Highlights of the World Allergy Congress, 2007
The World Allergy Congress (WAC) is a biennial scientific meeting hosted by the World Allergy Organization (WAO). The WAO is an international umbrella organization consisting of 74 regional and national allergy and clinical immunology societies. The 20th WAC held in Bangkok, Thailand, consisted of lectures from the worlds' leading experts in basic and clinical allergy and immunology as well as lectures given by respected thought leaders from sites less familiar. This mix resulted in a unique scientific dialogue that at times challenged current scientific thinking and convention.

Hereditary Angioedema

Hereditary angioedema (HAE) is a rare autosomal-dominant deficiency of C1 esterase inhibitor production or function. Although the condition likely affects no more than 1 in 10,000 persons, there are numerous therapeutics currently under development for the treatment of HAE ( Table ). The WAC HAE symposium highlighted data from clinical trials involving these new therapeutics and additionally reviewed current HAE treatments in an attempt to better understand where these novel therapies may fit in with established HAE medications.

Attenuated androgens are the primary prophylactic medications used the world over for HAE. Antifibrinolytics also have prophylactic use, although they have fallen out of favor in the United States. The side effects attributed to both classes of prophylactic medications used for HAE have in part driven the search for new therapeutics. Side effects include hepatic toxicity, virilization, weight gain, acne, and prostate carcinoma associated with attenuated androgens and thrombosis and gastrointestinal distress associated with antifibrinolytics. Further driving the search for new therapeutics is the lack of approved medications for the treatment of acute attacks. Whereas therapy with concentrated C1 esterase inhibitor has been available in some parts of Europe for more than 20 years, no such acute therapies exist in the United States. Thus acute attacks in the United States are treated only with supportive care. Fresh frozen plasma is an option for the treatment of acute HAE; however, its use is somewhat controversial.

DX-88 is a selective kallikrein inhibitor with a strong affinity to human plasma kallikrein. Kallikrein inhibition blocks bradykinin production. It is bradykinin that is a primary mediator of vascular leak during acute HAE attacks. In the United States, DX-88 has undergone 8 clinical trials, and there are 2 trials ongoing. The recently completed EDEMA 3 trial was a phase 3 randomized, placebo-controlled study on treating acute HAE attacks with 30 mg of subcutaneous DX-88. The majority of attacks were abdominal (55%); 31% were peripheral, and 14% were laryngeal. The primary endpoint was improvement in total symptom score (TOS) at 4 hours postinjection. Secondary endpoints included change in mean symptom complex severity at 4 hours and time to significant improvement.

At 4 hours, the DX-88-treated group had a significant improvement in TOS when compared with patients taking placebo (P = .021). At 4 hours there was also a significant change in mean symptom complex score in the DX-88 group compared with patients taking placebo (P = .024). Median time to significant improvement was 149 minutes. Treatment-related adverse events were comparable between the 2 groups, and no antibodies were detected against DX-88.

Icatibant is a bradykinin receptor-2 blocker. Data from the FAST 1 and 2 trials were reported at the WAC. The FAST trials were double-blind, placebo-controlled trials with a primary endpoint of median time to onset of symptom relief during acute HAE attacks. The placebo arms differed in the FAST 1 and 2 studies in that the FAST 1 trial used a true placebo and in FAST 2, Icatibant was compared with tranexamic acid. When compared with placebo in FAST 1, Icatibant reduced the duration of skin swelling, skin pain, and abdominal pain. When compared with tranexamic acid in FAST 2, there was a significant reduction in symptom duration for all 3 parameters. Time for onset of early symptom improvement was 0.8 hours for both trials. Median time to complete symptom relief in FAST 1 and 2 was 8.5 and 10 hours, respectively, compared with 23.3 and 51 hours for the placebo arms. Icatibant was well-tolerated in both trials.

Nanofiltered plasma-derived C1 esterase inhibitor is also undergoing clinical trials in the United States for both acute and prophylactic use. The product is similar to C1 esterase inhibitor concentrates that have been available in Europe for some time. Cinryze may be available in the United States as early as 2008. Results from the CHANGE trial, a double-blind, placebo-controlled study were reviewed at the WAC.

CHANGE part A was completed in December 2006 and confirmed the efficacy and safety of Cinryze as a therapeutic agent for acute attacks. Part B examined Cinryze as a prophylactic agent for the prevention of acute HAE attacks (data not reported at WAC). In part A, the median time to significant relief with Cinryze was 2 hours and with placebo it was greater than 4 hours (P = .026). The relative likelihood of significant relief was 2.248 with a 95% confidence interval. Time to complete attack resolution was 12.2 hours vs 34.1 hours for placebo (P = .064). There were no drug-related serious adverse events reported with Cinryze and no reported immunogenicity.

Like Cinryze, Berinert P is a human plasma-derived C1 esterase inhibitor concentrate. It undergoes cryoprecipitation, ion exchange chromatography, and polyethylene glycol precipitation. Results of the IMPACT trial were reviewed by Marco Cicardi, MD. In IMPACT, patients with HAE who were in acute attack were assigned to full dose (20 U/kg), half dose, or placebo. Berinert P significantly reduced the time to onset of symptom relief compared with placebo (P = .003), hastened complete symptom resolution, and lessened symptom intensity.

Rhucin is a rabbit-derived recombinant C1 esterase inhibitor (rhC1INH). Preliminary data from European phase 3 trials were presented. Median time to onset of symptom relief was 60 minutes vs 8.5 hours for placebo (P = .0009). Patients also reported minimal symptoms at 6.1 hours vs 20.2 hours for placebo (P = .0038), and analysis also revealed that 100% of patients receiving active drug responded.

Currently, 5 products for HAE are under US Food and Drug Administration review. It is unlikely that all of these will come to the market, but inevitably patients with HAE will have far more treatment options in the years to come. What is also important is that all of the therapeutics currently under investigation will potentially be able to treat acute attacks. Until now, acute HAE therapies have been very much lacking in the United States.