Firazyr Safe for Attacks in Patients With Normal C1-INH Activity
Firazyr (icatibant injection) appears to be at least as safe and effective at controlling swelling attacks in hereditary angiodema (HAE) patients with normal C1 inhibitor (C1-INH) activity as among those with reduced or no C1-INH activity, according to real-world data from Brazilian patients.
Most attacks were successfully treated with a single Firazyr injection, regardless of HAE type, scientists reported. Patients with normal C1-INH activity also showed a trend toward faster responses.
Researchers noted these findings expand current knowledge on the clinical features and treatment responses to Firazyr among Brazilian HAE patients and, more generally, among patients with normal C1 inhibitor activity, who currently lack any approved therapies.
The study, “Icatibant use in Brazilian patients with hereditary angioedema (HAE) type 1 or 2 and HAE with normal C1-INH levels: findings from the Icatibant Outcome Survey Registry Study,” was published in the journal Anais Brasileiros de Dermatologia.
HAE is characterized by sudden and recurrent episodes of swelling in the face, tongue, hands, feet, gastrointestinal tract, genitalia, and upper airways.
Its two main types — 1 and 2 — are caused by mutations in the SERPING1 gene, which provides instructions to produce C1-INH, a protein that helps control blood clotting and inflammation. Those mutations either lead to low levels of the protein (type 1 HAE) or to the production of a protein with low activity (type 2 HAE).
Some patients experience typical disease symptoms, but have normal C1-INH levels and activity and no SERPING1 mutations. They are diagnosed with HAE with normal C1-INH activity (HAE-nC1-INH), formerly known as type 3 HAE. Of note, mutations in several genes other than SERPING1 have been associated with this type of HAE.
Since swelling attacks in HAE-nC1-INH, like in HAE types 1/2 (HAE-1/2), are thought to be associated with excess levels of a pro-inflammatory protein called bradykinin, approved therapies that target bradykinin or related processes are likely to work for HAE-nC1-INH.
Firazyr, by Takeda Pharmaceuticals, is approved to treat acute attacks in people with HAE-1/2. Administered through under-the-skin injections, the therapy works by suppressing the activity of bradykinin. Several generic forms of the medication are also available.
Multiple case and observational studies have reported encouraging outcomes with Firazyr in HAE-nC1-INH patients, supporting its current inclusion in international treatment guidelines.
However, no controlled clinical trials have been conducted in this subgroup of patients to date, and “an urgent unmet need remains for further evaluation of treatment options in this patient population,” the researchers wrote.
Takeda scientists and researchers in Brazil evaluated Firazyr’s real-world safety and effectiveness in Brazilian HAE patients participating in the Icatibant Outcome Survey (IOS; NCT01034969).
Firazyr has been available in Brazil since 2009, but its use is not funded by the government, “so patient access to this therapy remains a challenge,” the researchers wrote.
IOS is an ongoing international, observational registry study monitoring the outcomes of HAE patients treated in a real-world setting with Firazyr and/or Takeda’s Cinryze (C1 inhibitor), a therapy approved to prevent severe HAE attacks.
As of Sept. 30, 2019, 42 HAE patients (26 with HAE-1/2 and 16 with HAE-nC1-INH) had enrolled in the study at its only Brazilian site, the ABC Medical School. Most were female (84.6% in HAE-1/2, and 100% in HAE-nC1-INH) and reported a family history of the disease (80.8% in HAE-1/2 and 93.8% in HAE-nC1-INH).
Compared with HAE-1/2 patients, those with HAE-nC1-INH had an older median age at both symptom onset (16.5 vs. 10 years) and diagnosis (40.9 vs. 31.1 years), and a prolonged time between symptom onset and diagnosis (23.8 vs. 15 years). However, group differences only reached statistical significance for age at symptom onset.
Over the course of about four years of follow-up, HAE-nC1-INH patients experienced fewer HAE attacks than those with HAE-1/2 (maximum of 17 vs. 29 attacks per patient). Attacks involving the larynx, or voice box, were more common in the HAE-nC1-INH group than in the HAE-1/2 group, in which the abdomen was more frequently affected.
Results showed that, in both groups, more than 95% of attacks were effectively treated with a single Firazyr injection. Compared with the HAE-1/2 group, HAE attacks in people with HAE-nC1-INH resolved faster from both onset (9.8 vs. 19.6 hours) and first dosing (1.0 vs. 5.5 hours) and had a shorter median total duration (7.0 vs. 18.5 hours).
Since earlier Firazyr treatment is linked to faster attack resolution, the team noted that these findings may be due to the shorter interval between attack onset and first Firazyr injection observed in the HAE-nC1-INH group (0.5 vs. 1.0 hour).
The therapy’s safety profile was comparable between the two patient groups, with most adverse events being mild in severity and most often involving injection site-related reactions (34.6% in HAE-1/2, 18.8% in HAE-nC1-INH).
These findings, concerning both clinical features and Firazyr’s safety and efficacy in HAE-1/2 and HAE-nC1-INH patients, were generally consistent with those reported in previous studies.
“The current analysis provides support for the effectiveness, safety, and tolerability of [Firazyr] in Brazilian patients with HAE,” including those with HAE with normal C1-INH activity, the researchers wrote.
“It is hoped that the continued reporting of [Firazyr] effectiveness and safety findings, such as those reported herein, will help improve the accessibility of this agent for the treatment of HAE in Brazil,” they added.
“Characterization of various forms of HAE around the world continues to grow, paving the way to improved understanding of underlying genetic mutations, patient demographics, and treatment outcomes across varied HAE patient populations,” the team added.