron in Newly Emerging multiple sclerosis For Initial Treatment) trial conducted at 98 sites in 20 countries. The trial enrolled patients presenting with a first clinical episode suggestive of MS and typical MRI findings. The primary outcome measures were time to diagnosis of CDMS, time to confirmed EDSS progression, and patient reported Quality of Life outcomes (FAMS-TOI). A total of 468 patients receivde either 250 µg of Betaseron or placebo daily as a subcutaneous injection. The placebo-controlled period lasted up to 24 months or up to the time when patients experienced a second attack and were diagnosed with clinically definite MS. All study participants were then invited to participate in a follow-up study with Betaseron to prospectively assess the impact of early versus delayed treatment with Betaseron on the long-term course of the disease for a total observation time of five years.

The BENEFIT trial at two years showed that 250 µg dosing with Betaseron significantly delayed the onset of CDMS by 1 year vs. placebo, with 25% of placebo patients developing CDMS at day 255, while 25% of patients taking Betaseron developed CDMS at day 618. At 2 years, 28% of Betaseron patients developed CDMS vs. 45% on placebo (p <0.0001); and 28% and 69% of Betaferon patients developed MS after 6 months and within 2 years, respectively, vs. 51% and 85% with placebo (p <0.00001). BENEFIT showed that most patients who appear to be at high risk of developing MS do so within only two years, and Betaseron cut the risk of progression to the second clinical event by nearly 50% compared to placebo.

In April 2006, results were reported from the Betaseron 16-Year Long-Term Follow-up (16-Year LTF) Study, the longest follow-up study for any disease modifying therapy in multiple sclerosis (MS). The trial examined patients in the Betaseron pivotal trial between 1988 and 1990. Betaseron remained consistently safe, effective and well tolerated over the long term. Patients with relapsing forms of MS taking Betaseron had a sustained reduction in the annual rate of relapses of up to 40% over 16 years. Patients remaining on long-term treatment had a slower disease progression compared to patients who did not. Among the patients who reached Expanded Disability Status Scale (EDSS) level 6.0 (e.g., needing a cane for walking), those on long-term treatment reached EDSS 6.0 after a median time of 13 years compared to seven years for patients on short-term treatment. Long-term treatment was defined as use of Betaseron for more than 80% of the time since the start of the pivotal trial (~12 years or longer), while short-term treatment was defined as use for less than 10 percent of the time (~1.6 years or less). Long-term use over 16 years revealed no new or unexpected adverse events. Betaseron was well accepted by patients in this long-term study. The median treatment duration with Betaseron of the analyzed trial participants was almost 10 years, while the longest duration on therapy is 17.1 years.

In the April 2007 of the Journal of International Medical Research, results were reported from a 6,600 patient international retrospective study showing that the presence of neutralizing antibodies (NAbs) that can develop in response to Betaseron therapy does not predict clinical response in patients with multiple sclerosis (MS). This study confirmed that the Nabs tend to disappear over time. This was the largest dataset ever analyzed for the relevance of NAbs to interferon beta therapy. The development of NAbs is specific to each medication and it is unclear how these findings apply to other beta interferons, but Nabs do not appear to be a significant problem with Betaseron.

In the Aug. 2007 issue of Lancet, results were reported from a pre-planned analysis of the “ landmark” BENEFIT at three years. The trial provided the first controlled evidence that delaying Betaseron treatment has an effect on later accumulation of disability, as observed over the three-year study period. Patients treated with Betaseron shortly after their first clinical MS event or “attack” showed a 40% lower risk of developing confirmed disability progression compared to patients in whom treatment was delayed. The findings support actively treating patients at the first clinical sign of MS to delay the accumulation of disability. Betaseron was safe and well-tolerated, with adverse events similar to those previously reported; and 90% of the patients who entered the follow-up study elected to receive Betaseron treatment. Development of neutralizing antibodies did not have an impact on disability-related or relapse-related outcomes in the trial.

In Oct. 2007, Bayer reported results from a Phase III BEYOND (Betaferon Efficacy Yielding Outcomes of a New Dose) trial in 2,244 treatment-naive patients comparing compared the relative efficacy of high-dose, high-frequency Betaferon 250 mcg every other day to a 500 mcg dose of Betaferon every other day and to glatiramer acetate 20 mcg administered subcutaneously every day. The overall outcome of the trial did not show a statistically significant superiority of the 500 mcg Betaferon dose compared to the 250 mcg Betaferon® dose and Copaxone. The risk for relapses, which was the primary end point of the trial, was similar in all three study arms. There was a very low relapse rate in the entire study population, unlike in previous trials. Bayer abandoned plans to file for approval of the 500 µg dose, and took an "impairment" (wrote off a loss)0 of -152 million Euro in 3rd quarter 2007.

In Sept. 2008, results were reported from the BENEFIT (BEtaseron in Newly Emerging multiple sclerosis For Initial Treatment) trial confirming that early initiation of Betaseron treatment in patients with a first event suggestive of multiple sclerosis (MS) significantly delayed the onset of clinically-definite MS (CDMS) by 37% (p=0.003) and McDonald MS by 45% (p<0.0001) over five years compared to delayed treatment. A total of 468 patients with a first clinical demyelinating event suggestive of MS and typical MRI findings were randomized to receive either 250 micrograms of Betaseron every other day or placebo as a subcutaneous injection in a double blind fashion for a maximum of two years. These results are the first and only prospectively planned data to confirm a continuous benefit over five years when treatment is initiated shortly after the earliest sign of MS. BENEFIT also showed that early treatment with Betaseron had a beneficial effect on cognition that became even more pronounced over time. At five years, patients with early treatment had better cognitive function (mean PASAT score) compared to patients with delayed treatment (p= 0.0045). PASAT, or the Paced Auditory Serial Addition Test, is a widely accepted tool that measures intellectual function and cognition. The study was the first to show a reduction in the risk of confirmed EDSS progression, as measured by the Expanded Disability Status Scale (EDSS), with early versus delayed treatment. This effect first appeared at year three, with a significant risk reduction of 40% (p=0.022). Over five years, a nominal risk reduction of 24% (p=0.177; not statistically significant) was observed for early vs. delayed treatment. This difference over five years was not statistically significant. Starting Betaseron after the first clinical event delayed the development of CDMS by more than two years (750 days) in the 40th percentile. Patients treated early with Betaseron had a greater reduction in relapse rate over 5 years compared to patients with delayed treatment, (0.21 vs. 0.27), despite the latter receiving at least 3 years of treatment after the second attack or after 2 years (p=0.014; Poisson model). This effect was mainly due to the differences between the groups during the first two years. Early treatment significantly reduced the development of newly active brain lesions (new or enlarging T2 lesions, Gd-enhancing lesions) compared to delayed treatment (p=0.006).

Medical: The recommended dose of Betaseron for the treatment of ambulatory relapsing-remitting multiple sclerosis (MS) is 0.25 mg (250 µg) injected subcutaneously every other day (compared to 30 µg administered by intramuscular injection once weekly for Avonex).

Experts convened by the American Academy of Neurology have suggested that higher doses of interferon beta, taken more frequently, appear to be more effective in fighting MS than lower doses taken less often (see Neurology, 58:169-178, 2002). Betaseron is the only high-dose, high-frequency interferon beta approved in the U.S. for patients having a first clinical event suggestive of MS.

Market: Betaseron/Betaferon was Schering AG’s (now merged into Bayer Schering Pharma) most important product, providing the largest share, about 20%, of its revenue. This is particularly true now, with Schering having experienced recent setbacks, including delay of FDA approval of its Yazmin contraceptive.

Bayer Schering claims (March 2007), “Betaseron is the only high-dose, high-frequency interferon beta indicated for patients at the earliest stage of MS;” “Betaferon has the broadest experience of any MS medication;” and “Sixteen years’ follow up of people treated with Betaferon has shown that it is safe and well tolerated.”

Total worldwide 2009 Betaseron/Betaferon sales were $1.649 billion; $1.480 in 2008 and $1.6 billion. Total 2006 sales were ~$1.273 billion; and 2005 sales were euro 867 million/year ($1.033 billion), then providing the largest single share (~16%) of Schering AG’s sales. U.S. 2005 sales were $370 million. Total sales were ~$1 billion in 2004, with one source reporting $1.057 billion; $970 million in 2003; $821 million in 2002; euro 593 million (then ~$563 million) in 2000; $430 million in 1999; $350 million in 1998; and $325 million in 1997. [See the other interferon beta entries for further market size and share information].

Total revenues to Chiron (now merged into Novartis) from sales of Betaseron to Berlex were $142 million in 2005; $131 million in 2004; $125 million in 2003, $118 million in 2002, $96 million in 2001, $82 million in 2000, $66 million in 1999, $63 million in 1998. The 2005 increase in product sales to Berlex/Schering for marketing and resale was primarily due to price increases and a shift from third-party to in-house production, partially offset by a reduction in shipments to Berlex and inventory ordering patterns.

Total revenues (royalties) to Chiron from sales of Betaferon by Schering AG were $60 million in 2005, and $52 million in 2004. The 2005 increase was due to an increase in demand and price, partially offset by a shift from third-party to in-house production.

Biogen’s royalties from Schering AG’s European sales were $64 million in 2003, $47 million in 2002, $39 million in 2001, $36 million in 2000, $30 million in 1999, and $28 million in 1998.

The 2007 Average Wholesale Price (AWP) is $1,897,50 for fifteen 0.3 mg kits ($1,402.80 in 2004) (Red Book, 2007). The AWPS were $1517.82 in 2005, and $1,402.80 in 2004.

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 had considered the £10,000 (approx. $15,000) annual cost per patient to be too expensive. In early 2002, NICE recommended use of beta interferon for MS, and estimated the annual cost for treatment of MS with Betaferon (plus glaritamer acetate) to be $10,292 (at the cost it had negotiated).

R&D:      Transgene Biotek (India) is developing a generic (biogeneric, biosimilar, follow-on biologic, etc.) version of intereron beta-1b. Therapeutic Proteins, Ltd. (U.K.) is developing a biosimilar/biogeneric, E. coli expressed interferon beta-1b (and also interferon beta-1a) product for treatment of multiple sclerosis.