SAN ANTONIO — Among patients with hereditary angioedema (HAE), monthly injections of the investigational biologic garadacimab reduced the mean attack rate substantially in the phase III VANGUARD clinical trial.
During the 6-month trial, the average monthly HAE attack rate dropped to 0.27 in the garadacimab group versus 2.01 for the placebo group (P<0.001), representing a relative 89.2% reduction (95% CI 75.6-95.2) after adjusting for baseline differences, reported Timothy Craig, DO, of Penn State University in Hershey in Pennsylvania.
Overall, 61.5% of patients in the active drug arm of the study had no HAE-related attacks, whereas all patients in the placebo arm of the trial experienced HAE attacks, according to findings presented at the annual meeting of the American Academy of Allergy, Asthma & Immunology.
Craig told MedPage Today that, in addition to the once-monthly dosing, garadacimab’s novel pathway represents a potential advantage over drugs currently approved for HAE prophylaxis.
The monoclonal antibody, previously dubbed CSL312, is a first-in-class inhibitor of the plasma protein FXIIa, which resides at the top of the coagulation pathway. Craig said targeting FXIIa and the HAE cascade from the top of the pathway, instead of intervening downstream, “could help stop the process in its tracks.”
“Given this position, we also looked for signals associated with clotting and thrombosis, as well as bleeding,” Craig said. “We did not see these signals, which is also what the phase II studies showed.”
HAE is a rare genetic condition involving recurrent attacks of severe swelling, which can be life threatening. The autosomal dominant disorder is characterized by a deficiency of functional C1 esterase inhibitor.
Prophylactic therapies designed to prevent HAE attacks include C1 and C1-esterase inhibitors, and one other biologic — lanadelumab (Takhzyro) — has been approved by the FDA for HAE prophylaxis.
The VANGUARD trial involved 64 patients 12 years of age and older with type I or II HAE randomized to receive either monthly injections of garadacimab (n=39) at a dosage of 200 mg 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, and patients were included in the trial after undergoing a run-in period to determine the baseline attack rate.
The primary study endpoint was 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.
A total of 24 (61.5%) patients in the biologic treatment arm of the study remained attack-free during the 6-month trial, and 74.4% achieved a 90% or greater reduction in attacks compared with the run-in period.
The mean number of HAE attacks per month requiring on-demand medication was 0.23 (95% CI 0.02-0.45) in the garadacimab-treated patients versus 1.86 (95% CI 1.26-1.84) in the placebo group. The mean number of moderate-to-severe HAE attacks per month was 0.13 in the biologic therapy group (95% CI 0.03-0.22) versus 1.35 (95% CI 0.86-1.84) in the placebo arm of the study.
Average reduction in AE-QoL score was 26.5 points from baseline to the end of the study in the garadacimab arm versus 2.2 points in the placebo arm. A 6-point reduction is considered clinically meaningful.
In both treatment groups, 40 patients had treatment-emergent adverse events, totaling 129 events. The most common treatment-emergent events were injection site reactions, headache, and nasopharyngitis.
No adverse events leading to study discontinuation occurred. One serious adverse event occurred in the garadacimab group (laryngeal attack requiring overnight hospitalization), which was not considered by investigators to be related to treatment with the biologic.
There were no reported occurrences of anaphylaxis, thromboembolic events, or abnormal bleeding in the study cohort.
Disclosures
This research was funded by CSL Behring. Craig reported receiving speaker and/or other fees or conducting research for CSL, Takeda, and others, as well as serving on the advisory board of the U.S. Hereditary Angioedema Association.
Primary Source
American Academy of Allergy, Asthma & Immunology
Source Reference: Craig T “Efficacy and safety of subcutaneous garadacimab for the prophylaxis of hereditary angioedema attacks in adults and adolescent patients with HAE: results from a multicenter, placebo-controlled phase 3 trial” AAAAI 2023; Poster 406.