Status: approvals withdrawn (was the 1st interferon)

Organizations Involved

Glaxo Wellcome Inc. – Manuf. other; USA mark.; Former

Wellcome Foundation, Ltd. – Manuf.; R&D; Tech.; Former

Glaxo Wellcome plc – Former inv.; Parent; Former

Sumitomo Pharmaceuticals Co., Ltd. – Manuf. other; Japan mark.; Former

Cross ref See Interferon Products entry (#793).

Description Interferon alfa-n1, Lymphoblastoid or Well-feron is a liquid formulation of a mixture of alpha interferon proteins isolated from culture of a human leukocyte/lympho-blastoid cell line (Namalva cell line) after induction of interferon secretion by infection of the cells with murine parainfluenza virus type 1 (Sendai virus), with purification including immunoaffinity chromatography using matrix-bound interferon alpha monoclonal antibodies. Wellferon is a Type I and alpha interferon. Each of the nine predominant alpha interferon species in Wellferon consists of 165 to 166 amino acids with a molecular weight of about 20 kDa.

Wellferon is formulated with ethanamine/glycine-buffered saline (consisting of 8.50 mg/ml sodium chloride, 0.75 mg/ml glycine, 1.21 mg/ml tromethamine and Water for Injection). Albumin (Human) is added as a stabilizer to give a total protein content of 1.5 mg/ml and the pH is adjusted to 6.8-7.2 pH with hydrochloric acid or sodium hydroxide. The product contains no preservatives. The dating period for this product is 24 months from the date of manufacture when stored at 5˚C. The date of manufacture is the date of final sterile filtration of the formulated product. The dating period for the purified bulk blend is 4 weeks when stored at 5˚C and 6 months when stored cryogenically. The dating period for the formulated final bulk is 7 days when stored at 5˚C.

Wellferon is no longer manufactured or marketed. The product was officially abandoned by Glaxo Wellcome in August 1999 (less than 1/2 year after U.S. approval), was never launched in the U.S., and its product license was subsequently voluntarily withdrawn.

Wellferon was a pioneering biopharmaceutical product in many respects. It was the only marketed interferon product manufactured on a large-scale competitive with recombinant production techniques. Wellferon was the first product to use transformed cells for large-scale biopharmaceutical production, and large-scale purification and viral inactivation processes were developed, resulting in very pure product capable of meeting rigorous regulatory standards (including production from transformed cells). Wellferon’s research, development and manufacturing costs were largely recovered, almost from the very start, by sales of the product for reagent, research and clinical trials use and from technology transfer. Development of the product included a multi-company/U.K. government laboratory consortium involved in early research and development.

Nomenclature: Interferon alfa-n1 [BIO]; Wellferon [TR]; interferon alfa-n1, Lymphoblastoid [FDA]; 9008-11-1 [CAS RN, for alpha interferons]; human interferon alpha (lympho-blastoid)] [SY]; HuIFN-alpha [SY]; Sumiferon [TR Japan]; Biological Intermediate 777 [SY]; Ga23-901-532 [NCI BRM repository]; NSC-339140 [NSC NCI]

History In 1974, seeking methods for larger-scale manufacture of lymphoblastoid alpha interferon for clinical trials, Wellcome Research Labs. (Burroughs Wellcome plc; later Glaxo Wellcome plc; become GlaxoSmithKline in late 2000), adopted the use of transformed host cells. These immortalized cells, resembling tumor cells in some respects, could be repeatedly subcultured and grown in large suspension steel culture tanks for interferon production. Using knowhow obtained from large-scale (2,000 liter) production of foot and mouth disease vaccines in cultured transformed baby hamster kidney (BHK) cells, Wellcome adapted use of the Namalva cell line, a transformed human leukocyte (lymphoblastoid) cell line which expresses high yields of interferon upon induction (infection) with Sendai virus. The Namalva cell line was originally obtained from a Ugandan girl who died from lymphoma (Burkitt’s tumor).

FDA and other regulatory authorities in major pharmaceutical markets had, at the time, never approved a product manufactured from transformed cells, and major regulatory and safety concerns had to be addressed. The key to obtaining approval (a safe product) was development of purification methods, which also substantially eliminated the risk of viral, cellular oncogene, and other contamination.

Wellcome researchers (M. Johnston, et al.) found that treatment of Namalva cell cultures with sodium butyrate (naturally in butter) for 24-36 hours before stimulation with Sendai virus resulted in a slowing of growth and consistent increases in the yield of interferon. Wellcome obtained a patent on this, and this method came to be widely used for its interferon production. Subsequently, Wellcome (K. Fantes, et al.) devised a highly effective, large-scale purification process using highly acidic conditions and an organic solvent (both of which disrupt viral, oncogene/DNA and other nucleic acid contaminants, but do not affect acid-stable alpha interferon). Using samples spiked with various markers, e.g., model viruses, this method was validated. Wellferon became the first interferon available commercially and the first biopharmaceutical in the world market (but not the U.S. for many years later) produced using transformed cells.

Wellcome began manufacture of Wellferon in 1,000 liter culture tanks at Beckenham, U.K., in 1977. With increasing demand, another plant was opened in Porrino, Spain in 1980. The bulk interferon produced by this plant, sent to the U.K. for finishing, was called Biological Intermediate 777 to avoid identifying the product during shipping (to avoid theft of the product, which was new and very much in demand).

By this time (late 1970s), “interferonmania” had set in, with the press and public believing interferon to be a wonder drug, cure for cancer, etc. Wellcome began the first clinical trials with Wellferon in 1979, and trials began in the U.S. in 1980. Also, in 1980, Biogen reported cloning of recombinant leukocyte (alpha) interferon in E. coli. In 1981, a new subsidiary, Wellcome Biotechnology Ltd. (WBL), was formed with interferon as its main product. New, 8,000 liter culture tanks (deep cell culture, DCC) came online at Beckenham in 1983. Analytical methods, particularly isoelectric focusing and reverse phase high pressure chromatography (RP-HPLC) became available, showing that Wellferon was composed of multiple interferon types, and were adapted for quality control.

Dr. Sidney Pestka, et al., Hoffmann-La Roche Inc., expressed the first recombinant interferons in 1975. Dr. Pestka, et al., made another important advance (among many attributable to him and co-workers) in 1977 with the development of reverse-phase high performance liquid chromatography (HPLC) and its application to natural interferon purification. As further discussed in the entries for recombinant interferon alpha-2a (Roferon) and interferon alpha-2b (Intron A), the discovery that natural interferon was actually a large family of proteins had major implications, particularly affecting patents.

Clinical trials with Wellferon were conducted starting in the 1970s in children with juvenile laryngeal papillomatosis (warts in the throat). In the 1980s, analysis of results from these and other Wellferon trials were delayed for years, as Wellcome concentrated on several new (then revolutionary) antiviral drugs – acyclovir for herpesvirus infections and AZT for HIV-infection. Wellcome planned to file for U.S. approval for juvenile laryngeal papillomatosis in 1985, but this was further delayed as resources were devoted to new antiviral, particularly HIV, drugs. An application (with only partial analysis from 6 months of a 1-year controlled U.S. trial) was submitted to FDA in 1985. The company had intended to update this application, but did not get around to it, and FDA rejected this as an incomplete application in 1987. Wellferon received its first approval (for hairy cell leukemia) in the U.K. in March 1986, only days ahead of the original approval of recombinant interferon alpha-2b (Intron A) from Schering-Plough Corp. In parallel with this U.S. activity, the product was being used and approved for various indications: in other countries worldwide.

Starting in 1982, Wellcome focused much of its biologics efforts on development and scale-up of production of tissue plasminogen activator (t-PA). The large-scale DCC plant at Beckenham was converted to t-PA manufacture. Wellcome abandoned this t-PA project in 1990, which further diverted resources from Wellferon, after losing a U.S. patent dispute with Genentech (see Activase entry, #269). Having encountered some Wellferon production problems in Spain, in early 1988 Wellcome decided to abandon Wellferon. However, circumstances resulted in a reversal of this decision. The company’s abandonment of recombinant t-PA resulted in idling of a large biologics manufacturing plant in Greenwich, RI, built through a collaboration (WelGen) with Genetics Institute for manufacture of t-PA. When this became available, it was converted to Wellferon manufacture.

Sales of Wellferon increased worldwide and the product was the largest-selling interferon during much of the 1980s, prior to being overtaken by recombinant products (e.g., Intron A and Roferon A). Wellferon began losing market share to recombinant products starting in 1983, and recombinant products were approved in the U.S. starting in 1987. Wellcome divested its human and animal vaccines businesses in 1990. A decision was made at the time not to pursue U.S. approval of Wellferon. In the mean time, Wellferon was being used for treatment of chronic hepatitis B in Singapore and S.E. Asia, and received approval for this indication in the U.K. in February 1991. By 1994, Wellferon was still the most widely used interferon product in many countries for hepatitis B indications:. However, with its declining market share, difficulty of manufacture (and involving human cells and animal-derived products), and with newer interferon products on the horizon (e.g., pegylated versions), Wellferon, then the company’s only biologic product, was abandoned by Glaxo Wellcome in August 1999.

Companies Wellferon was developed and manufactured by the Wellcome Foundation, Ltd., Wellcome Research Labs., Glaxo Wellcome plc (now GlaxoSmithKline plc), Beckenham, Kent, UK, FDA CBER est. no. 0129. The product was marketed internationally for decades by Burroughs Wellcome plc, which became Wellcome Co. plc, subsequently merging with Glaxo plc to form Glaxo Wellcome plc, but was never marketed in the U.S. Glaxo Wellcome has merged with SmithKline Beecham plc to form GlaxoSmithKline plc.

Sumitomo Chemical Co. licensed Well-feron manufacturing technology and began producing the product, marketed as Sumiferon, in Japan in 1986. Sumiferon was approved in Japan in 1987. Sumitomo paid royalties to Wellcome on sales of Sumiferon through 2001. Sumiferon is still apparently marketed in Japan.

Manufacture Namalva cells are cultured in large-scale suspension culture in a medium such as RPMI 1640 (Moore, G.E., et. al., 1967, J. Amer. Med. Assoc. 199, 519-524) supplemented with serum, for example calf or horse serum, usually at 5%-10% (v/v), after stimulation of interferon secretion by the cells through infection with murine parainfluenza virus type 1 (Sendai strain). Purification includes immuno-affinity chromatography using matrix-bound interferon alpha antibodies (perhaps polyclonal rather than antibodies, since the start of manufacture predates commercial manufacture of monoclonal antibodies).

FDA class: Biologic PLA

Approvals: Date = 19990325; first approval, original PLA and supplemental ELA (ref. no. 97-l 148 and 97-1157) granted to Wellcome Foundation Ltd., Wellcome Research Labs. CBER/FDA est. no. 0129, subsidiary of Glaxo Wellcome plc.

Date = 19990800; license voluntarily withdrawn

Date = 20000425; license revoked

Indications: [unofficial; U.S. product insert/labeling never became available]; for the treatment of chronic hepatitis C in patients ≥18 years of age without decompensated liver disease

Status The product license was voluntarily withdrawn by Glaxo Wellcome Inc. in Aug. 1999, only months after U.S. approval. The product was experiencing declining market share in its international markets, it was difficult to manufacture (and involved human cells and animal-derived products), and newer interferon products on the horizon (e.g. pegylated recombinant versions) were among the factors contributing the to company’s decision.

The ELA supplement accompanying the product approval included manufacture at the facility in West Greenwich, Rhode Island; purification and production of the final bulk at the company’s facility in Beckenham, Kent, United Kingdom; and filling, labeling and packaging at the facility in Dartford, Kent, United Kingdom. Interferon alfa-nl, Lymphoblastoid was distributed from a facility in Durham, NC. The West Greenwich, RI, facility is now used for manufacture of TNF Receptor-IgG Fc, rDNA (Enbrel; #267) by Immunex/Amgen.

Tech. Transfer Exemplary patents include U.S. 4,216,203, “Process for Producing Interferon,” assigned to Wellcome Co., August 5, 1980. This patent describes exposure of interferon-producing cells to straight chain, saturated carboxylic acids, preferably butyric acid, to induce higher yields of interferon. Examples describe aspects of Wellferon manufacture. Improvements in manufacture are claimed in U.S. 4,780,413, assigned to Burroughs Wellcome Co., including use of tetramethylurea as an interferon inducer in virus-infection cells.

As discussed in the Companies section, Sumitomo licensed Well-feron manufacturing technology and has marketed Sumiferon in Japan since 1987. Sumitomo paid royalties to Wellcome on sales through 2001.