VANGUARD sets the stage for a novel biologic in HAE

Monthly injections of the investigational biologic garadacimab substantially reduced the mean attack rate in patients with hereditary angioedema (HAE) in the phase III VANGUARD trial.

HAE involves recurrent and serious episodes of severe swelling, which can be life-threatening. This autosomal dominant disorder is characterized by a deficiency of functional C1 esterase inhibitors.

During the 6-month trial, the average monthly HAE attack rate dropped to 0.27 with garadacimab vs 2.01 with placebo (p<0.001).

“This translated to an 89.2 percent reduction (95 percent confidence interval (CI), 75.6–95.2) after adjusting for baseline differences,” reported Dr Timothy Craig of Penn State University in Hershey, Pennsylvania, US. [AAAAI 2023, poster 406]

Overall, 61.5 percent of patients in the garadacimab arm had no HAE-related attacks, whereas all patients in the placebo arm experienced HAE attacks.

Garadacimab has the upper hand

In addition to the once-monthly dosing, the novel pathway of garadacimab represents a potential advantage over pharmacotherapies approved for HAE prophylaxis.

Garadacimab, previously called CSL312, is a first-in-class inhibitor of the plasma protein FXIIa. Targeting FXIIa and the HAE cascade from the top of the pathway, instead of intervening downstream, could help stop the process in its tracks, explained Craig.

“Given this position, we also looked for signals associated with clotting and thrombosis, as well as bleeding,” he shared. “But there weren’t any signals, similar to the phase II studies.”

Looking into VANGUARD

The trial included 64 patients ≤12 years of age with type I or II HAE who were randomly assigned to monthly injections of garadacimab 200 mg (n=39) or placebo (n=25), after an initial loading dose of 400 mg or volume-matched placebo.

The study was conducted at 28 treatment sites in seven countries. Prior to enrolment, patients underwent a run-in period to determine their baseline attack rate.

The primary study endpoint was the time-normalized number of HAE attacks per month during the 6-month study period. Secondary endpoints included the time-normalized number of HAE attacks requiring on-demand therapy, the time-normalized number of moderate-to-severe HAE attacks, and quality of life, as measured by the Angioedema Quality of Life (AE-QoL) score.

At 6 months, 24 patients (61.5 percent) in the garadacimab arm remained attack-free, and 74.4 percent achieved a 90 percent or greater reduction in attacks vs the run-in period.

The mean number of HAE attacks per month requiring on-demand medication was 0.23 (95 percent confidence interval [CI], 0.02–0.45) with garadacimab vs 1.86 (95 percent CI, 1.26–1.84) with placebo. Moderate-to-severe HAE attacks per month were 0.13 (95 percent CI, 0.03–0.22) and 1.35 (95 percent CI, 0.86-1.84) with garadacimab and placebo, respectively.

The average reduction in AE-QoL score from baseline to study end was 26.5 points with garadacimab vs 2.2 points with placebo, which was clinically meaningful.

Overall, 40 patients had treatment-emergent adverse events, totaling 129 events.  The most common of which were injection site reactions, headache, and nasopharyngitis.

There was no adverse event leading to study discontinuation. One serious adverse event (laryngeal attack) occurred in the garadacimab group, but it was not drug-related. There were no reports of anaphylaxis, thromboembolic events, or abnormal bleeding either.

Prophylactic therapies for HAE attacks include C1 and C1-esterase inhibitors. Lanadelumab, another biologic, is US-FDA approved for HAE prophylaxis in children as young as 2 years old.