SAN FRANCISCO – The experimental drug icatibant relieved moderate or severe acute attacks of hereditary angioedema faster than placebo in the third randomized, double-blind, controlled trial of the experimental drug in 98 patients.
Among 88 patients with cutaneous and/or abdominal acute attacks, the 43 patients randomized to treatment with a single subcutaneous injection of 30 mg of icatibant reported that symptom relief started a median of 2 hours after treatment, compared with 20 hours for the 45 patients randomized to saline placebo injection. Symptom relief was defined as at least a 50% decrease in the combined Visual Analog Scale (VAS) symptom score, compared with baseline.
Dr. William R. Lumry
"I think this represents a very exciting, important advance in the treatment of an underserved population," Dr. William R. Lumry said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
A significant difference between groups was seen as early as 1 hour after treatment, but the 50% or greater reduction in VAS symptom scores was not achieved until 2 hours after treatment, Dr. Lumry and his associates reported.
The third For Angioedema Subcutaneous Treatment (FAST-3) trial followed two earlier phase III trials of the drug for acute attacks of hereditary angioedema, FAST-1 and FAST-2 (N. Engl. J. Med. 2010;363:532-41).
A "not approvable" letter from the Food and Drug Administration prompted Shire, the company developing icatibant, to provide more data to the FDA. The company’s response and results from FAST-3 are scheduled to be reviewed by the FDA in August 2011.
The FAST-3 study enrolled adults in 11 countries with moderate to very severe swelling from type I or type II hereditary angioedema that had been going on for no more than 12 hours and included at least one VAS score of 30 mm or greater. Patients were observed for 8 hours after injection, and their skin swelling, skin pain, abdominal pain, difficulty swallowing, and voice changes were assessed every 30 minutes for 4 hours after injection and at 5, 6, 8, and 12 hours. Rescue therapy was permitted but withheld if possible for 8-9 hours after injection.
Only the cutaneous and abdominal attacks were considered in the primary results, said Dr. Lumry, medical director of the Allergy and Asthma Research Associates Research Center, Dallas.
The 10 patients with laryngeal swelling attacks provided additional data. Five patients with severe laryngeal attacks immediately received open-label icatibant and reported onset of relief of symptoms a median of 2.3 hours later. Among five patients with mild to moderate laryngeal attacks, three patients who were randomized to icatibant treatment reported onset of symptom relief a median of 2.5 hours after treatment.
The two patients with mild to moderate attacks who were randomized to placebo both ended up getting icatibant, one whose attack was severe enough to warrant treatment, and the other a patient who received icatibant as rescue therapy 3.4 hours after randomization. Combined, the two patients with mild to moderate laryngeal attacks who were randomized to placebo reported onset of symptom relief a median of 3.2 hours after treatment.
Secondary outcomes in the nonlaryngeal cohort were significantly improved in the icatibant group, compared with the placebo group, Dr. Lumry said. The median time to initial symptom relief (assessed by the patients and the investigators) was less than 1 hour in the icatibant group and about 3.5 hours in the placebo group. The median time to onset of relief of the primary symptom (skin pain, skin swelling, or abdominal pain) was 1.5 hours in the icatibant group and 18.5 hours in the placebo group. The median time to almost complete symptom relief was less than 1 hour with icatibant and 36 hours with placebo.
Safety measures were recorded daily for 5 days and at a final 14-day safety visit.
Rescue medications were needed before the onset of symptom relief by 17 patients randomized to placebo – 16 in the nonlaryngeal cohort and 1 in the laryngeal cohort – compared with none in the icatibant groups. In the nonlaryngeal cohort, 3 patients in the icatibant group and 18 in the placebo group used rescue medications at some time during the attack or within 5 days of the injection.
All patients who got icatibant developed injection site reactions that resolved within 4 hours. Of the patients who initially received placebo, 10 developed at least one severe adverse event, compared with 2 patients who were randomized to icatibant and none who received open-label icatibant, a significant difference between the drug and placebo groups. One patient in the placebo group died of a myocardial infarction around 10 days later.