Interferon alfa-2 - Intron A; Interferon, alpha-2b, recombinant
Status - approved; marketed
Organizations involved:
Schering-Plough Corp. – Manuf; R&D; Tech.; World mark.; Parent; Former
Merck & Co., Inc. – Parent
SP (Brinny) Chemical Co. – Manuf. other
Biogen Idec, Inc. – Tech.
Biogen Corp. – Tech.; Patent dispute; Former
Genentech, Inc. – Tech.; Patent dispute
Hoffmann-La Roche Inc. – Tech.; Patent dispute
Boehringer Ingelheim Pharma KG – Patent dispute
Bender & Co. GmbH – Patent dispute
Boehringer Mannheim GmbH – Patent dispute
Valeant Pharmaceuticals, Inc. – Patent dispute
ICN Pharm., Inc. – Tech.; Patent dispute; Former
Three Rivers Pharm. – Tech.; Patent dispute
Kadmon Pharmaceuticals LLC – Parent
Geneva Pharmaceuticals – Patent dispute
Novartis AG – Parent
City of Hope National Medical Center – Tech.; Patent dispute
Cross ref.: See Interferon Products entry in the Blood Products, Human section, and other interferon alpha entries, both recombinant and cell cultured natural.
Description: Interferon alfa-2b or Intron A refers to lyophilized (freeze-dried) and aqueous formulations of a recombinant non-glycosylated alpha interferon protein expressed by Escherichia coli (E. coli) transformed with the gene for interferon alpha-2b from human leukocytes. Interferon alfa-2b is a type I water-soluble interferon consisting of 165 amino acid residues with arginine in position 23, a molecular weight of 19,271 Daltons (19.271 kDa), and molecular formula of C860H1353 N229O255S9. The lyophilized powder formulations contain Albumin (Human) as a stabilizer.
Interferon alfa-2b has a specific activity of about 2.6 x 108 (260 million) International Units/mg as measured by HPLC assay. The antiviral bioassay used to measure its potency is based on the ability of interferon alfa-2b to protect human foreskin fibroblast FS-71 cells from the cytopathic effects of encephalomyocarditis virus, and is calibrated against the World Health Organization (WHO) standard for interferon alpha-2b.
Intron A is packaged in vials as Powder for Injection containing lyophilized powder, as Solution Vials for Injection, and as Solution for Injection Multidose Pen for intramuscular, subcutaneous, intralesional, or intravenous injection using an pre-filled injection device. The Powder for Injection is packaged in 3, 5, 10, 18, 25, and 50 million IU (MIU) vials containing 0.012, 0.019, 0.038, 0.069, 0.096, and 0.192 mg interferon alfa-2b, respectively. Each Intron A vial also contains 20 mg glycine, 2.3 mg sodium phosphate dibasic and 0.55 mg sodium phosphate monobasic buffers, and 1.0 mg of Albumin (Human). Prior to administration, vials are reconstituted with Diluent for Intron A (bacteriostatic water for injection) containing 0.9% benzyl alcohol as a preservative.
Solution Vials for Injection contain interferon alfa-2b at concentrations of 3 MIU/0.5 mL, 5 MIU/0.5 mL, 10 MIU/1.0 mL, 3 million IU/0.5 mL, and 25 MIU/0.5 mL; respectively containing 0.012, 0.019, 0.038, 0.088 and 0.123 mg interferon alfa-2b. Each mL of solution also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium (sodium EDTA), 0.1 mg polysorbate 80 (Tween 80), and 1.5 mg m-cresol as a preservative. The 18 MIU multidose vial contains a total of 22.8 million IU of interferon alfa-2b per 3.8 mL, in order to provide for the delivery of six 0.5-mL doses, each containing 3 million IU (for a label strength of 18 million IU). The 25 MIU multidose vial contains a total of 32.0 million IU of interferon alfa-2b per 3.2 mL, in order to provide the delivery of five 0.5-mL doses, each containing 5 million IU (for a label strength of 25 million IU).
Intron A Solution for Injection Multidose Pen is available for chronic hepatitis C and several other indications:. This is a subcutaneous injection system pre-filled with Intron A Solution, can deliver up to six injections, 0.2 mL each, and is portable and easy to store. Pens are available containing 18, 30, or 60 MIU interferon alfa-2b; at final concentrations of 22.5 MIU/1.5 mL, 37.5 MIU/1.5 mL and 75 MIU/1.5 mL, respectively; and containing 0.087, 0.144 and 0.288 mg interferon alfa-2b, respectively. Each mL also contains 7.5 mg sodium chloride, 1.8 mg sodium phosphate dibasic, 1.3 mg sodium phosphate monobasic, 0.1 mg edetate disodium, 0.1 mg polysorbate 80, and 1.5 mg m-cresol as a preservative.
Nomenclature: Interferon alfa-2b, rDNA [BIO]; Intron A [TR]; Interferon alfa-2 [FDA MESH]; Interferon Alfa-2b [USAN INN BAN]; Interferon alpha2b (human leukocyte clone Hif-SN206 protein moiety reduced) [CAS]; 98530-12-2 [CAS RN]; 99210-65-8 [CAS RN]; 9008-11-1 [CAS RN, for alpha interferons]; rIFN-alpha [SY]; Sch 30500 [SY]; Interferon alpha 2b [SY]; Interferon, alpha-2b recombinant [SY]; IFN-alpha [SY]; Virtron [TR EU]; NDC 00085-1179-02; NDC 00085-0571-02; NDC 00085-1110-01; NDC 00085-0539-01; NDC 00085-1168-01; NDC 00085-1133-01; NDC 00085-1242-01; NDC 00085-1235-01; NDC 00085-1254-01 [NDC]
Intron A, interferon alfa-2b, and other nomenclature terms are often used ambiguously or imprecisely to refer to the active ingredient and/or formulated product.
Companies.: Intron A was developed and is manufactured and exclusively marketed worldwide by Schering-Plough Corp. (main headquarters then in Madison, NJ; acquired by Merck in 2009). It is manufactured by Schering-Plough Corp. (Kenilworth, NJ; CBER/FDA est. no. 0994), with Avondale (Brinny) Chemical Co. (Innishannon, County Cork, Ireland), now SP (Brinny) Co., a subsidiary of Schering-Plough, also approved for formulation, filling, lyophilization, and final container tests.
Intron A is marketed by Schering-Plough in the U.S., and internationally by Schering-Plough affiliates.
In March 2009, Merck & Co. acquired Schering-Plough in a deal valued at over $41 billion.
Three Rivers Pharmaceuticals, a source for ribavirin marketed in association with Intron A, was acquired by Kadmon Pharmaceuticals LLC in fall 2010.
Manufacture: The E. coli used for manufacture contains the KMAC-43 cytoplasmic expression vector (plasmid) incorporating the gene for expression of human interferon alpha-2b. The protein is expressed intracellularly in soluble form. Fermentation is reported to be performed in custom 42,000 liter stainless steel vessels. Chromatographic purification is performed in large cold-rooms under clean-room conditions. Final purification includes crystallization. Crystalline product is dissolved and formulated in phosphate buffer also containing glycine and, optionally, Albumin (Human). Vials are filled and lyophilized (freeze-dried).
The active component of Intron A (like that of many other recombinant E. coli-expressed proteins) is a mixture of the true amino acid sequence encoded by the interferon alpha-2b expressed by the host cells, E. coli, plus molecular variants, including deamidated products, oxidized forms, and N-terminal blocked molecules. The exact concentration and other characteristics of the product, including safety and efficacy, are determined largely by the manufacturing process.
Various aspects of interferon alpha-2b manufacture, quality control, and characterization are discussed in Trotta, P.P, et al., “Approval Standards for Alfa Interferon Subtypes,” Drug Info. J., vol 34, no. 4, p. 1231-46, Oct.-Dec. 2000. This article, including several authors from Schering-Plough, discusses the factors affecting manufacture of recombinant interferon alpha products, particularly Intron A. Validation tests applied to host E. coli and expression constructs (the Master Cell and Working Cell Banks) include: 1) cultural purity assessed by streak on nutrient agar +/- selection (antibiotic); microscopic examination; tests for bacteriophage (uninduced and mitomycin C induced); and streak on MacConkey agar; 2) host characterization by inability to ferment lactose; API 20E biotyping; and thiamine autotrophy; 3) plasmid characterization by restriction enzyme analysis of isolated plasmid DNA on agarose gel electrophoresis; antibiotic resistance (stability of the selectable marker); and DNA sequencing; and 4) fermentation performance by 10 L scale fermentation.
In process manufacturing parameters controlled during fermentation include: 1) plasmid stability, growth profile (optical density), purity (microscopic exam plus Gram stain), cell count, absence of lytic and lysogenic bacteriophages, and absence of nonviable recombinant E. coli; 2) temperature; 3) agitation; 4) pressure; 5) pH; 6) dissolved oxygen; and 7) conductivity. Purification parameters include: temperature; pH; conductivity; water and air quality; protein content; interferon purity by RP-HPCL; and microbiologic monitoring (total viable count; LAL assay).
Release tests applied to interferon alpha-2b “drug substance” (bulk interferon alfa-2b) are description; antiviral activity (MTT-CPE assay), SDS gel electrophoresis, IEF gel electrophoresis, and peptide mapping; purity tests including SDS-PAGE (reducing conditions) with silver stain, SDS-PAGE (nonreducing conditions) with silver stain, E. coli proteins, N-terminal methionine, isoelectric focusing, and component A (sulphoxide variant) tests; potency determined by antiviral assay (MTT-CPE); specific activity (antiviral potency by MTT-CPE divided by protein determined by RP-HPLC); and absence of antibiotics (tetracycline). Drug substance batches are also tested for compliance with the European Pharmacopeia.
Release tests applied to Intron A (“finished drug product”) are description; pH; moisture content (for lyophilized formulation); identification of interferon alpha by antiviral assay, SDS-PAGE, and RP-HPLC; protein content; MTT-CPE-inhibition assay for antiviral activity and potency determination; LAL assay (endotoxin); sterility; preservatives (identification and quantification, if appropriate); purity (if appropriate); and particulate matter. Other physiochemical characterization tests applied to thoroughly characterize and ensure consistent reproducible structural integrity of product from different batches/lots include circular dichroism to determine secondary structure; analysis of proper disulfide pairing through tryptic mapping of the nonreduced protein and determination of free thiols; size exclusion chromatography and capillary zone electrophoresis to analyze quanternary structure and charge characteristics, respectively; C-terminal amino acid sequencing; measure of residual E. coli DNA; and analysis of amino acid sequence by mass spectrometry of tryptic fragments.
The Drug Info. J. article includes discussion of the cytopathic effect (CPE) inhibition assay used to determine potency and specific activity. For Intron A, the assay involves incubation of the test sample and a reference standard preparation of interferon alfa-2b (calibrated against the NIH standard for human leukocyte interferon) with human foreskin fibroblast cells, which are then infected with murine encephalomyocarditis virus and examined for cytopathic effects (CPE) after overnight incubation, quantified using a spectrophotometric assay with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide. Specific activity is calculated by dividing the potency by CPE-MTT by protein content determined by RP-HPLC. Many factors between and even within laboratories contribute to variations in interferon potency as determined by CPE-MTT, and this test is not suitable for measuring or comparing the potency and therapeutic equivalency of different interferon alpha products.
FDA class: Biologic PLA
CBER class: Biological Response Modifiers
CBER to CDER: Among the products transferred within FDA on June 30, 2003
Approvals: Date = 19860604; first approval, PLA (no. 83-415); Indication = hairy cell leukemia
Date = 19881121; PLA supplement 86-0306; orphan designation (expires 11/2005); Indication = Kaposi’s sarcoma, AIDS-related, and new 50 million IU lyophilized dosage form
Date = 19910222; PLA supplement; Indication = chronic hepatitis C (non-A, non-B) virus infection
Date = 19920713; PLA supplement; Indication = chronic hepatitis B virus infection with compensated liver disease
Date = 19930514; PLA supplement; Indication = condylomata acuminata (genital warts due to human papillomavirus infection) in association with podophyllum treatment
Date = 19951206; PLA supplement; Indication = malignant melanoma
Date = 19970400; PLA supplement; Indication = extended use for chronic hepatitis C. [Intron A was previously approved for six months of treatment for chronic hepatitis C. Extending the use of Intron A therapy to 18-24 months can nearly double patients’ sustained virological response rates compared to only six months of treatment].
Date = 19971106; PLA supplement; Indication = for follicular lymphoma in conjunction with chemotherapy
Date = 19971106; PLA supplement; Indication = for injection in conjunction with anthracycline-containing chemotherapy for the initial treatment of aggressive non-Hodgkin’s lymphoma
Date = 19980603; PLA supplement; first approval of Rebetron Combination Therapy [use of Intron A plus Rebetol (oral ribavirin from Ribapharm/ICN Pharmaceuticals)]; Indication = Rebetol (ribavirin, USP) Capsules in combination with Intron A Injection for treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with alpha interferon or having relapsed on prior alpha interferon therapy
Date = 19980818; PLA supplement; Indication = chronic hepatitis B treatment in pediatric patients 1 year of age or older
Date = 19981209; PLA supplement, Indication = approval of Rebetron Combination Therapy for first-line use; for combination use with Rebetol capsules for the treatment of chronic hepatitis C in patients with compensated liver disease previously untreated with interferon alpha monotherapy
Date = 20010726; BLA supplement; Indication = approval of stand-alone or unbundled packaging of oral ribavirin (Rebetol) for use with Intron A (which also allowed off-label use of Rebetol with other interferon products)
Date = 20030731; NDA; orphan designation (expires 7/2010); Indication = approval of Rebetol Capsules and Oral Solution for use in combination with Intron A for the treatment of pediatric hepatitis C [in patients ages 3 and older with compensated liver disease not previously treated with interferon alpha]
Date = 20040405; abbreviated NDA (ANDA) granted to Three Rivers Pharmaceuticals, LLC for Ribasphere (first of several generic oral ribavirin approvals)
Indications: [portions of the "INDICATIONS AND USAGE” section of product insert/labeling]:
Hairy Cell Leukemia INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of patients 18 years of age or older with hairy cell leukemia.
Malignant Melanoma INTRON A Interferon alfa-2b, recombinant for Injection is indicated as adjuvant to surgical treatment in patients 18 years of age or older with malignant melanoma who are free of disease but at high risk for systemic recurrence, within 56 days of surgery.
Follicular Lymphoma INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the initial treatment of clinically aggressive (see Clinical Experience) follicular Non-Hodgkin’s Lymphoma in conjunction with anthracycline-containing combination chemotherapy in patients 18 years of age or older. Efficacy of INTRON A in patients with low-grade, low-tumor burden follicular Non-Hodgkin’s Lymphoma has not been demonstrated.
Condylomata Acuminata INTRON A Interferon alfa-2b, recombinant for Injection is indicated for intralesional treatment of selected patients 18 years of age or older with condylomata acuminata involving external surfaces of the genital and perianal areas (see DOSAGE AND ADMINISTRATION).
The use of this product in adolescents has not been studied.
AIDS-Related Kaposi’s Sarcoma INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of selected patients 18 years of age or older with AIDS-Related Kaposi’s Sarcoma. The likelihood of response to INTRON A therapy is greater in patients who are without systemic symptoms, who have limited lymphadenopathy and who have a relatively intact immune system as indicated by total CD4 count.
Chronic Hepatitis C INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of chronic hepatitis C in patients 18 years of age or older with compensated liver disease who have a history of blood or blood-product exposure and/or are HCV antibody positive. Studies in these patients demonstrated that INTRON A therapy can produce clinically meaningful effects on this disease, manifested by normalization of serum alanine aminotransferase (ALT) and reduction in liver necrosis and degeneration.
Chronic Hepatitis B INTRON A Interferon alfa-2b, recombinant for Injection is indicated for the treatment of chronic hepatitis B in patients 1 year of age or older with compensated liver disease. Patients who have been serum HBsAg positive for at least 6 months and have evidence of HBV replication (serum HBeAg positive) with elevated serum ALT are candidates for treatment. Studies in these patients demonstrated that INTRON A therapy can produce virologic remission of this disease (loss of serum HBeAg), and normalization of serum aminotransferases. INTRON A therapy resulted in the loss of serum HBsAg in some responding patients.
Status: The original PLA was granted on June 4, 1986 for hairy cell leukemia. This allowed alternate use of Avondale (Brinny) Chemical Co., now SP (Brinny) Co. (Ireland), a subsidiary of Schering-Plough, for contract formulation, filling, lyophilization and final container tests.
On March 9, 2000, the EU granted approval for Intron A.
Intron A is marketed in nearly all countries worldwide for 16 or more major indications. Novolin did not receive centralized EU approval, with European approvals country-by-country.
Warrick Pharmaceuticals, a subsidiary of Schering-Plough, and Sandoz Inc., the generic drug subsidiary of Novartis, both received approval and launched generic ribavirin in the U.S. in April 2004. The companies received shared 180-day Hatch-Waxman Act-based exclusivity from FDA.
On April 7, 2004, FDA approved an ANDA for generic ribavirin, Ribasphere, from Three Rivers Pharmaceuticals, LLC for use in combination with interferon alfa-2b (Intron A) for the treatment of chronic hepatitis C, with marketing to be handled by Par Pharmaceuticals. As discussed in the Tech. transfer section below, other companies also sought approval of generic ribavirin, notably Teva Pharmaceuticals and Geneva Pharmaceuticals, a subsidiary of Novartis AG. Each of these companies has concluded a license agreement with Schering-Plough and each is involved in a continuing ribavirin patent dispute with ICN/Ribapharm, now Valeant Pharmaceuticals.
In fall 2004, Schering-Plough launched a generic version of Rebetol (ribavirin) through its generic subsidiary, Warrick Pharmaceuticals. On Oct. 10, 2004, Teva Pharmaceuticals received FDA approval for its generic ribavirin. Other companies have subsequently received FDA approval for generic ribavirin.
In late April 2006, the European Union granted supplemental MAA approval for a label change to include information from a 5-year follow-up study evaluating sustained virological response (SVR) in chronic HCV infected patients. The study confirmed that sustained loss of serum HCV RNA at 6 months following the completion of treatment is a strong predictor of long-term clearance of the virus, providing resolution of the hepatic infection and clinical “cure” from chronic HCV. However, long-term clearance of the virus does not preclude the occurrence of hepatic events in patients with cirrhosis, including hepatocarcinoma.
In April 2006, the European Medical Evaluation Agency (EMEA), issued a “concept paper” (Annex to the Guideline on Similar Biological Medicinal Products Containing Biotechnology Derived Proteins as Active Substance – (Non) Clinical Issues; CHMP/BMWP/7241/2006) concerning biosimilar (biogeneric) versions of recombinant alpha interferon, with Intron A, rather than Roforon-A, being the primary target for biosimilar development.
Tech. transfer: The patents and licensing, cross-licensing, and patent disputes concerning Intron A and other interferon alpha products are complex, with the major companies involved and others having both challenged and cross-licensed various U.S. and international patents, and some patent disputes stretching over decades. In summary: Biogen (now Biogen Idec) and Genentech/Roche originally filed competing U.S. patent applications in 1980-1981 covering the composition and manufacture of recombinant forms of alpha interferon, and disputes quickly arose. Roche licensed an early key patent (4,503,035) covering natural, purified forms of interferon alpha; Roche’s partner, Genentech, obtained key recombinant interferon manufacture-related patents; and Schering-Plough licensed key Biogen recombinant interferon alpha patents including coverage for the gene sequence for interferon alfa-2b (Intron A). By the late 1980s, Biogen/Schering-Plough and Genentech/Roche had minimally cross-licensed their respective issued patent properties, allowing continued marketing of their others’ products in the U.S. and other major markets. In mid-1998, Biogen, Inc., Schering-Plough Corp., Hoffmann-La Roche Inc. and Genentech Inc., for the most part, settled their long-running patent disputes concerning interferon products, essentially cross-licensing their respective patent portfolios. The agreement only covered rights in the U.S., and allowed for continued U.S. marketing of Intron A by Schering-Plough and Roferon A by Hoffmann-La Roche, and development of next generation products, e.g., pegylated alpha interferons. Genentech subsequently received another broad recombinant interferon patent, and nonexclusively licensed it to Schering-Plough, Roche and others.
U.S. patent 4,530,901, “Recombinant DNA molecules and their use in producing human interferon-like polypeptides,” by C. Weissmann, July 23, 1985, assigned to Biogen (now Biogen Idec), originally licensed exclusively to Schering-Plough (for Intron A), describes recombinant plasmids and methods for expression of mature interferon alpha. Equivalents have issued in many major markets worldwide. The preferred cloning vehicle is the bacterial plasmid pBR322, the preferred restriction endonuclease site is the PstI site, and the preferred host is E. coli HB 101. This is the main patent covering recombinant alpha interferons. Biogen has asserted that it applies to all patents assigned to Biogen Corp. (and licensed to Schering-Plough Corp.) covering recombinant alpha interferons was upheld in 1993; and Boehringer Ingelheim Pharma, Boehringer Mannheim GmbH, and Bender & Co. lost an appeal of a 1990 decision supporting the Biogen patent.
In 1986, Genentech licensed recombinant alpha interferon manufacturing technology to Hoffmann-La Roche, Inc. for Roferon A (Genentech is still majority owned by Roche). Genentech patents concerning recombinant methods used for alpha interferon manufacture include U.S. 4,704,362, “Recombinant Cloning Vehicle Microbial Polypeptide Expression,” and U.S. 5,221,619 (issued summer 1994 after considerable delay and disputes). Biogen, Schering and Eli Lilly & Co. challenged 4,704,362 and the 5,221,619 application. Genentech counter-claimed that the two companies were in violation of its earlier patent - Schering-Plough with its interferon alpha (Intron A) and Lilly with its recombinant insulin. As part of its suit, Schering-Plough claimed that no matter what the result, its earlier mutual cross-licensing of interferon patents with Hoffmann-La Roche Inc. (which then owned a controlling interest in Genentech) included licensing of these Genentech patents.
In 1995, after nearly a decade, the U.S. patent office ruled that Genentech/Roche patent had the earlier invention date. In April 1996, Biogen filed suit seeking to reverse this decision. The patent office subsequently issued a patent (6,482,613) to Genentech (Roche).
A U.S. patent office reexamination of the Sloan-Kettering/Roche purified interferon patent (4,503,035) was initiated in Dec. 1992 after the Federal Trade Commission (FTC) provided the patent office with documentation allegedly showing that Roche had misrepresented data in its patent application as a means to control the interferon market. In May 1994, the patent office issued an office action rejecting a number of the patent’s claims. In spring 1996, the patent office confirmed the validity of all 14 patent claims as originally issued, and a number of newer claims were added. This ruling finally ended this patent dispute that had lasted well over a decade, leaving Roche holding a key U.S. (and equivalent foreign filings) on purified interferons.
In mid-1998, Biogen, Inc., Schering-Plough Corp., Hoffmann-La Roche Inc. and Genentech Inc. signed agreements “conclusively” settling their long-running disputes concerning interferon products, essentially cross-licensing their respective patents. This agreement allowed for continued U.S. marketing of Intron A by Schering-Plough and Roferon A (recombinant alfa-2a-interferon) by Hoffmann-La Roche, and future marketing of other alpha interferon products, e.g., pegylated interferons. This agreement only covered rights in the U.S. Schering-Plough received rights to the Genentech patents and agreed to pay royalties to Biogen (now Biogen Idec) until expiration of the Roche/Genentech recombinant patents (extending Biogen’s licensing income stream). Without this agreement, Schering-Plough would have stopped paying royalties to Biogen in July 2002 with the expiration of 4,530,901. Schering-Plough and Roche also modified their agreement concerning cross-licensing of various alpha interferon patents under which Schering-Plough has rights to the newer Genentech/Roche patent.
In 2002, the patent office issued a new patent (6,482,613, “Microbial production of mature human leukocyte interferons”, which traces its lineage back to application 06/164,986, filed Jul. 1, 1980) to Genentech and Roche. Genentech then concluded royalty-bearing licenses with Schering-Plough, Biogen, and Lilly. U.S. 6,482,613 claims various forms of recombinant “mature leukocyte interferon” (interferon alpha) expressed in E. coli and other bacterial expression systems. This patent, which expires in 2019, essentially covers bacterial-expressed recombinant alpha interferons.
With Roche, Schering-Plough, Genentech, and Biogen Idec now largely having settled their disputes and cross-licensed their patents to each other, generic (biogeneric, biosimilar, biocomparable, follow-on) recombinant alpha interferon products may have a difficult time entering the U.S. market until these patents expire.
In Oct. 2002, a binding arbitration ruling settled a patent royalty dispute between Biogen and Schering-Plough concerning U.S. sales of interferon products. Schering-Plough had halted paying royalties to Biogen in 2001 after an appeals court narrowly interpreted the scope of Biogen’s key interferon patent. Schering-Plough paid Biogen a partial settlement of about $45-$50 million, and resumed paying royalties on sales starting Oct. 1, 2002.
EP 00032134, the European Patent Office (EPO) equivalent of Weissmann U.S. 4,530,901, assigned to Biogen Corp., exclusively licensed to Schering-Plough, covering recombinant interferon alpha, was upheld in 1993. Boehringer Ingelheim Pharma, Boehringer Mannheim GmbH (now merged into Hoffmann-La Roche) and Bender & Co. lost an appeal of a 1990 EPO decision supporting this Biogen patent. Schering-Plough has received supplemental protection (patent extension) certificates in France where Biogen’s patents expire in 2003 and in Italy where they expire in 2007 (and perhaps also in other European countries). Other parties reported to be involved in challenging or infringing this European patent or equivalents include Amgen Inc., Cetus (later Chiron Corp.; now merged into Novartis AG)/Triton Biosciences (now Berlex Biosciences), Ciba-Geigy AG (now merged into Novartis AG), Hoechst AG (now Sanofi Aventis S.A.), and Pharmacia & Upjohn (merged into Pfizer).
The licensing and payment of royalties to Biogen from interferon sales in Japan and most of Europe (except in countries with patent extensions) expired in 2001.
Schering-Plough originally exclusively licensed from ICN Pharmaceuticals (and subsequently its Ribapharm subsidiary, then 80% owned by ICN), now Valeant Pharmaceuticals International, worldwide rights for use of patents covering oral ribavirin (1-beta-D-ribofuranosyl-1,2,4-triazole-3-carboxamide) use in combination with interferon products for treatment of chronic hepatitis C. For Schering-Plough, this covers both Rebetron Combination Therapy (Intron A plus oral ribavirin) and use of PEG-Intron in combination with oral ribavirin. Ribavirin is a relatively old drug, one of the first antiviral drugs, and there are no active U.S. patents covering it as a composition-of-matter, which generally provides stronger protection for drugs than methods-of-use, e.g., combinations, and manufacturing process patents.
Schering-Plough and ICN/Ribapharm (now Valeant Pharmaceuticals) collectively hold U.S. patents, including those related to use of oral ribavirin for treatment of hepatitis C and combination use of ribavirin and alpha interferons (reportedly providing protection to Jan. 2016). These include U.S. 6,387,365 and 6,299,872, both entitled “Combination Therapy for Chronic Hepatitis C Infection, assigned to Schering-Plough; and U.S. 6,403,564, “Ribavirin-Interferon Alfa Combination Therapy for Eradicating Detectable HCV-RNA in Patients Having Chronic Hepatitis C Infection, “ covering combination use of interferon products and ribavirin for hepatitis C. DataMonitor and ABN Ambro report that U.S. patent coverage for Rebetron Combination Therapy expired in 2001 (although Schering-Plough and Valeant, holding newer use patents, would likely disagree; this conclusion appears to be based only on composition-of-matter patents).
In 2000, an arbitration panel ruled against Biogen, Inc. in favor of Schering-Plough Corp. in a proceeding initiated by Biogen in Dec. 1998. Biogen had claimed it should received (and have received) higher royalties from sales of Rebetron Combination Therapy (Intron A plus oral ribavirin) by Schering-Plough. The arbitration concerned deciding whether Rebetron Combination Therapy is a combination therapy (as described in the license agreement). If this were the case, Biogen would receive royalties calculated at a higher rate based on combination product sales, rather than just sales of the Intron A component. This claim for higher royalties based on total combination sales was rejected. Biogen, continues to receive the same royalty rate it has been receiving from sales of Intron A.
As discussed in the peginterferon alfa-2b (Pegasys) entry, Hoffmann-La Roche received approval of Pegasys in combination with its own oral ribavirin (Copegus), and Ribapharm/ICN filed patent infringement suits against Roche. In Jan. 2003, Roche settled its patent dispute with Ribapharm/ICN (now Valeant), with Roche receiving a license for use of oral ribavirin with Pegasys and paying Ribapharm/ICN royalties on its sales of Copegus. See the Pegasys entry for further information.
As discussed in the Recombinant DNA Product entry (at the beginning of this section), Genentech is appealing a $500+ million award to the City of Hope Medical Center (COH) arising from a 1976 contract and patent licensing dispute involving COH developing basic cloning technology for Genentech, including involvement in recombinant insulin development. Genentech is appealing to the California State Supreme Court.
Various U.S. generic drug companies have been seeking to market generic oral ribavirin in the U.S and other countries. Schering-Plough filed U.S. patent infringement suits against companies including Three Rivers Pharmaceuticals LLC, Teva Pharmaceutical Industries Inc., and Geneva Pharmaceuticals Inc., a subsidiary of Novartis AG. Each of these companies had filed an ANDA seeking approval of generic ribavirin. Three Rivers has granted Par Pharmaceutical, Inc. U.S. marketing rights to its generic.
Schering-Plough reached out-of-court settlements with Three Rivers in Feb. 2003, and with Teva and Geneva in March 2003. The generic firms received nonexclusive non-sublicensable royalty-bearing licenses for Schering-Plough’s patents concerning use of interferon products in combination with ribavirin for treatment of chronic hepatitis C, and pay unspecified royalties on product sales. However, these settlements did not affect ongoing patent infringement suits with generic drug companies filed by Ribapharm/ICN, now Valeant.
In July 2003, the U.S District Court granted a summary judgement in favor of the Three Rivers, Par and another generic drug company, ruling that the companies were not infringing Ribapharm/ICN (Valeant) patents, but did not rule on the validity of the patents. Ribapharm/Valeant is appealed the decision.
In Aug. 2003, ICN Pharmaceuticals/Ribapharm won an arbitration with Schering-Plough concerning it not paying royalties to ICN/Ribapharm for ribavirin sales that were part of the company’s indigent care program prior to 2002, with neither entitled to royalties after this date.
In April 2004, Warrick Pharmaceuticals, a subsidiary of Schering-Plough, launched its own generic ribavirin. With this launch, as stipulated in its nonexclusive license, Three Rivers was no longer obligated to pay royalties to Schering-Plough on its sales of generic ribavirin.
Medical: Intron A is used for a variety of cancer indications:, including hairy cell leukemia, AIDS-related Kaposi’s sarcoma, and as adjuvant therapy for malignant melanoma and in combination with chemotherapy for non-Hodgkin’s lymphoma; and for infectious disease indications: including treatment of chronic hepatitis B and C and condylomata acuminata (genital warts due to human papillomavirus). The product is injected by various routes for various indications:. Intron A in combination with Rebetol (oral ribavirin, USP) Capsules from Schering-Plough or Rebetron Combination Therapy is also approved for treatment of chronic hepatitis C, and was the standard-of-care for chronic hepatitis C virus infection prior to the introduction of pegylated forms of interferon alpha (PEG-Intron from Schering-Plough and Pegasys from Roche).
The most common side effects associated with Intron A therapy include flu-like symptoms, such as fever, headache, myalgia, rigors, and asthenia. These are common side effects of alpha interferon products. Other frequently occurring side effects are nausea, alopecia, abdominal pain, depression, musculoskeletal pain and somnolence. As with other alpha interferon products, very infrequent reports of suicidal behavior (ideation, attempts, and completed suicides) have been associated with treatment.
Intron A has been shown to have a low potential for inducing neutralizing antibodies. This occurred in fewer than 1% in clinical trials. In contrast, Roferon A (interferon alpha-2a), which differs by only one amino acid position, resulted in neutralizing antibody activity in about 25% of patients.
Market: Worldwide sales were $194 million in 2011; $209 million in 2010; $231 million in 2009, $234 million in 2008, $233 million in 2007, $286 million in 2006 and 2005, and $318 million in 2004, with Intron A then losing market share to pegylated alpha interferons, particularly Pegasys from Roche and Schering-Plough’s own PEG-Intron. Sales of Intron A were $865 million in 2002, $598 million in 1997, and $524 million in 1996.
The majority of Intron A sales have been for hepatitis C treatment.
Worldwide sales of Rebetol reported by Schering-Plough were $311 million in 2006, $331 million in 2005, and $287 million in 2004. Note, sales of Rebetol (which is primarily sold for use in combination Intron A and PEG-Intron) exceeded those of Intron A.
Combined worldwide sales of Intron A and Rebetron Combination Therapy [combination use of Rebetol (ribavirin) capsules plus Intron A] totaled about $548 million in 2006; $617 million in 2005; $605 million in 2004; $1.1 billion in 1999 (achieving blockbuster status), up 56% from $719 million in 1998 (with much of this increase due to Rebetron Combination Therapy). Schering-Plough recorded U.S. Rebetol (ribavirin) sales of $865 million in 2003. Sandoz/Novartis, a foreign manufacturer/marketer of generic ribavirin, has reported that sales of Rebetol (by Schering-Plough) were $645 million in 2003 (based on IMS data).
The 2007 Average Wholesale Price (AWP) for Intron A is $977.20 for six 10 million IU vials with syringes; $162.84/10 million IU vial powder; $293.14/18 million IU vial powder;; 814.33/50 million IU vial powder; $293.14/3 mL, 6 million IU/mL solution vial; $407.17/2.5 mL, 10 million IU/mL solution vial; $293.14/1.5 mL, 3 million IU/0.2 mL solution vial; $488.59/1.5 mL, 5 million IU/0.2 mL solution vial (Red Book, 2007). These prices are unchanged from 2004.
The 2007 Average Wholesale Price (AWP) for Rebetol (ribavirin) is $445.04/42 200 mg capsules; $594.49 for 56; $741.74 for 70; and $890 for 84.
The consumer cost for Rebetron Combination Therapy is about $1,000 per month than for Intron A alone, i.e., the additional purchase of oral ribavirin, Rebetol, from Schering-Plough costs added ~$1,000 month (prior to pricing pressure from generics). However, ribavirin is relatively inexpensive and is sold cheaply in many foreign countries. Schering-Plough’s high mark-up for addition of ribavirin to Intron A sparked protests among hepatitis, treatment, and consumer activists. Ribavirin has been imported and sold by some AIDS activist groups, e.g., the People with AIDS Health Group (New York, NY) had charged $410 for a one-month supply. Custom compounding pharmacies in the U.S. have also offered less expensive oral ribavirin. With the mid-2001 approval of unbundled (separately sellable) oral ribavirin (Rebetol), the drug finally became available for use with other interferon products, e.g., Roferon and later pegylated interferons. However, protests over Schering-Plough’s high prices for the product persisted.
Sales of oral ribavirin (rebetol) have been very profitable for Ribapharm/ICN and Schering-Plough. Patent royalties from oral ribavirin have constituted the majority of profits reported by Ribapharm/ICN/Valeant. Total oral ribavirin (Rebetol) sales by Schering-Plough were about $865 million in 2002, with Ribapharm reporting $270.3 million in related revenues. ICN reported royalties from ribavirin sales of $155 million in 2000, and $180-190 million in 2001. By early 2003, peginterferon (PEG-Intron or Pegasys) in combination with oral ribavirin (Rebetol or Copegus) was rapidly being adopted as the standard-of-care for treatment of chronic hepatitis C. The current availability of multiple generic versions of oral ribavirin have reduced Schering-Plough’s sales of Rebetol (Manufactured by Ribapharm/Valeant).
Multiple companies now market generic versions of ribavirin in the U.S. and other markets.
Competition: Various companies worldwide are developing, manufacturing and marketing generic (biogeneric, biosimilar, biocomparable, follow-on, etc.) versions of recombinant interferon alfa-2b (Intron A) and other interferon products (where lack of patents or their enforcement allows). For example, Sicor Pharmaceuticals Inc., acquired by Teva Pharmaceutical Industries in late 2003, manufactures interferon alpha-2b at facilities in Lithuania, with this product marketed in 16 countries. Helix BioPharma Corp. is developing interferon alpha-2b for topical administration, with positive results from a Phase II study for human papillomavirus (HPV)-associated cervical lesions and ano-genital warts reported in Nov. 2006. Nautilus Biotech initiated Phase I trials with Belerofon, an injectable protease-resistant long-lasting interferon-alpha mutein, in Oct. 2006. BioLex Therapeutics is (in 2007) conducting Phase II trials with Locteron in combination with ribavirin for treatment of chronic hepatitis C. Locteron is a biogeneric, controlled release formulation of interferon alpha-2b (BLX-883) expressed by Lemna (duckweed), a small aquatic plant (alga) formulated with PolyActive controlled-release drug delivery technology from OctoPlus NV. Therapeutic Proteins Inc. (Chicago, IL) is developing a biogeneric version of interferon alpha-2b, and has contracted with Angel Biotechnology Holdings plc for its manufacture.
See the Interferon Products entry in the Blood Products, Human section for further information about interferons in development and biogeneric competition.
Companies involvement:
Full monograph
206 Interferon alfa-2b, rDNA
Nomenclature:
Interferon alfa-2b, rDNA [BIO]
Intron A [TR]
Interferon alfa-2 [FDA MESH]
Interferon Alfa-2b [USAN INN BAN]
Interferon alpha2b (human leukocyte clone Hif-SN206 protein moiety reduced) [NUM CAS]
9008-11-1 [CAS RN, for alpha interferons]
98530-12-2 [CAS RN]
99210-65-8 [NUM CAS]
IFN-alpha [SY]
Interferon alpha 2b [SY]
Interferon, alpha-2b recombinant [SY]
rIFN-alpha [SY]
Sch 30500 [SY]
Alfatronol [TR EU]
Virtron [TR EU]
NDC 00085-0571-02; NDC 00085-1110-01; NDC 00085-0539-01; NDC 00085-1168-01; NDC 00085-1133-01; NDC 00085-1242-01; NDC 00085-1235-01; NDC 00085-1254-01 [NDC] [NDC]
molecular weight (kDa) = 19.3
FDA Class: Biologic PLA
Year of approval (FDA) = 1986
Date of 1st FDA approval = 19860604
(in format YYYYMMDD)
Biosimilars/biobetters-related U.S. Patents: | 2020, claimed by Merck; 2019, presuming 6,482,613 licensed from Roche applies
Visiongain in 2009 reported patents expired. |
U.S. Patent Expiration Year: | 2019 |
U.S. Biosimilars Data Exclusivity Expiration: | 1998 |
U.S. Biosimilars Orphan Exclusivity Expiration: | 1993 |
U.S. Biosimilars Launchability Year: | 2020 |
U.S. Biobetters Launchability Year: | 2020 |
Biosimilars/biobetters-related EU Patents: | 2001, based on EP 0032134; biosimilar applications already filed in the EU
Visiongain in 2009 reported patents expired. |
EU Patent Expiration Year: | 2001 |
EU Biosimilars Data Exclusivity Expiration: | 2010 |
EU Biosimilars Orphan Exclusivity Expiration: | |
EU Biosimilars Launchability Year: | 2010 |
EU Biobetters Launchability Year: | 2001 |
Index Terms:
biopharmaceutical products
exempt from CBER lot release requirements
human materials used<!-- humansource -->
Interferon, Human Fibroblast (Gb-23-902-531), Second International Standard
recombinant DNA
bacterial culture <!-- bacterialculture -->
Escherichia coli (E. coli)
KMAC-43 vector
media, defined nutrient
Albumin (Human)
Bacteriostatic Water for Injection
glycine
lyophilized (freeze-dried)
sodium phosphate, dibasic
sodium phosphate, monobasic
tetracycline
approval dates uncertain (FDA reports erroneous, conflicting, or simply has lost the original approval dates) (FDAapproved)
catheter clearance
orphan status
Park-William no. 8, Corynebacterium diphtheriae
EU200 Currently Approved in EU
UM001 Marketed Product in US
US200 Currently Approved in US
EM001 Marketed Product in EU
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