HEALTH-SYSTEM EDITION
SPECIAL REPORT

HELPING HEMOPHILIACS

The new therapies are safer, simpler, and cover treatment-on-demand to prophylaxis

For the individual born today with hemophilia, the future looks bright. What was once an early death sentence was commuted to a life sentence then to a productive life sentence and perhaps someday, in the not-too-distant future, to a cure via gene therapy. The possibilities are mind-boggling, but so are the costs.

Over the years, hemophilia treatment has evolved from treatment-on-demand for acute bleeding to prophylactic therapy to prevent joint bleeding and crippling arthropathy. But life for an individual with hemophilia is far from simple. To attain the benefits of prophylactic treatment, factor VIII (for hemophilia A) must usually be given every other day—intravenously. Not only is this a difficult regimen for adherence, but also for a 70-kg man, the cost can accrue to more than $200,000 per year.

If an individual develops inhibitors to factor VIII—which happens in 15%-30% of previously unexposed patients—the cost for immune tolerance induction can be as high as $1 million for a four- to 18-month course of therapy. So even though hemophilia is a rare disorder, it is difficult to manage, and the costs associated with it have a significant impact on health expenditures.

Worldwide, manufacturers are committed to improving the quality of life for hemophilia patients, by increasing production (because demand for products far exceeds supply), improving available options, and simplifying regimens.

Newest treatments

Advate (antihemophilic factor [recombinant] plasma/albumin-free method) by Baxter Healthcare, approved in 2003 for the prevention and control of bleeding episodes in people with hemophilia A (see Drug Topics, Sept. 1, 2003), represents an advance in therapy: It is a factor VIII product made with no added human or animal plasma proteins and albumin in the cell culture process, purification, and final formulation—protecting patients from blood-borne viruses.

Mononine, a factor IX concentrate by Aventis Behring, has been approved by the European Commission for continuous infusion in the treatment of individuals with hemophilia B who are undergoing surgery, exposed to trauma, or experiencing severe, spontaneous hemorrhage.

A genetically engineered product, OBI-1 by Octagen Corp. of Bala Cynwyd, Pa., and Beaufour Ipsen, based in Paris, is undergoing phase I trials as a potential new hemophilia treatment. Trials are planned in 20 clinical centers throughout the United States and United Kingdom.

Bayer has several developments "in the works" for the more immediate future. BIO-SET, a needleless device that includes a prefilled syringe for the reconstitution of Kogenate (antihemophilic factor [recombinant] formulated with sucrose) products, is poised for Food & Drug Administration approval and launch this fall. Peter Larson, M.D., global clinical director for the hemophilia franchise of Bayer Biological Products, explained that BIO-SET takes the administration process that involves many steps down to essentially three steps.

"The traditional method has seven components: two vials, the alcohol prep to wipe them off, the transfer needle, the filter needle, the syringe, and the butterfly needle," explained Larson. "The BIO-SET has the prefilled syringe, the BIO-SET container that holds the lyophilized powder, and the butterfly needle. You go from seven pieces to three. You go from four actual sharps [because the transfer needle has two sharps] to one sharp which is on the butterfly."

Bayer is also working with Arrowhead Electronic Healthcare on a handheld patient diary. This diary will help patients manage product information, track and report home treatments, access educational materials, communicate with healthcare providers, and so on. Larson explained, "We have acquired a software package that helps make this process simpler, and currently the input device is a palm pilot or a personal data assistant [PDA] that will be able to be downloaded into a database at the Hemophilia Treatment Center. This is meant to make it easier for the patient. It incorporates a bar-code scanner onto the PDA itself, a product would have attached to it a bar code that contains the lot number and the number of international units that were used. The patient just has to scan it in and record the date and where he had the bleed."

In the long term, Bayer Corp. also has ongoing research working toward a molecule that has less frequent dosing that could simplify a hemophilia patient's prophylactic therapeutic regimen.

Inhibitor complication

Novo Nordisk Pharmaceuticals has a corporate commitment to individuals with hemophilia, specifically those with inhibitors. Formation of inhibitors, or antibodies, occurs in previously untreated patients who receive factor VIII products, making replacement therapy problematic. Sam Marshall, senior director of marketing for the biopharmaceuticals division for Novo Nordisk, remarked, "Hemophilia is a big enough challenge. Then to get inhibitors on top of it and to find out the primary therapy now has been rendered ineffective is devastating."

Marshall noted that in the United States, the population of patients with hemophilia who have inhibitors numbers about 2,000. "These patients are probably the most severely ill, afflicted patients because they've become resistant to their factor VIII and factor IX replacement therapy," he explained. "So what we're doing starts with NovoSeven." NovoSeven is recombinant factor VIIa. Approved in March of 1999, it is a treatment that "bypasses" clotting factors to which there are inhibitors, allowing blood clotting to occur. It has been approved by the FDA for the treatment of bleeding episodes in patients with hemophilia A or B who have inhibitors.

"Since the initial launch of the drug, we've tried to do several things to address what we feel has been an underserved community—that is, specifically, the hemophilia patient with inhibitors," said Marshall. "Because there are so few of them and there were not—until NovoSeven—many products available to treat these patients, we undertook an initiative with the National Hemophilia Foundation last year to try to bring this small group of patients together via the on-line community so patients could register through the on-line community, involve themselves in threaded discussions, ask questions, and get responses back." In conjunction with their NovoSeven product, the company also recently introduced a reconstitution kit to the U.S. market.

Genmab, headquartered in Copenhagen, and the Dutch not-for-profit organization Sanquin Blood Supply Foundation recently agreed to collaborate on a treatment that can block inhibitory antibodies from binding to factor VIII. At present, research is being conducted in mice, and it is probably years away from trials in humans.

Behind the scenes, the FDA is considering whether or not existing clinical trial protocol for drug approval adequately addresses the inhibitor issue, particularly with regard to factor VIII in previously treated patients. The FDA's current definition of heavily pretreated patients is an exposure of 150 days. In a presentation to the FDA in the fall of 2003, Gilbert White, M.D., University of North Carolina School of Medicine, maintained that 15%-20% of patients who are going to develop an inhibitor would not have done so after 50 exposure days. He believes the incidence does not reach an asymptote with 100% until exposure has been continued until close to 250 days.

Cost considerations

With or without inhibitors, the cost of treating hemophilia is high. Larson commented, "That's a special problem in the United States where patients are covered by insurance policies that have caps." But in other countries, "those that have nationalized health services, in Canada and the United Kingdom for instance, economic decisions have to be made at the national level in terms of allocating funding for specific diseases. For this reason, it is critical to provide pharmacoeconomic and quality-of-life data [about the benefit of therapeutic regimens] to convince the governments that there is value from these therapies." Several studies authored by A. H. Miners and associates have shown that in some scenarios, primary prophylaxis is cost-effective in comparison with treatment-on-demand.

Key to cost-effectiveness is benefit in terms of quality of life. Bayer has funded researchers at the University of Hamburg, Germany, in the testing and validation of two quality-of-life scales for patients with hemophilia. The first, for pediatric patients, is Haemo-Qol, which will be published within the next month in Haemophilia. An adult instrument is also expected in the near future.

Ideally, because hemophilia is a genetic disorder, it would be treated by gene therapy. Indeed, within the past two years, five gene transfer trials have been approved. To date, most of the trials have been in animals, but a review of the existing preclinical data suggests animal studies may not adequately predict the outcome in humans. In 2000, Bayer and Avigen agreed to collaborate on phase II/III clinical trials for Coagulin-B, a gene therapy treatment for hemophilia B.

Although much progress has been made in the diagnosis and treatment of hemophilia, much more remains to be accomplished. Still, the future looks bright.

Kathy Hitchens, Pharm.D.

The AUTHOR  is a medical writer based in the Indianapolis area.

Hemophilia in brief

According to the National Hemophilia Foundation, roughly 17,000 people in the United States have hemophilia. Because it is an X-chromosome-linked disorder, it is predominantly a disease of males, occurring in only one of 25,000,000 live births in females. Hemophilia A, a deficiency in factor VIII, is more common than hemophilia B, a deficiency in factor IX. However, the disorders are clinically indistinguishable, and diagnosis must be confirmed by a specific factor assay.

 

Kathy Hitchens. Special Report: Helping Hemophiliacs. Drug Topics Mar. 22, 2004;148:HSE17.