Garadacimab for hereditary angioedema

Last updated April 3, 2024, by Marisa Wexler, MS
Fact-checked by Joana Carvalho, PhD

 

What is garadacimab for hereditary angioedema?

Garadacimab, formerly known as CSL312, is an antibody-based therapy that CSL Behring is developing as a prophylactic or preventive treatment to reduce the risk of swelling attacks in people with hereditary angioedema (HAE). It is administered via a subcutaneous  (under-the-skin) injection.

Regulatory authorities in the U.S. and the European Union are now reviewing applications from CSL Bering that seek approval of garadacimab for HAE. Garadacimab previously received orphan drug designation for the treatment of HAE in both the U.S. and the EU.

Therapy snapshot

Treatment name:	Garadacimab
Administration:	Being tested in hereditary angioedema as a subcutaneous injection
Clinical testing:	Tested in a Phase 3 trial; now being considered for US, EU approval

 

How does garadacimab work in hereditary angioedema?

HAE is marked by recurrent swelling attacks; they are the condition’s defining symptom.

Garadacimab is a recombinant or man-made monoclonal antibody that’s designed to block a blood protein called factor XII (FXII). When this protein is activated, it sets off a chain of molecular signaling events that triggers swelling. By inhibiting FXII, garadacimab aims to stop this signaling chain of events and prevent swelling.

If approved, garadacimab would become the first HAE treatment that works by specifically targeting activated FXII.

How will garadacimab be administered in hereditary angioedema?

In a Phase 3 trial involving HAE patients, garadacimab was given by subcutaneous injection once monthly.

Patients received an initial loading dose of 400 mg (two 200 mg injections) in the first month, followed by 200 mg monthly doses thereafter. Garadacimab doses following the initial loading dose were either self-administered or administered by a caregiver.

If cleared by regulatory authorities, garadacimab would be supplied as an auto-injector (prefilled pen), enabling patients to benefit from a therapy with a convenient mode of administration.

Garadacimab in hereditary angioedema clinical trials

Garadacimab has been evaluated across a range of clinical studies involving HAE patients. The therapy was assessed in a Phase 3 clinical trial and is now under regulatory review in the U.S. and Europe.

Phase 2 trial

In a Phase 2 clinical trial (NCT03712228) completed in 2021, 32 adults with HAE types 1 or 2 were randomly assigned to receive monthly subcutaneous injections of garadacimab. at doses ranging from 75 to 600 mg, or a placebo, for about three months. Subcutaneous treatment followed the administration of an initial loading dose that was given intravenously, or directly into the bloodstream.

All patients had experienced at least four swelling attacks during a consecutive two-month period in the three months prior to screening.

Preliminary results showed the trial met its main goal, with fewer swelling attacks seen for individuals on garadacimab versus those on the placebo. In patients given garadacimab at a dose of 200 mg monthly, swelling attack rates significantly decreased by 100% compared with the placebo. No serious adverse events were reported.

VANGUARD Phase 3 trial

CSL’s applications seeking the approval of garadacimab were mainly based on data from the Phase 3 VANGUARD trial (NCT04656418). The study enrolled 64 people with HAE types 1 or 2, ages 12 and older, who had experienced at least three attacks in the three months before entering the trial. The participants were randomly assigned to receive garadacimab or a placebo for six months. To start, each patient received a 400 mg loading dose of subcutaneous garadacimab or the placebo. This was followed by five additional 200 mg doses of subcutaneous garadacimab or the placebo, either self-administered or given by caregivers.

The results showed that patients given garadacimab had a mean rate of 0.27 swelling attacks per month, while those in the placebo group had a mean of 2.01 attacks per month — a statistically significant difference of more than 85%.

Nearly two-thirds of patients (62%) given garadacimab were free of swelling attacks during the six-month study, whereas none of the patients given the placebo were attack-free. Participants given garadacimab also reported improvements in life quality not seen for those on the placebo.

Ongoing trials

Participants who completed VANGUARD had the option to enroll in an extension study (NCT04739059), in which all are being treated with monthly injections of garadacimab and monitored for long-term outcomes. The open-label study — meaning that both researchers and participants know the exact treatment given — is expected to run through late 2025.

CSL also is sponsoring a Phase 3 trial (NCT05819775) to test garadacimab in children with HAE, ages 2 through 11. The goal of this study is to evaluate the therapy’s safety, efficacy, and pharmacological properties in younger patients. The study aims to enroll a dozen children; recruitment is ongoing at sites in the U.S. and Israel.

Common side effects of garadacimab

In the Phase 3 VANGUARD trial, the most frequently reported treatment-emergent side effects among patients given garadacimab were upper respiratory tract infections, cold-like symptoms, and headache. There was one serious adverse event, a laryngeal attack, in the garadacimab treatment group, but it was deemed to be unrelated to the therapy. No deaths or treatment discontinuations were brought on by adverse events.

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