Hereditary Angioedema (HAE)

Haegarda® (C1 esterase inhibitor subcutaneous [human]) gained US Food and Drug Administration (FDA)-approval in 2017, becoming the first subcutaneous C1 esterase inhibitor (C1-INH) approved for the treatment of hereditary angioedema (HAE). Haegarda is a human plasma-derived, purified, pasteurized, lyophilized concentrate prepared from large pools of human plasma.¹ It is indicated for routine prophylaxis to prevent HAE attacks in patients 6 years of age and above.²

Haegarda Mechanism of Action

C1-INH belongs to the serpins group of serine protease inhibitors along with antithrombin III, α1-protease inhibitor, α2-antiplasmin, and heparin cofactor II. It is a normal constituent of human plasma and plays important roles in regulating the complement, fibrinolytic, and coagulation cascades. Low to absent levels of endogenous or functional C1-INH are characteristic of HAE and are thought to be the main cause of HAE attacks through the unregulated activation of the contact system. This leads to increased vascular permeability, which is the underlying mechanism explaining the clinical manifestation of an HAE attack. Haegarda replaces C1-INH in these patients and prevents attacks.²

All plasma used in the manufacturing process is obtained from US donors and is tested for human immunodeficiency virus (HIV)-1/2, human parvovirus B19, and hepatitis A, B, and C. Additional steps taken to minimize the risk of virus transmission include pasteurization in aqueous solution at 60 °C for 10 hours, hydrophobic interaction chromatography, and virus filtration (nanofiltration) with 2 filters.²

Haegarda comes as a single-dose vial containing 2000 or 3000 IU of C1-ING, which is reconstituted with sterile water (included) to a concentration of 500 IU/mL. The 2000 IU and 3000 IU vial must be reconstituted with 4 ml and 6 ml of sterile water respectively. The recommended dose is 60 IU per kg of body weight administered subcutaneously every 3 or 4 days. It may be self-administered or administered by a caregiver.²

Get full prescribing information for Haegarda at MPR

Safety and Efficacy of Haegarda

The efficacy and safety of Haegarda for routine prophylaxis to prevent HAE attacks were demonstrated in a multicenter, randomized, double-blind, placebo-controlled, crossover study (Study 1) and a multicenter, randomized, open-label, active treatment-controlled study (Study 2).²

In Study 1, 90 adults with HAE type I or II were randomized to receive either 40 or 60 IU/kg of Haegarda over a 16-week treatment period and placebo in the crossover study period, which also lasted 16 weeks. The time-normalized numbers of HAE attacks in participants dosed with 40 and 60 IU/kg were 1.19 (vs 3.61 in the placebo group) and 0.52 per month (vs 4.03 in the placebo group), respectively (both P <.001). The percentage of responders with a ≥50% reduction in the time‑normalized number of HAE attacks on Haegarda relative to placebo was 83%. Additionally, 90% of participants on 60 IU/kg responded to treatment, and 76% of patients on 40 IU/kg responded to treatment.²

In Study 2, 120 adult and pediatric patients with symptomatic HAE type 1 or II were randomized to receive 40 or 60 IU/kg and were treated for a mean of 1.4 years. Mean steady-state C1-INH functional activity increased to 52.0% with 40 IU/kg and 66.6% with 60 IU/kg.² Furthermore, 93.1% of participants in both treatment arms experienced a ≥50% reduction in time-normalized number of HAE attacks. The percentages of patients with a time-normalized HAE attack frequency of <1 HAE attack per 4-week period were 79.7% with 40 IU/kg and 86.9% with 60 IU/kg.² 

The most common adverse reactions to Haegarda are injection site reactions, hypersensitivity, nasopharyngitis, and dizziness. There is a theoretical risk for the transmission of infectious agents, such as viruses and variant Creutzfeldt-Jakob disease, since Haegarda is derived from human plasma. The risk of transmission of an infectious agent can be reduced by screening plasma donors for prior exposure to certain viruses, inactivating and/or removing certain viruses during manufacturing. Haegarda is contraindicated in patients with a history of life-threatening immediate hypersensitivity reactions, including anaphylaxis, to C1-INH preparations or their excipients.²

References

1. FDA approves first subcutaneous C1 esterase inhibitor to treat rare genetic disease. News release. US Food and Drug Administration (FDA); June 22, 2017.

2. Haegarda. Prescribing information. CSL Behring; 2020. Accessed June 7, 2022.

Reviewed by Debjyoti Talukdar, MD, on 6/29/2022.

---

Kyle Habet, MD

Kyle Habet, MD, is a physician at Belize International Institute of Neuroscience where he is a member of a multidisciplinary group of healthcare professionals involved in the care of patients with an array of neurological and psychiatric diseases. He is a published author, researcher and instructor of neuroscience and clinical medicine at Washington University of Health and Science.