AAAAI: New Therapies on Horizon for Angioedema Attacks
PHILADELPHIA, March 18 — Several new, specific treatments for hereditary angioedema attacks may soon be available in the U.S., researchers said here.
Favorable safety and efficacy data on five investigational drugs in late-stage development were reported at the AmericanAcademy of Allergy, Asthma, and Immunology meeting.
Marketing applications have been or soon will be filed in the U.S. for four of them, according to their manufacturers.
The flurry of activity is especially remarkable given that fewer than 20,000 people in the U.S. are believed to have hereditary angioedema.
- Explain to interested patients that the drugs studied in these trials are investigational and are not currently FDA-approved.
- Point out that these studies were presented orally at a conference and should be considered preliminary until they are published in peer-reviewed journals.
The condition results from a genetic deficiency in C1 esterase inhibitor, a key regulatory protein in the classical complement pathway. As a result, patients are subject to frequent, painful, and disfiguring inflammatory attacks affecting the abdomen, face, or other parts of the body.
Current treatments include fresh frozen plasma and androgen drugs, said Timothy Craig, D.O., an allergist at PennsylvaniaStateUniversity in Hershey. Both can have significant adverse effects and are not reliably effective, he said.
And neither treatment is approved specifically for treating hereditary angioedema attacks.
Three of the five new products are human C1 esterase inhibitor proteins intended as replacement therapy, two of which are now being developed for the U.S. market.
One, purified from blood donated by the German firm CSL Behring, has been marketed in Europe for more than 20 years under the name Berinert.
In a recently completed randomized, placebo-controlled U.S. registration trial, Berinert was highly effective for severe attacks, reported Jonathan A. Bernstein, M.D., of BernsteinClinicalResearchCenter in Cincinnati.
Onset of symptom relief in 32 patients with severe abdominal and facial attacks occurred in a median of 30 minutes with Berinert, versus 810 minutes for placebo ( P values not reported).
In 53 patients with moderate attacks, the difference was less pronounced. Onset of relief was seen in 48 minutes with Berinert versus 78 minutes for placebo.
Similar results were reported for another C1 esterase inhibitor protein purified from blood donations, called Cinryze, being developed in the U.S. by Lev Pharmaceuticals. Like Berinert, the protein is currently produced and sold in Europe.
The C1 esterase inhibitor protein is delivered by intravenous infusion, and thus must be administered in a suitably equipped clinic or hospital.
Because hereditary angioedema attacks may come on with little warning, two companies are developing alternative drugs that can be given by subcutaneous injection.
Another German company, Jerini AG, has developed a synthetic bradykinin B2 receptor antagonist called icatibant, and the U.S. firm Dyax Corp. has a plasma kallikrein inhibitor called ecallantide (DX-88).
Both drugs target inflammatory processes triggered by the pathological complement activation that causes hereditary angioedema attacks.
Marc Riedl, M.D., of the University of California Los Angeles, presented phase III data on icatibant.
A total of 130 patients participated in two separate randomized trials comparing the drug to placebo and to tranexamic acid, an antifibrinolytic.
In both studies, icatibant significantly shortened response times and duration of attacks: 74% of 61 patients receiving icatibant experienced onset of symptom relief within four hours, compared with 31% for tranexamic acid ( P<0.001) in 34 patients and 46% for placebo ( P=0.012) in 27 patients, Dr. Riedl said.
Median time to 90% symptom relief was 5.3 hours for icatibant versus 12.1 hours for placebo (P=0.011) and 28.5 hours for tranexamic acid ( P<0.001).
With ecallantide, median time to significant improvement was about 150 minutes compared with more than 300 minutes for placebo in a randomized study of 72 patients, reported Robyn Levy, M.D., of Family Allergy and AsthmaCenter in Atlanta.
No serious drug-related adverse events were seen with either ecallantide or icatibant in the trials.
Although the time to symptom improvement was generally longer with the synthetic drugs relative to C1 esterase inhibitor protein, the prospect of subcutaneous injection may be beneficial to many patients.
“The route of administration is a significant advantage,” Dr. Riedl said. “Patients want to be relatively self-sufficient and don’t want to have to go to the emergency room,” he said.
Said Dr. Levy, “We have patients that come from great distances and have IV access problems,” making reliance on an infusion product a major drawback.
Dr. Craig, who helped conduct the Berinert studies, agreed that both of the synthetic drugs are very effective.
But, he said, in addition to faster onset of action, C1 esterase inhibitor protein also has longer duration of action. Its half-life in circulation is about 36 hours and may remain clinically active for several days, he said.
CSL Behring, Lev Pharmaceuticals, and Jerini have all announced that they have filed marketing applications with the FDA.
A Dyax spokesman refused to confirm whether it had submitted an application, but said the company expected to receive approval by the end of 2008.
Also reported at AAAAI were favorable clinical results with Rhucin, a recombinant C1 esterase inhibitor protein expressed in rabbit milk.
The Dutch company Pharming Technologies has applied to sell Rhucin in Europe. An EU regulatory panel recently recommended against approval because of what it said were unanswered questions about the product’s safety and efficacy in repeat dosing. Pharming is appealing the decision.
Pharming has completed a phase III trial in the U.S. but has not announced results or commercial marketing plans.
Primary source: Journal of Allergy and Clinical Immunology
Bernstein J, et al “Treatment of acute abdominal and facial attacks of hereditary angioedema (HAE) with human C1 esterase inhibitor (C1-INH): Results of a global, multicenter, randomized, placebo-controlled, phase II/III study (I.M.P.A.C.T.1),” Journal of Allergy and Clinical Immunology 2008; 121:795.
Additional source: Journal of Allergy and Clinical Immunology
Riedl M, “Icatibant, a selective bradykinin B2 receptor antagonist, proves effective and safe in treating the symptoms of hereditary angioedema (HAE) attacks” Journal of Allergy and Clinical Immunology 2008; 121: S103.
Additional source: Journal of Allergy and Clinical Immunology
Levy R et al “Results of a 2-stage, phase 3 pivotal trial, EDEMA3: A study of subcutaneous DX-88 (ecallantide), a plasma kallikrein inhibitor, in patients with hereditary angioedema (HAE),” Journal of Allergy and Clinical Immunology 2008; 121: S231.