Week 3, February 2025: Hereditary Angioedema

On January 24, 2025, the novel monoclonal antibody Andembry (garadacimab) was approved in Australia! The drug is now approved for routine prevention of recurrent hereditary angioedema (HAE) attacks in patients aged 12 years and older with C1-esterase inhibitor deficiency or dysfunction. Andembry is a novel Factor XIIa-inhibitory monoclonal antibody (anti-FXIIa mAb) developed by CSL. It works by inhibiting the plasma protein factor XIIa, which when activated, initiates the cascade of events leading to oedema at various sites of the body. Garadacimab binds to βFXIIa through an unusually long CDR-H3 that inserts into the S1 pocket in a non-canonical way. This structural mechanism is likely the primary contributor to the inhibition of activated FXIIa proteolytic activity in HAE.

HAE is a form of bradykinin-mediated angioedema. It is a rare, debilitating, and potentially life-threatening genetic disorder affecting approximately 1 in 50,000 people globally, caused by deficient or dysfunctional C1-INH, a protein in the blood that helps to control inflammation. Inadequate amounts of properly functioning C1-INH can lead to the accumulation of fluid in body tissues, causing considerable swelling referred to as angioedema. HAE attacks can affect many parts of the body and can spread to multiple sites, including the face, abdomen, larynx, and extremities. Patients who have abdominal attacks of HAE can experience extreme pain, diarrhea, nausea, and vomiting caused by swelling of the intestinal wall. HAE attacks that involve the face or throat can result in airway closure, asphyxiation and, if left untreated, death. 

A recent study looked at the real-world effectiveness of lanadelumab, a subcutaneously administered human IgG1 recombinant monoclonal antibody that potently inhibits active plasma kallikrein. Kallikrein is a protease that functions to cleave kininogen, subsequently creating kininogen and bradykinin, a potent vasodilator. Uncontrolled plasma kallikrein leads to excessive bradykinin production. Takeda’s lanadelumab, sold under the brand name Takhzyro, was previously approved by the FDA in August 2018, for the treatment of type I or type II HAE. This real-world study demonstrates that lanadelumab long-term prophylaxis is effective in improving AFR in patients with type I/II HAE on every 2-week dosing and dose interval increases. Effectiveness with lanadelumab is rapid and was observed starting from the first month of starting therapy. 

A third novel monoclonal antibody that was recently given FDA Orphan Drug Designation to treat HAE is Astria Therapeutics’s navenibart (STAR-0215). Like lanadelumab, navenibart targets plasma kallikrein, with the goal to provide rapid and sustained HAE attack prevention. In a healthy blood vessel, C1 inhibitor blocks the function of plasma kallikrein. However, in HAE, a missing C1 Inhibitor allows plasma kallikrein to process HMWK, generating cleaved HMWK (cHWK) and releasing bradykinin. Bradykinin then binds to receptors allowing fluid to leak through blood vessel walls and causing edema/pain. Navenibart inhibits/blocks plasma kallikrein, even in the absence of Cl Inhibitor. Based on positive results from the ALPHA-STAR Phase 1b/2 trial in people living with HAE, navenibart is advancing to Phase 3 development with trial initiation expected in Q1 2025 and top-line results expected in early 2027.