Preventative Haegarda Therapy Quickly Reduces Number of HAE Attacks, Trial Analysis Shows

Prophylactic, or preventive treatment with Haegarda quickly reduced the number of attacks — sudden episodes of swelling — in people with hereditary angioedema (HAE) caused by C1-inhibitor deficiency, an exploratory analysis of a Phase 3 trial shows. The number of attacks were reduced regardless of baseline patient characteristics.

The findings of the study, “Subcutaneous C1 inhibitor for prevention of attacks of hereditary angioedema: additional outcomes and subgroup analysis of a placebo-controlled randomized study,” were published in Allergy, Asthma & Clinical Immunology.

HAE is a rare genetic disorder characterized by sudden and recurrent episodes of swelling in the deeper layers of the skin, the upper airway, and the gastrointestinal tract.

The disease is caused by genetic mutations in the SERPING1 gene. In HAE type 1, those mutations lead to lower levels of C1-inhibitor (C1-INH), while in HAE type 2, they lead to a dysfunctional C1-INH, with levels that remain normal or elevated.

CSL Behring‘s Haegarda is one of two C1-INH replacement medications currently approved by the U.S. Food and Drug Administration (FDA) for the long-term prophylactic treatment of adolescents and adults with HAE. It was approved by the FDA in June 2017.

That approval was based on findings from the randomized, double-blind, placebo-controlled COMPACT Phase 3 trial (NCT01912456). The main goal of that study was to assess the effectiveness of Haegarda at preventing attacks in people with HAE type 1 and 2, ages 12 or older, compared with a placebo.

The trial’s findings showed that, when administered through an under-the-skin injection at a dose of 60 IU/kg twice-per-week, Haegarda reduced the frequency of HAE attacks by a median of 95%. It also reduced the use of rescue medications by a median of 100%.

Safety assessments showed that both doses of Haegarda used during COMPACT — 40 and 60 IU/kg — were well-tolerated by patients. The most common side effects observed during the trial were mild injection-site reactions. Such reactions were observed in a similar number of people treated with Haegarda versus a placebo.

Now, investigators reported the findings of a post-hoc exploratory analysis of COMPACT designed to further characterize the therapeutic effects of Haegarda in people with HAE type 1 and 2.

The analysis was based on data from the 90 participants originally enrolled in COMPACT, who had been randomly assigned to one of four treatment groups. All participants received treatment twice-per-week through an under-the-skin injection, in two 16-week periods. The four treatment groups were:

• High-dose placebo followed by Haegarda, at a dose of 40 IU/kg
• Haegarda, at a dose of 40 IU/kg, followed by high-dose placebo
• High-dose placebo followed by Haegarda, at a dose of 60 IU/kg
• Haegarda, at a dose of 60 IU/kg, followed by low-dose placebo

The pre-specified primary efficacy endpoint was to determine the time it took for the treatment to normalize the number of HAE attacks.

Secondary efficacy endpoints, also pre-specified, included determining the percentage of participants who had a greater than 50% reduction in the time it took for the treatment to normalize the number of HAE attacks, and on the time until they had to resort to rescue medications. Pre-specified exploratory endpoints included assessing the severity of HAE attacks, with and without simultaneous use of rescue medications.

Sub-group analyses stratified by several patients’ baseline characteristics, including attack location or prior prophylactic treatment, confirmed that Haegarda consistently prevented HAE attacks.

In addition, the findings revealed that, within the first two weeks of treatment, only 23% of those treated with Haegarda at a dose of 60 IU/kg experienced attacks. Meanwhile, 81% of those treated with a placebo during the same time period had attacks.

Analysis also showed that people treated with a placebo had to resort to rescue medications to control their attacks 10 times more often than patients who had been treated with the highest dose of Haegarda — 358 treated attacks versus 35 treated attacks.

A qualitative analysis performed on four patients who had less than 50% reduction in the number of attacks despite having received the highest dose of Haegarda, demonstrated that their attacks were less severe and their need to resort to rescue medications was lower. These results indicate a milder, but still clinically meaningful, treatment effect.

“Our analyses provide additional evidence that [Haegarda] prophylaxis is effective in reducing the number of angioedema attacks independent of any baseline patient characteristics, ” the researchers said.

“Current data suggest that [Haegarda] can provide substantial and clinically meaningful relief from disease and treatment burden for all patients with type I or II HAE. The preventive effect of [Haegarda] is already evident within 2 weeks of treatment initiation,” they concluded.