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Companies line up for hereditary angioedema market Brady Huggett At the end of this month, the first therapeutic for hereditary angioedema (HAE) could receive approval for marketing in the US. By end of next year, there could be as many as five biotech products on the HAE market from separate companies. Being first to receive approval in a small, niche indication will ensure a competitive edge, but differences in mode of action, delivery and eligibility for orphan status for the different therapies, as well as the heterogeneity of the patient population itself, might mean later entrants could still be successful as the market becomes segmented. Berlin-based Jerini is poised first in line to receive a decision from the US Food and Drug Administration (FDA). The company's Icatibant, a synthetic peptidomimetic drug licensed from Paris-headquartered Sanofi Aventis, has a Prescription Drug User Fee Act date of April 26. Approval is by no means certain, however, as the HAE field has a history of late-stage regulatory setbacks (Box 1). HAE is caused by low serum levels of C1 esterase inhibitor (C1-INH). As well as inhibiting components of the fibrinolytic, clotting and kinin pathways, C1-INH also blocks the activation of C1 and the rest of the classic complement pathway by binding to C1r and C1s (sub-components of C1). Low levels of C1-INH lead to unchecked complement activation that is important in inflammation and the clearance of pathogens from the body. There are two types of HAE patients: most are type 1 and have levels of C1-INH <35% lower than normal; those with type 2 have normal or elevated levels of C1-INH, but the protein is nonfunctional. Either way, both types suffer attacks that swell the hands, feet, larynx, facial features and genitals, with gastro-intestinal swelling that sometimes causes vomiting, diarrhea and severe pain. The condition is rare but autosomal dominant. One key problem for drug developers is how to estimate the HAE market size. A "pretty standard" estimated prevalence is 1 person with HAE in every 30,000 people, says Samir Singh, president of US operations at Pharming (headquartered in Leiden, The Netherlands). This suggests about 10,000 people in the US and 22,000 people in the Western world with HAE. "When you look at the US, Europe and Japan, that's total treatable attacks of 200,000 [annually]," he estimates. All the players think the market is set to grow and that the disease is often mis- or underdiagnosed. Cambridge, Massachusetts–based Dyax's general counsel and executive vice president of administration, Ivana Magov evi-Liebisch, says diagnosing the disease can take as long as ten years, as patients repeatedly leave hospitals after the attack resolves without a physician fingering HAE as the culprit. "Patients look like they are having an allergic reaction," she says, and even as they suffer vomiting and diarrhea, doctors "can't find anything wrong." Eventually an allergist suggests HAE, and the patient begins mining the family history to discover a pattern of illness in relatives. Once diagnosed, there is no consensus on whether those individuals should receive acute or prophylactic care, mostly because the frequency of attacks is also unclear. CSL Behring of King of Prussia, Pennsylvania, already markets its C1-INH product Berinert in Germany, Austria and Switzerland, where the drug has been administered >300,000 times. Published data from these European patients point to about seven attacks per year, though many assume it's higher and Pharming's Singh says certain surveys have it pegged as high as 20 annually. If people with HAE are having 20 or more attacks yearly, then "one could make a case for prophylactic use," says Singh, though personally he's doubtful. In fact, only New York-based Lev is developing its product, Cinryze, to include the prophylactic market. Dyax's executive vice president and chief business officer, Gustav Christensen, doubts that market exists. Prophylactic treatment could mean two injections a week, driving the cost per patient to $250,000 annually, so insurance carriers would probably begin pushing cheaper acute treatment as preferred. Three of the five drugs vying for approval aim to address HAE by supplementing the individual's endogenous C1-INH with a functional version of the human protein (Table 1). Lev and CSL Behring are both developing a purified plasma protein version, whereas Pharming has developed a recombinant C1-INH produced in transgenic rabbits. The other two companies—Dyax and Jerini—are developing proteins aimed at dampening the inflammatory cascade. Dyax's recombinant protein DX-88 (ecallantide) inhibits kallikrein, an enzyme that liberates bradykinin, which causes fluid to leak from blood vessels into the tissues. Jerini's Icatibant attacks one step further down the line; it's a competitive bradykinin B2 receptor antagonist. All five drugs are deemed comparably efficacious (though there have been no head-to-head clinical trials to help determine this), which means it's difficult to predict which product will have the competitive edge. One differentiating factor is delivery. DX-88 is just 60 amino acids long and can be administered subcutaneously, as can Icatibant, but the C1-INH products must be given by intravenous (i.v.) infusion. Jerini CEO Jens Schneider-Mergener says that, based on feedback from physicians, his firm sees "a big advantage" in the subcutaneous route over the i.v. one. Bret Holley, analyst with New York-based Oppenheimer, which covers Lev but receives no compensation from the firm, tends to agree, venturing that i.v. infusion can be seen as a "killing handicap." But Holley also argues that attacks are foreseen by people with HAE, much like migraines, allowing them time to seek a physician for an infusion, and he points out that Dyax's DX-88 needs to be refrigerated anyway. So far, Jerini boasts the only subcutaneous administration that does not need to be refrigerated—the company has data showing sterility exceeding 18 months at room temperature. Dyax is working on a room-temperature formulation. The final uncertainty is orphan drug status—all have it except CSL Behring. The FDA makes the final decision here, but it is assumed DX-88 and Icatibant will be viewed as independent molecules and thus each drug's orphan drug status will not block another from entering the market. Pharming's Samir says that his company's C1 inhibitor should stand alone, as it is a recombinant molecule. Whether the plasma-derived C1 inhibitors will be viewed as the same molecule isn't clear. There is general consensus, however, on what's at risk: a $500 million-a-year market. The small patient population and unmet medical need means the community will tolerate a "Genzyme-like pricing," Holley says, referring to the empire Cambridge, Massachusetts-based Genzyme has built by developing niche products for rare diseases. The HAE market, Holley believes, will be shaped in much the same way as the one formed around Genzyme's products. "Patients will be treated on a physician-by-physician basis," he says, so the first step is to "get a therapy out there." Only then, as patients choose the product that works best for them, physicians become comfortable and usage is bent to individual needs, will there be hints as to how these products will settle out.
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