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Hemophilia market awaits next-generation therapies

Nature Biotechnology volume 29, page 960 (2011) | Download Citation

Water fountains in Bucharest coloured red by Romanian Hemophilia Association to draw attention to the disease. Recombinant coagulation factors control symptoms but the short duration of hemophilia products remains a major limitation. Image: Daniel Mihailescu/Newscom

As Biogen Idec and Swedish Orphan Biovitrum prepare to report phase 3 data from a pivotal trial in hemophilia patients of their long-acting, recombinant version of the serum coagulation factor VIII (FVIII) next year, several next-generation hemophilia therapies are progressing in the clinic. In addition to Biogen/Biovitrum's product FVIII:Fc, a FVIII linked to the amino terminus of the Fc domain of IgG1, Recoly of Brussels, and its partner Bayer, of Leverkusen, Germany, have already filed for approval in undisclosed territories for LongAte, a liposome-formulated plasma-derived FVIII, with a recombinant-based counterpart (BAY-79-4980) in phase 2 studies. Several other companies are developing hemophilia products with half-life extension technologies, including Freising, Germany–based XL Protein, Amunix, of Mountain View, California, and Bagsværd, Denmark–based Novo Nordisk.

A recent report on hemophilia treatments from London-based market research firm GlobalData concludes that recombinant FVIII and other coagulation products will soon supersede plasma-derived products and foresees that hemophilia regimens will increasingly shift from symptomatic treatments to prophylactic approaches that prevent joint bleeding. Hemophiliacs with access to these costly therapies (FVIII therapies run up to $100,000/year) can expect normal or near-normal life expectancy, particularly if they start therapy at an early age. Even so, they face considerable quality-of-life constraints. Because of the short serum half-lives of both FVIII (deficient in hemophilia A) and coagulation factor IX (deficient in hemophilia B), many patients need to take intravenous injections on alternate days. Compliance is a major issue. Moreover, the development of neutralizing antibodies—known in the hemophilia community as 'inhibitors'—can occur in up to 30% of hemophilia A cases (and in a smaller percentage of hemophilia B) and complicates management of the condition even further. There is, therefore, considerable scope for technological improvement in the field, according to analyst Ankita Ahuja, who authored the report.

In the near term, Biogen/Biovitrum's FVIII:Fc and Recoly/Bayer's LongAte look most likely to reach the hemophilia A market. FVIII:Fc has been shown to have a half-life 1.7 times longer than Deerfield, Illinois–based Baxter's Advate (recombinant human FVIII) in a phase I/IIa trial. And Recoly/Bayer claim that the improved hemostatic efficacy of LongAte enables once-a-week prophylactic treatment compared with conventional regimens where plasma-derived FVIII is injected at two- to three-day intervals.

Several other half-life extension technologies are also being explored. XL-protein is using a process it terms PASylation, involving the addition of a 600-residue unstructured (random coil structure) polypeptide chain containing proline, alanine and serine residues to FVIII. Amunix, of Mountain View, California, is working with Biogen-Idec on extended life versions of recombinant blood factors (FVIII, Factor IX and Factor VIIa) that have been fused to a long unstructured and nonrepetitive polypeptide (>100–3,000 residues in length). And Novo Nordisk is trialing a technology it acquired from former partner Neose Technologies (which ceased trading in 2008) whereby FVIII can be modified in a 'site-specific' manner with polyethylene glycol (PEG; PEGylation), leading to easier production and greater product consistency. “We do not need to modify the amino acid backbone,” says Soren Erik Bjørn, vice president of hemostasis science at Novo Nordisk. It could double the half-life of FVIII. “We will investigate an infusion frequency of once every four days,” he says.

Several other firms are exploring more experimental approaches that could complement classic coagulation factor therapy. Baxter has acquired a program from Cambridge, Massachusetts–based Archemix involving the development of aptamers to target tissue factor pathway inhibitor. Alnylam Pharmaceuticals, also of Cambridge, is developing RNA interference (RNAi)-based agents targeting protein C. And Thrombotargets, of Castelldefels, Spain, is developing several anti-hemorrhagic drugs against targets implicated in coagulation, such as lipidated tissue factor. These treatments are as yet unproven in terms of clinical validation of safety and efficacy. “We need to have human trials to give us a clear answer,” says Rebu Ninan, center of excellence manager, oncology and blood disorders, at GlobalData.

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