Hereditary Angioedema (HAE)

Cinryze^®, manufactured by ViroPharma Biologics, part of Takeda, was approved by the US Food and Drug Administration (FDA) in October 2008 for routine prophylaxis in persons at least 6 years of age with acute attacks of hereditary angioedema (HAE).¹ The European Medicines Agency (EMA) approved Cinryze in 2011, and in 2017, the FDA expanded its use to the treatment of acute attacks in patients at least 2 years of age.²

HAE is a rare, life-threatening genetic condition characterized by recurrent episodes of swelling of the skin and mucous membranes.^2,3 Typically, the skin, gastrointestinal tract, and upper airway are affected.³ 

Mode of Action and Use of Cinryze

HAE is currently subdivided into 3 types. Types 1 and 2 are characterized by deficiency and/or malfunction of C1-esterase inhibitor enzyme (C1-INH).² C1-INH is a serine protease inhibitor that is typically present in human blood; its main function is to regulate the complement and fibrinolytic systems and the coagulation pathway.¹ Persons with HAE have low levels of C1-INH and therefore abnormally low levels of complement, including C4.² The lack of functional C1-INH results in the release of bradykinin, followed by the release of fluid from blood vessels; fluid accumulation causes the swelling and pain that characterize episodes of HAE.⁴ Cinryze is a pasteurized and nanofiltered concentrate of C1-INH prepared from fractionated pooled human plasma. It is administered to patients with HAE to increase plasma levels of C1-INH and prevent the excessive release of bradykinin, reducing the risk for HAE attacks.^2,4 Cinryze was the first C1-INH preparation approved by the FDA to prevent episodes of HAE.^2,4

The recommended dose of Cinryze for the routine prophylaxis of HAE attacks is 500 IU every 3 or 4 days in pediatric patients 6 to 11 years old and 1000 IU every 3 or 4 days in adults and adolescents (12 years old and above). Doses up to 1000 IU every 3 or 4 days may be used in children and up to 2000 IU (not exceeding 80 IU/kg) every 3 or 4 days can be considered in adults and adolescents based on individualized patient responses. Cinryze is administered intravenously after reconstitution with sterile water for injection.¹ A single dose of Cinryze has a half-life of 56 hours, and the peak plasma concentration is reached in approximately 4 hours.² 

Common adverse reactions to Cinryze include headache, nausea, rash, vomiting, and fever.¹ Severe hypersensitivity reactions and serious arterial and venous thromboembolic events may develop following the use of this drug. Additionally, because Cinryze is prepared from human blood, the transmission of various infectious agents, including viruses, is theoretically possible. Steps to reduce viral contamination are part of the manufacturing process.¹

Read full prescribing information for Cinryze at MPR

Clinical Efficacy of Cinryze

The safety and efficacy of Cinryze as prophylaxis and in the treatment of acute attacks of HAE have been evaluated in phase 3 clinical trials.⁵ 

The double-blind phase 3 trial CHANGE 1, part A (NCT00289211), compared Cinryze with placebo for safety and efficacy in the treatment of acute attacks of HAE.^5,6 The median time to the onset of relief was of 2 hours with Cinryze and 4 hours with placebo, a significant difference.⁵ An open-label extension trial, CHANGE 2 (NCT00438815), followed participants in the first study for 2.5 years after repeated exposure to Cinryze, administered as intravenous infusions at 1000 IU per dose to treat moderate to severe attacks of HAE.^7,8 In this second trial, which included 101 participants, 95% of the attacks reported resolved within 4 hours, and the median time to the onset of relief was 0.75 hour.⁷

The prophylactic use of Cinryze was further studied in the double-blind, placebo-controlled phase 3 trial CHANGE 1, part B (NCT01005888), and in the open-label phase 3 trial CHANGE 3 (NCT00462709). Patients were randomly assigned to receive either 1000 IU of Cinryze or placebo every 3 to 4 days during 2 successive 12-week intervals.⁵ The administration of Cinryze was associated with significant reductions in the need for open-label rescue therapy and with a reduction in the total number of days in which patients experienced swelling.⁵ 

Clinical studies of Cinryze have also been conducted on children. Four phase 3 trials included 46 children who received 2237 infusions of Cinryze.⁹ Cinryze was well tolerated; symptom relief began within 4 hours in 89% of cases, and the number of attacks was reduced by approximately 2-fold when the drug was compared with placebo.⁹ 

A multicenter randomized phase 3 trial, NCT02052141, studied the safety and efficacy of Cinryze in preventing episodes of HAE in patients between 6 to 11 years old; the administration of 500 or 1000 U of C1-INH twice weekly for 12 weeks before crossover was effective, safe, and well tolerated, with a favorable effect on quality of life.¹⁰ An open-label, single-dose, phase 2 trial evaluated the pharmacokinetics and pharmacodynamics of several doses of Cinryze for treating attacks of HAE in patients younger than 12 years of age (NCT01095510).¹¹

References

1. CINRYZE® (C1 esterase inhibitor [human]) for intravenous use. Prescribing information. Revised March 2022.

2. Gupta R, Balduzzi J, Davis-Lorton M. C1-esterase inhibitor (Cinryze®) use in the treatment of pediatric hereditary angioedema. Immunotherapy. 2018;10(8):635-642. doi:10.2217/imt-2017-0049

3. Hereditary angioedema. Genetic and Rare Disease Information Center (GARD). Accessed June 7, 2022.

4. What is Cinryze and how does it work? Takeda. Accessed June 7, 2022.

5. Zuraw BL, Busse PJ, White M, et al. Nanofiltered C1 inhibitor concentrate for treatment of hereditary angioedema. N Engl J Med. 2010;363(6):513-522. doi:10.1056/NEJMoa0805538

6. C1 esterase Inhibitor (C1INH-nf) for the treatment of acute hereditary angioedema (HAE) attacks (NCT00289211). ClinicalTrials.gov. April 13, 2007. Accessed June 7, 2022

7. Riedl MA, Hurewitz DS, Levy R, Busse PJ, Fitts D, Kalfus I. Nanofiltered C1 esterase inhibitor (human) for the treatment of acute attacks of hereditary angioedema: an open-label trial. Ann Allergy Asthma Immunol. 2012;108(1):49-53. doi:10.1016/j.anai.2011.10.017

8. Open-label C1 esterase inhibitor (C1INH-nf) for the treatment of acute hereditary angioedema (HAE) attacks (CHANGE 2). (NCT00438815). Clinical Trials.gov. June 9, 2010. Updated June 8, 2021. Accessed June 7, 2022.

9. Lumry W, Manning ME, Hurewitz DS, et al. Nanofiltered C1-esterase inhibitor for the acute management and prevention of hereditary angioedema attacks due to C1-inhibitor deficiency in children. J Pediatr. 2013;162(5):1017-1022.e1-2. doi:10.1016/j.jpeds.2012.11.030.

10. Aygören-Pürsün E, Soteres DF, Nieto-Martinez SA, et al. A randomized trial of human C1 inhibitor prophylaxis in children with hereditary angioedema. Pediatr Allergy Immunol. 2019;30(5):553-561. doi:10.1111/pai.13060

11. CINRYZE for the treatment of hereditary angioedema attacks in children under the age of 12 (NCT01095510). July 25, 2014. Updated June 3, 2021. ClinicalTrials.gov. Accessed June 7, 2022.

Reviewed by Kyle Habet, MD, on 6/26/2022.

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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.