Rfactor VIII Deficit Questioned
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© 2000 Nature America Inc. • http://biotech.nature.com ANALYSIS BUSINESS AND REGULATORY NEWS rFactor VIII deficit questioned There is a serious worldwide shortage of struction and approval of new production nies strongly deny. “I would not want to recombinant factor VIII, a critical blood- facilities. Baxter (Deerfield, IL), which owns directly make that allegation,” says Skinner. clotting protein that hemophilic patients use over half the market share, recently doubled “I would say there’s a lot of information that to prevent and control their bleeds, according the capacity of its Thousand Oaks, CA manu- we don’t have…There are some who believe to the National Hemophilia Foundation facturing facility, and is awaiting FDA clear- that there are supplies of product that aren’t (NHF; New York); although recombinant ance to ship product. It is also constructing a being released to the market. If that were the factor VIII has been on the market since third production site. Genetics Institute case, it would be tragic.” 1993, manufacturing capacity is falling short (Cambidge, MA), which received US market- In addition, Bayer is under fire from the of demand. At the same time, leaders of the ing approval for its recombinant factor VIII NHF for plans to sell its “next-generation” hemophilia community charge Bayer AG product, Refacto, in March, has postponed recombinant factor VIII product, Kogenate (Leverkusen, Germany) of using the shortage product launch until 2001 due to production FS, directly to consumers who sign up to its to drive fearful patients into its new, contro- problems and high demand in Europe. It is Bayer Direct program, bypassing normal dis- versial direct purchase program. building a production plant in St. Louis, MO. tribution channels. Kogenate FS, unlike About 35,000 people in North America Meanwhile, Bayer is awaiting FDA approval Kogenate (the previous version), does not and Europe have hemophilia A, an X-chro- for a new, 200-liter fermenter (to replace one use human albumin to stabilize the protein .com mosome-linked bleeding disorder caused by half the size) in its Berkeley, CA facility. “We’ve during purification or formulation, thus fur- a defective factor VIII gene. Beginning in the moved forward as quickly as science would ther reducing the theoretical risk of viral con- 1960s, factor VIII concentrate, which is pre- allow, and keeping safety and efficacy in tamination. pared from multiple plasma donations, was mind,” says Doug Bell, Bayer’s director of While Bayer says it wants to ensure the h.nature used to stop bleeds. However, during the global public policy and communications drug gets into the hands of patients and does- 1970s and ‘80s, more than 40% of hemophil- Recombinant proteins were expected to n’t sit in a distribution chain, the hemophilia ia patients contracted HIV from concentrate be a virtually unlimited source of blood community is angry that the limited supply of and cryoprecipitate, and the majority of products and a permanent solution to chron- Kogenate FS will only be available to enrollees http://biotec • adults that injected concentrate now harbor ic shortages. Although the fast growth in of Bayer Direct, and that patients could be hepatitis C. Since its introduction, recombi- demand appears to have caught all the com- “cherry-picked” based on the reimbursement nant factor VIII, which is produced in fer- panies by surprise, they admit no responsi- generosity of their insurance plans (some- mentation tanks from hamster ovary or kid- bility for the shortfall. “I don’t think it’s a fail- thing Bayer denies). “There’s a concern that ney cells, has become the treatment of choice ure of strategic planning, I think it’s a matter Bayer will be using the [current factor VIII] because the chance of viral contamination is of timing,” says Margaret Shubny, director of shortage as a way of getting people to sign up virtually nonexistent. “Eighty percent of the corporate communications for Baxter. “If the for the program. Coercion is the word,” says US has transitioned [from concentrate] to planets had been aligned a little bit different- Skinner. “Forced into a sole vendor at a higher recombinant product,” says NHF president- ly, I think we might not find ourselves in the price, just to get the next generation product.” elect Mark Skinner. same situation.” The NHF finds Bayer Direct so objectionable 2000 Nature America Inc. © Although recombinant factor VIII peri- Moreover, Bayer claims recombinant fac- that it no longer accepts donations from odically is in short supply, the current short- tor VIII, an enormous, 265 kDa protein, is Bayer. (In 1999 Bayer gave $185,000 to the age is especially severe. According to an exceptionally hard to make compared to other Foundation.) Although Bayer points out that August NHF survey of hemophilia treatment recombinant proteins. “The folding, the pro- Kogenate FS will also be available through centers, half were having difficulty obtaining cessing, and the glycosylation—there are 26 Aventis Behring (King of Prussia, PA) as the drug and the NHF expects the situation separate glycosylation steps—all are challeng- Helixate, NHF believes supplies will be very to worsen. “Many companies have cut back ing,” says Mike Kamarck, senior vice president limited. Lou Aledort, a prominent hemophil- on orders and have stopped accepting new of operations for Bayer’s biological products ia clinical investigator at Mt. Sinai Medical customers,” reads a recent NHF medical unit. He says Bayer is only able to recover Center in New York, says Bayer Direct “is a advisory. “At the present rate, the companies 1/1000th the level of the typical antibody or ploy to directly sell and make more money,” stated they could not keep up with existing cytokine expressed in mammalian cells adding, “What they’re doing is probably legal, demand much longer.” because the size of factor VIII makes it exquis- but totally immoral and unethical.” One factor is the rapid adoption of itely sensitive to denaturing by proteases from These accusations coincide with US state recombinant factor VIII by the hemophilia ruptured cells. As a result, Bayer continually and federal investigations of more than 20 population, many of whom are starting to removes protein and adds new medium to the drug makers for drug-pricing schemes. take factor VIII prophylactically to prevent fermenter to avoid denaturing—an expensive Prosecutors reportedly obtained Bayer AG bleeds. “Worldwide demand is growing and inefficient process prone to glitches. (Germany) documents outlining the need to tremendously….Production has just not However, some in the hemophilia com- quote higher average wholesale prices to doc- kept pace,” says Skinner. munity suspect other factors are at work tors and providers as a way to get them to In addition, only three companies account besides technical problems and lack of fore- choose Bayer products over those of com- for all recombinant factor VIII made in the sight. Specifically, they wonder about price petitors. (The higher the price, the higher the US, and there have been delays in the con- manipulation, especially as treatment with reimbursement to the provider). Kogenate recombinant factor VIII can cost well over was one of the drugs cited. Bayer settled with $100,000 a year per patient. Some suspect the government at the end of September for Ken Garber is a freelance writer working in stockpiling by manufacturers or distributors $14 million, without admitting wrong doing. Ann Arbor, MI. to keep prices high—something the compa- Ken Garber NATURE BIOTECHNOLOGY VOL 18 NOVEMBER 2000 http://biotech.nature.com 1133.