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06-Mar-09 17:00 Dyax's DX-88 subcutaneous delivery would be an advantage, despite safety concerns, physicians say
Story Dyax's (NASDAQ:DYAX) DX-88 (ecallantide) subcutaneous delivery would be an advantage in treating acute attacks of hereditary angioedema (HAE), physicians said.

Hereditary angioedema (HAE) is a rare disorder caused by deficient or improper function of the plasma protein C1 inhibitor (C1-INH), which causes swelling in various parts of the body. Disease severity is wide ranging; some patients experience weekly attacks while others can go years between attacks. The disease can be fatal when swelling occurs in the larynx. In the US, there are no marketed treatments available for acute attacks of HAE.

DX-88 is a small protein that has shown to inhibit plasma kallikrein, an enzyme in the inflammatory cascade, in laboratory experiments. C1 inhibitors, which are the standard of care in Europe, are not approved in the US for acute attacks. DX-88 was granted orphan drug designation for HAE in the US and Europe, and a Fast Track designation in the US.

Dr Hilary Longhurst, an immunologist at Barts and the London NHS Trust, London, said she believes that the subcutaneous aspect of ecallantide would be advantageous because the drug could potentially be self administered. Even if it's not self administered, it is simply much easier to administer a subcutaneous form rather than an IV form, she added.

Dr Marc Riedl, an immunologist at the David Geffen School of Medicine at UCLA, cautioned that while a subcutaneous form is preferable in any setting, self-administration may be too risky since there is a risk of anaphylaxis. The safety risk does reduce the attractiveness, particularly in regard to self-administration of the subcutaneous form, he added. Despite the potential for adverse events, "I am very much in support of it, but it should be managed and monitored carefully," he said.

A source familiar with the FDA regulatory process agreed, asserting that the risk of anaphylaxis challenges whether DX-88 is sufficiently safe. However, the unmet need for acute treatments is pressing and must be weighed into the equation, he said. The drug works and patients are in great need of treatment for this disease, he added.

C1 inhibitors have been widely used in Europe with good effect, according to Dr Andreas Lehmann, of the Clinic for Anesthesiology and Operative Intensive Medicine, Germany. The subcutaneous aspect of ecallantide will be an advantage, particularly if there is the possibility of self administration, he noted.

Although no current treatments are approved for acute attacks of HAE in the US, fresh frozen plasma has been used in the US with some benefit, according to Dr Albert Sheffer, clinical professor of medicine at Harvard Medical School. Given limited options, fresh frozen plasma may be used but in some cases has led to worsening the condition, Riedl noted.

Historically, anabolic steroids have been administered as a preventative in severe HAE. When taken daily, androgens are effective at suppressing 80 to 90% of attacks in patients, but there are many side effects, Reidl said. Viropharma's Cinryze (NASDAQ:VPHM) was the first C1 inhibitor to be approved in the US in 2008, but is limited to prophylactic treatment of HAE. The data showed that about half of patients are breaking through, and though it is a useful strategy, "it is no magic bullet," according to Reidl.

Dyax has set a PDUFA date for 23 March 2009 after an FDA advisory committee voted six to five in favor of approval. Viropharma is seeking approval for Cinryze as an acute therapy in HAE, with a PDUFA set for 3 June 2009.

by Janan Cargile
source: Pharmawire