Garadacimab Shuts Down Contact Pathway to Treat HAE: Timothy Craig, DO

Today, the FDA approved CSL’s garadacimab-gxii (Andembry), a first-in-class factor XII (FXIIa) inhibitor for patients with hereditary angioedema (HAE).

Timothy Craig, DO, professor at Penn State University and principal investigator of the VANGUARD phase 3 trial (NCT04656418) on garadacimab, spoke with The American Journal of Managed Care® about what HAE is and how garadacimab works to treat those with the rare disease.

This transcript has been edited for clarity; captions were auto-generated.

Transcript

What is HAE and how does it affect individuals who have the diagnosis?

HAE is a disease where there's an increased level of bradykinin produced, which causes vessels to dilate and endothelial cells to change their internal structure and tight junctions between them to change. And what happens is fluid moves from the vascular space into the interstitial space. It mainly affects any skin service, but it can also affect the [gastrointestinal] tract, and unfortunately, also the upper airway, which you know is critical, obviously, for survival, that you [are] able to breathe. And so what happens is, if you have a lack of C1 inhibitor protein or a dysfunctional protein, then the controlled contact system is limited, and with that, you get that extra increase of bradykinin that causes those changes I just mentioned.

How does garadacimab work to treat HAE?

Garadacimab works at the very, very top of the contact pathway, or the kallikrein pathway, some people call it. And what happens is, factor XII can be activated by multiple things, including negative charges. Once it becomes activated, factor XIIa, which is the activated factor XII, then it can activate kallikrein, and then kallikrein can activate high-molecular-weight kininogen, causing it to fragment, and that fragment becomes bradykinin, and it binds to the receptor on the endothelial cell. The whole thing is, if you can stop that whole chain of events right up top, it would be successful in shutting down the production of bradykinin and preventing a swell, if you want to call it that, or angioedema. That's exactly how garadacimab works. It's a human antibody against activated factor XII, so it shuts down the entire contact pathway.