Hereditary angioedema (HAE) is a rare inherited disease causing periodic swelling of the skin and walls of the respiratory and gastrointestinal tract. It occurs in 1:10,000 to 1:50,000 individuals, though lower prevalence numbers have also been reported. Airway swelling can be fatal. Swelling in the gastrointestinal tract, and sometimes the skin, can be quite painful. Patients vary in their frequency of attacks: while some may have less than 1 attack a year, others have weekly episodes. HAE is caused by a deficiency or dysfunctionality of C1 Inhibitor (C1 INH), a protein in the blood that inhibits the kallikrein-kinin and classic complement pathways, which have inflammatory and immune functions.

There are a number of drawbacks to current treatment options. Treatment involves giving drugs prophylactically to reduce the incidence of attacks, or acutely to treat attacks. While oral attenuated androgens, which build up the level of C1 INH, reduce the frequency of attacks when given prophylactically, they can have significant long-term side effects. C1 INH replacement is available in Europe, but not the US, and is efficacious for treating and preventing attacks. However, it currently must be given intravenously, making it less suitable for long-term prophylaxis, and only human-derived products are available. While these have a good safety record, there is still a concern that they could potentially transmit serious infectious agents. Nevertheless, because of the side effects associated with attenuated androgens, some centers in Europe favor home treatment of acute attacks with C1 INH instead of prophylaxis, and in a minority of patients with the most frequent attacks, prophylactic C1 INH. Antifibrinolytics, oral agents that effect part of the pathway involved in HAE, are available in the US and Europe, but are not very efficacious. Antifibrinolytics are used prophylactically in children, since they cannot take androgens.

There are three intravenous C1 INH replacement products in development and two subcutaneous products that act elsewhere along the disease pathway. A major trend likely to be spurred by these new drugs should be the introduction of home treatment of acute attacks in the US and its expansion in Europe, though this could take several years and there will likely be some resistance from payors. This trend will involve a majority of patients now on attenuated androgens switching from prophylaxis to home treatment of acute attacks, as well as some patients not deemed suitable for prophylaxis, who have a moderate number of regular attacks.

Ultimately, we think the subcutaneous drugs, DX-88 (Dyax – DYAX and Genzyme - GENZ) and Icatibant (Jerini, Kos - KOSP, Sanofi-Aventis - SNY), will come to dominate this home treatment paradigm. Icatibant blocks the receptor for bradykinin, the chemical thought to ultimately cause the symptoms of HAE, and DX-88 blocks the enzyme that forms bradykinin. Both drugs are in Phase III development. While Icatibant should have an NDA submitted in early 2007, it missed the primary endpoint in its pivotal US trial, which had a Special Protocol Assessment. Though there is a significant chance it could still be approved (it showed a benefit in its European trial and on most secondary endpoints in the US trial), we think it is more likely that a confirmatory trial will be needed. It is yet unclear whether the two drugs have comparable onsets of action and retreatment rates, or whether DX-88 definitely leads to systemic drug reactions in some patients. We currently project DX-88 to reach the market first in the US, but because of formulation issues, to cede significant minority share to Icatibant. In Europe, we expect Icatibant to be approved first and take a majority share.

There are three C1 INH replacement products in development. Rhucin (Pharming), a recombinant product that has a shorter half-life than human derived C1 INH, is undergoing Phase II testing for acute attacks in the US and has an MAA submitted in Europe. A human derived C1 INH (Lev - LEVP), a nanofiltered version of a European product, is in late Phase III testing in the US for acute attacks and long-term prophylaxis. Finally, another human-derived product from ZLB Behring is already used in Europe and undergoing Phase III testing in the US. All of these drugs have orphan drug status, though Rhucin is sufficiently different from the other products that it would likely be allowed to market even if approved later. Also, the Lev product appears to be the only one being tested for long-term prophylaxis (the short half-life of Rhucin makes it unsuitable for this), which could allow it on the market in any case.

We currently project the Lev C1 INH to be used in the US for long-term prophylaxis in some patients with very frequent attacks. We expect Rhucin will be used at home in patients who do not get good results with the subcutaneous products, as well as for emergency room treatment. However, in the latter its share will be threatened by the subcutaneous products, particularly if it does not have any advantage in lower retreatment rates or if non-refrigerated formulations of the subcutaneous products are developed and kept with patients when they are away from home. We think the ZLB Behring product will be approved after the Lev one, excluding it from being marketed for 7 years, under the orphan drug rules.

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