Cinryze is approved by the U.S. Food and Drug Administration (FDA) as a means of preventing severe swelling attacks in people with hereditary angioedema (HAE).

Cinryze was initially developed by ViroPharma and acquired by Shire in 2013.

How Cinryze works

Acute attacks in HAE are marked by swelling of the deeper layers of the skin or the mucous membranes of the intestines or lungs. A buildup of bradykinin, a peptide in plasma, is responsible for triggering these attacks. Bradykinin levels normally are controlled by an enzyme called C1 esterase inhibitor. People with HAE have lower-than-usual levels of this enzyme — or the enzyme fails to work as it should — leading to excessive bradykinin, which causes blood vessels to leak fluid into surrounding tissues.

Cinryze works to replenish blood levels of the C1 esterase inhibitor. The recommended dosage of Cinryze contains about 1,000 units of C1 esterase inhibitor in the form of a powder, extracted from human plasma. It is given as an injection directly into the bloodstream.

Cinryze in clinical trials

A Phase 2 clinical trial (NCT01095497) compared the effectiveness of Cinryze — in doses of 1,000 or 2,000 units given as an injection under the skin, and in doses of 1,000 units injected directly into the bloodstream — twice a week for two weeks.  Results showed that Cinryze was safe and tolerable at all doses, but the group that received Cinryze through the bloodstream had the fewest side effects.

A Phase 3 clinical trial (NCT00289211) compared Cinryze treatment for safety and efficacy to placebo. Results showed that patients experiencing an HAE attack had their symptoms relieved within two hours after taking 1,000 units of Cinryze, compared to the four hours for those taking a placebo. Patients in this trial were invited to continue treatment in an open-label extension study (NCT00438815) that gave the medication to all groups in the earlier trial and followed them for 2.5 years.

Two other Phase 3 trials (NCT01005888, and its open-label extension NCT00462709) looked at the ability of Cinryze to prevent HAE attacks. Patients received 1,000 units of Cinryze twice a week for three months, or placebo, in the first study, and all were treated for the duration of the second trial. Cinryze was shown to cut by half the number of attacks experienced by patients compared to those in the placebo group.

The results of all four Phase 3 studies were published as a single article in the New England Journal of Medicine.

These trials also included 46 children who were analyzed separately. The results published in the Journal of Paediatrics showed that 89 percent of them experienced relief from acute HAE symptoms within four hours of taking 1,000 units of Cinryze, and the number of attacks decreased two-fold after using Cinryze as a preventive agent at doses of 1,000 units twice a week. The average monthly attack rate decreased from three attacks to nearly none (0.39).

A Phase 3 clinical trial (NCT02052141) specifically investigating Cinryze in children ages 6 to 11 found that two Cinryze regimens given at twice-weekly doses of 500 units for three months, followed by 1,000 units for another three months and vice versa, both were able to reduce the frequency, severity, and duration of attacks.

In a separate Phase 2 trial (NCT01095510), nine children, ages 11 or younger, received a single dose of Cinryze based on their body weight as a treatment for an acute attack. All experienced relief within four hours of receiving the medication. Overall, Cinryze was found to be well-tolerated in these pediatric patients.

A Phase 4 study (NCT00914966) investigated the effectiveness of progressively increasing doses of Cinryze (1,500, 2,000, and 2,500 units) in patients with uncontrolled HAE. About 20 participants were given the medication twice a week for three months at escalating doses. Almost half (45 percent) of the 20 experienced one attack or less while on each dose of the medication. Five of the 91 adverse events recorded during the entire study period were deemed to be related to Cinryze.

More details about Cinryze

Cinryze was approved by the FDA for use in adolescents and adults in 2008. More recently,  the FDA accepted for review a supplemental biologics license application from Shire requesting that Cinryze’s approval be extended to include children, ages 6 and older. A decision from the FDA is expected by June 2018. Cinryze also was approved to prevent HAE attacks in children ages 6 and older — who have a history of severe attacks not managed by other treatments, or are unable to tolerate them — by the European Commission in 2017. It also is approved in the EU for “the treatment and pre-procedure prevention” of attacks in children ages 2 and older.

The most common side effects of Cinryze use are nausea, vomiting, headache. and a rash. Patients may experience hives, chest tightness, wheezing and a drop in blood pressure (collectively known as hypersensitivity reactions). There also is a risk of Cinryze causing blood clots.

Other forms of C1 esterase inhibitor therapy include Haegarda and Berinert (both developed by CSL Behring). Haegarda is given as injections under the skin, while Berinert is given as injections directly into the bloodstream.

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