Hereditary Angioedema (HAE)

Berinert^® is a human plasma-derived, lyophilized concentrate of C1-esterase inhibitor (C1-INH) indicated for the treatment of acute attacks of hereditary angioedema (HAE) affecting the abdomen, face, and larynx.^1,2 

HAE is a rare condition with an autosomal-dominant pattern of inheritance in which fluids accumulate outside blood vessels.^3,4 The accumulated fluid blocks the flow of blood and lymph, causing edema in subcutaneous tissues, the intestinal wall, and the larynx. Patients experience skin swelling and abdominal pain, and they may suffocate as a result of airway obstruction.⁵ 

Berinert was developed by CSL Behring GmBH and approved by the US Food and Drug Administration (FDA) in 2009. It is also currently approved in several European countries and in Japan.^1,2,5

Get full prescribing information for Berinert at MPR

Mechanism of Action and Use

The main cause of HAE is an inherited deficiency of C1-esterase inhibitor (C1-INH), a protein that is a component of the complement system. In a less common form of HAE, affected individuals do not lack C1-INH, but the protein is dysfunctional.^2,4 The serine protease inhibitor C1-INH is commonly present in human plasma, and the formation of C1-INH/protease complexes inhibits activation of the complement system, coagulation cascade, and fibrinolytic system.^1,3 When administered to patients with HAE, Berinert replaces absent or malfunctioning C1-INH.¹ 

Berinert was first licensed in 1979 in Germany as an unpasteurized concentrate of human C1-INH; the first pasteurized formulation was licensed in 1985.² Currently, Berinert is prepared from pooled human plasma obtained from healthy donors.² The final pasteurized and nanofiltered formulation contains 500 IU of C1-INH per injection vial. The recommended dose for slow intravenous administration is 20 IU/kg of body weight.^1,2,5 Berinert is contraindicated in patients who have had severe hypersensitivity reactions (eg, anaphylaxis) to C1-INH formulations.¹

Because it is derived from human plasma, Berinert can transmit infectious agents such as blood-borne viruses. The risk is minimized by donor screening and by viral inactivation and removal through steps taken during the manufacturing process.¹ Additionally, arterial and venous thromboembolic events have been reported following the administration of Berinert. The use of oral contraceptives and the placement of catheters have been highlighted as a few of the risk factors for thromboembolic events. The most common adverse reaction to Berinert is dysgeusia, and the most severe reaction is the exacerbation of pain.¹

Following proper training, patients can self-administer Berinert. The procedure requires approximately 7 to 8 minutes.⁶

Berinert in Clinical Studies 

Before FDA approval in 2009, several observational studies reported the successful use of Berinert as a replacement therapy in patients having HAE attacks.^7,8 Two phase 2 and 3 randomized controlled trials, I.M.P.A.C.T.1 (NCT00168103) and I.M.P.A.C.T.2 (NCT00292981), led to drug approval.^9,10 I.M.P.A.C.T.1 was a multicenter randomized, double-blind, placebo-controlled trial that recruited 125 patients at least 6 years of age having acute attacks of abdominal or facial HAE.⁹ Berinert at doses of 10 and 20 U/kg was compared with placebo, and results showed that the drug provided a rapid onset of relief.⁹ Additionally, the median time to the complete resolution of HAE symptoms was significantly shorter in the patients treated with 20 U/kg than in those who received placebo.⁹ The most common adverse events reported in this study were nausea, abdominal pain, and muscle spasms.⁹

I.M.P.A.C.T.2 was an open-label extension study following I.M.P.A.C.T.1 in which patients from the first trial received Berinert at a dose of 20 U/kg to treat acute attacks of HAE, regardless of the part of the body affected and severity of the episodes.¹⁰ This study, which aimed to evaluate the safety and efficacy of long-term treatment with C1-INH, reported that the onset of symptom relief with Berinert was within 30 minutes. Also, a single dose of 20 U/kg was effective for the long-term treatment of 99% of HAE attacks in any location of the body. The most common adverse event reported was headache.¹⁰

The immunogenicity of Berinert was investigated in a multicenter prospective, nonrandomized, single-arm, open-label phase 4 study. In 46 evaluated patients, the administration of C1-INH was not associated with the formation of inhibitory antibodies.¹¹

Berinert has been used successfully as short-term prophylaxis in patients undergoing medical procedures such as abdominal surgery and dental procedures.² In 2013, the European health authorities approved an extended use of Berinert for the pre-procedural prevention of acute episodes of HAE in adult and pediatric patients.¹²

In another study, patients with HAE who self-administered Berinert at home as on-demand therapy experienced significant improvements in their quality of life.¹³

References

1. BERINERT. Prescribing Information. CSL Behring. Revised September 2021. Accessed June 5, 2022.

2. Bork K. Pasteurized and nanofiltered, plasma-derived C1 esterase inhibitor concentrate for the treatment of hereditary angioedema. Immunotherapy. 2014;6(5):533-551. doi:10.2217/imt.14.33

3. Caballero T. Treatment of hereditary angioedema. J Investig Allergol Clin Immunol. 2021;31(1):1-16. doi:10.18176/jiaci.0653

4. Hereditary angioedema.  National Organization for Rare Disorders (NORD). Accessed June 5, 2022.

5. Keating GM. Human C1-esterase inhibitor concentrate (Berinert). BioDrugs. 2009;23(6):399-406. doi:10.2165/11201100-000000000-00000

6. Take control of your HAE attacks with BERINERT self-administration. CSL Behring. Accessed June 5, 2022.

7. Farkas H, Jakab L, Temesszentandrási G, et al. Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy. J Allergy Clin Immunol. 2007;120(4):941-947. doi:10.1016/j.jaci.2007.06.026

8. Bork K, Staubach P, Hardt J. Treatment of skin swellings with C1-inhibitor concentrate in patients with hereditary angio-oedema. Allergy. 2008;63(6):751-757. doi:10.1111/j.1398-9995.2007.01577.x

9. Craig TJ, Levy RJ, Wasserman RL, et al. Efficacy of human C1 esterase inhibitor concentrate compared with placebo in acute hereditary angioedema attacks. J Allergy Clin Immunol. 2009;124(4):801-808. doi:10.1016/j.jaci.2009.07.017

10. Craig TJ, Bewtra AK, Bahna SL, et al. C1 esterase inhibitor concentrate in 1085 hereditary angioedema attacks–final results of the I.M.P.A.C.T.2 study. Allergy. 2011;66(12):1604-1611. doi:10.1111/j.1398-9995.2011.02702.x

11. Farkas H, Varga L, Moldovan D, et al. Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor. Ann Allergy Asthma Immunol. 2016;117(5):508-513. doi:10.1016/j.anai.2016.08.025

12. CSL Behring receives European health authorities’ approval of Berinert® for short-term prophylaxis in adults and children. News Release. CSL Behring. April 16, 2013.

13. Bygum A, Andersen KE, Mikkelsen CS. Self-administration of intravenous C1-inhibitor therapy for hereditary angioedema and associated quality of life benefits. Eur J Dermatol. 2009;19(2):147-151. doi:10.1684/ejd.2008.0603

Reviewed by Harshi Dhingra, MD, on 6/12/2022.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.