Haegarda (human C1 esterase inhibitor) for hereditary angioedema

Last updated Jan. 3, 2024, by Lindsey Shapiro, PhD
Fact-checked by Joana Carvalho, PhD

What is Haegarda for hereditary angioedema?

Haegarda (human C1 esterase inhibitor) is a prophylactic treatment approved to prevent acute swelling attacks in children and adults with hereditary angioedema (HAE).

Developed and marketed by CSL Behring, the therapy is given via routine subcutaneous, or under-the-skin, injections. In countries outside the U.S. and Canada, Haegarda may be known as Berinert 2000/3000 or Berinert SC.

Therapy snapshot

How does Haegarda work?

HAE is marked by the overproduction of bradykinin — a signaling molecule that plays a key role in inflammation and blood vessel dilation — that drives swelling attacks, a characteristic disease symptom. The C1 esterase inhibitor (C1-INH) protein is important for controlling bradykinin production, but it’s abnormally low or deficient in HAE types 1 and 2, the most common types of HAE.

Haegarda is a concentrated formulation of C1-INH obtained from the blood of healthy donors. When routinely administered to HAE patients, it helps to keep C1-INH levels high enough to slow bradykinin production and prevent swelling attacks.

Essentially, the medication is a concentrated, subcutaneous form of Berinert, an into-the-vein (intravenous) formulation of human C1-INH marketed by CSL Behring for the on-demand treatment of HAE attacks. As such, in some countries, it is known as subcutaneous Berinert, or Berinert SC.

Who can take Haegarda?

The U.S. Food and Drug Administration (FDA) initially approved Haegarda in June 2017 to prevent swelling attacks in adolescents and adults with HAE, making it the first subcutaneous prophylactic HAE therapy to enter the country’s market.

When the FDA extended Haegard’s approval to include children ages 6 and older in September 2020, it became the first subcutaneous prophylactic therapy approved for that age group.

Haegarda is approved as a routine prophylactic treatment for adults and adolescents with HAE in Canada. It is also approved under the name Berinert SC or Berinert 2000/3000 for similar indications in other parts of the world, including Japan, Australia, and Europe.

Who should not take Haegarda?

Haegarda is contraindicated, or not recommended, for patients with a history of life-threatening allergic reactions to C1-INH preparations or other inactive ingredients in their composition.

How is Haegarda administered?

Haegarda is given as a subcutaneous injection twice a week, or every three to four days. The recommended dose is 60 international units of C1-INH per kilogram of body weight (IU/kg). It is intended to be self-administered by patients or caregivers after receiving appropriate training.

The medication is stored as a freeze-dried white powder in single dose vials containing either 2,000 or 3,000 IUs of C1-INH, which must be dissolved in sterile water before being administered. It is provided in a kit that includes the medication, sterile water, and a Mix2Vial transfer set for reconstitution and administration. Each kit is as follows:

• 2,000 IU kit: fuchsia (pinkish-purplish) label; medication dissolved in 4 mL of sterile water
• 3,000 IU kit: yellow label; medication dissolved in 5.6 mL of sterile water

Haegarda should be injected immediately or within eight hours of being reconstituted, and should be administered at room temperature.

Injections may be given in areas such as the abdomen, upper arms, or thighs, and injection sites should be rotated to avoid using the same site repeatedly. New injections should be given at least five centimeters (about two inches) away from the site of a previous injection. Sites that are painful, swollen, or itchy, or those containing scars or stretch marks should be avoided.

Haegarda in clinical trials

Haegarda’s approval was supported by data from a placebo-controlled Phase 3 trial called COMPACT (NCT01912456) and its open-label extension, COMPACT OLE (NCT02316353).

COMPACT trial

The COMPACT trial evaluated Haegarda’s safety and efficacy against a placebo in 90 HAE type 1 and 2 patients, ages 12 and older, who were experiencing recurrent HAE attacks before enrolling in the study. Specifically, eligible patients had four or more attacks requiring immediate treatment or medical attention, or causing significant impairment over two months of the trial’s three-month run-in period.

Participants were randomized to receive a placebo for 16 weeks (four months) and either 60 IU/kg or 40 IU/kg of Haegarda for another 16 weeks in the crossover study. Haegarda was self-administered twice weekly.

Both doses resulted in statistically significant reductions in HAE attack rates compared with a placebo. Those given the approved 60 IU/kg dose experienced the greatest reductions, with a rate of 0.52 attacks per month compared with 4.03 while they were on a placebo — a median 95% reduction.

Most patients, 90%, treated with Haegarda at high dose were considered responders, meaning they experienced at least a 50% reduction in HAE attacks relative to the time they were on a placebo. Moreover, 40% of the patients on that dose remained attack-free while on the treatment.

Haegarda’s use nearly eliminated the need for on-demand rescue therapies, with a median reduction greater than 99% seen at the higher dose in comparison to the placebo period.

COMPACT OLE

COMPACT OLE evaluated the long-term effects of the same two doses of Haegarda in 126 type 1 and 2 HAE patients, ages 6 and older. Some had rolled over from the previous COMPACT trial and others were newly enrolled.

Participants were treated at either the 60 or 40 IU/kg dose of Haegarda twice weekly for up to one year, and those in the U.S. who completed that year could continue with treatment for up to 1.5 more years.

Haegarda continued to be well tolerated, with about 93% of the patients seeing at least a 50% reduction in HAE attack rates relative to their attack rates prior to entering the trial. The median annual swelling attack rate was one, and the median of rescue medication use was zero at Haegarda’s approved dose.

In a subgroup of 24 U.S. patients treated at the 60 IU/kg dose for more than one year in the extension study, 99% of their patient days were attack free for up to 2.7 years.

Additional analyses from these trials showed that Haegarda effectively reduced HAE attack rates in patients ages 65 and older and in pediatric patients, those ages 8 to 17. Haegarda also was seen to be safe and effective among women with HAE who were of childbearing age during the trial.

Haegarda’s use also lead to significant and sustained improvements in measures of health-related quality of life.

Common side effects of Haegarda

The most common side effects associated with Haegarda in clinical trials include:

• injection site reactions
• allergic reactions (hypersensitivity)
• cold-like symptoms (nasopharyngitis)
• dizziness.

Allergic reactions

Severe hypersensitivity reactions may occur when using Haegarda. Such reactions may be accompanied by symptoms such as hives, chest tightness, difficulty breathing, wheezing, low blood pressure, or anaphylaxis during or after an injection.

Should a severe reaction occur, Haegarda should be stopped and appropriate treatment initiated. All patients should have epinephrine — a life-saving medication for allergic reactions — readily available in case an allergic reaction occurs.

Blood clots

When used at its recommended dose, Haegarda has not been found to cause blood clots. However, blood clots have occurred with high doses of intravenous C1-INH therapies when used for unapproved indications. Haegarda should only be used at its prescribed dose; additional doses should not be taken on-demand to treat an acute swelling attack.

Symptoms of a blood clot may include pain, swelling, or warmth in the affected area, skin discoloration in the arms or legs, unexplained shortness of breath, chest pain, breathing discomfort, a rapid pulse, and numbness or weakness on one side of the body.

Transmission of infectious agents

Because Haegarda is made from human blood, it could pose a risk of transmitting infectious agents, such as viruses, when administered. To reduce that risk, donors are screened for the presence of certain viruses, and manufacturing processes are designed to inactivate and/or remove certain pathogens.

Still, there is a possibility that Haegarda may contain disease-causing agents, including ones not yet known or identified. The risk of their transmission to a treated patient cannot be eliminated.

Use in pregnancy and breastfeeding

No prospective clinical data currently cover the use of Haegarda during pregnancy or breastfeeding. However, C1-INH is a normal component of human blood and retrospective studies have not reported any adverse events before, during, or after pregnancy, or during breastfeeding by women who were using intravenous C1-INH formulations.

Patients who are pregnant or wish to become pregnant or to breastfeed while using Haegarda should discuss their status or intentions with their healthcare team.

Angioedema News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.