DE MONITOR schreef op 18 maart 2023 15:20:
CSL Behring to seek approval of garadacimab this year
Data from Phase 3 trial for hereditary angioedema treatment deemed significant
Garadacimab, a preventive treatment candidate from CSL Behring, led to significant and clinically meaningful reductions in swelling attacks in patients with hereditary angioedema (HAE), according to published data from the Phase 3 VANGUARD clinical trial.
The company expects to seek garadacimab’s approval from global health authorities later this year.
“Despite the availability of effective preventative treatments for HAE, patients still experience breakthrough attacks and a high burden of disease, and there is a need for new treatment options that offer more convenience, choice and control,” Catherine Milch, vice president of R&D Immunology at CSL, said in a press release.
“We believe garadacimab has the potential to become a transformative first-in-class therapy, providing a new option where there is significant unmet need,” Milch said.
Findings from the CSL-sponsored trial were detailed in the study, “Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial,” published in The Lancet.
Garadacimab, previously known as CSL312, is an antibody designed to block the activity of factor XIIa (FXIIa), which is responsible for kicking off a signaling cascade that ultimately leads to edema, or swelling.
By blocking FXIIa, garadacimab is expected to prevent the activation of that cascade, reducing the frequency of HAE swelling attacks. In contrast to other therapies that interfere with downstream components of this pathway, garadacimab targets it at its source.
The VANGUARD trial (NCT04656418) assessed the effectiveness and safety of garadacimab against a placebo in 64 HAE patients, ages 12 and older. All participants, who were recruited at 28 sites worldwide, had experienced at least three attacks in the three months before entering the trial.
Study design
Participants, who were mostly women (59%) and white (86%), were assigned randomly to receive garadacimab (39 people) or a placebo (25 people) as a monthly under-the-skin injection for six months.
All participants were asked to stop using other long-term preventive treatments before the trial started, but could continue using on-demand treatments as needed.
VANGUARD’s main goal was to determine the effect of treatment on monthly attack frequency during the six months of treatment.
As previously reported, the mean number of monthly attacks was lower in the garadacimab group compared with the placebo group over the six-month trial. Specifically, patients on garadacimab were having a mean of 0.27 monthly attacks, while those on placebo were having about two per month.
Decrease in attack frequency
After adjusting patients’ attack frequency before the trial, this amounted to a significant, 89.2% decrease in attack frequency.
Nearly three-quarters of the patients (72%) on the experimental therapy were attack-free within the first three months of the trial, which usually was sustained during the second three months.
Ultimately, 62% of those on garadacimab — 24 of 39 people — had no attacks at all over the course of the trial, whereas none of the patients in the placebo group achieved that.
Garadacimab-treated patients saw a 91% reduction in attack frequency compared with the period before the trial started. In contrast, those in the placebo group saw only a 20% reduction in attack frequency.
Patients using garadacimab also had fewer monthly attacks that required on-demand treatment, and fewer moderate or severe attacks compared with those on placebo.
Most participants felt their response to garadacimab was good or better (82%), compared with 33% of the placebo group.
Garadacimab-treated patients also saw clinically meaningful quality of life gains a month after starting treatment, which were improved more after six months.
The rate of adverse events was similar in both treatment groups. The most common treatment-emergent side effects were upper respiratory tract infections, cold-like symptoms, and headache.
No abnormal bleeding or blot clots were observed — an important finding given that FXII also plays a role in blood clotting, the team noted.
Three people in the placebo group stopped treatment early due to a lack of attack control; no discontinuations occurred in the garadacimab group.
Extension study ongoing
Following the end of the main trial, 57 participants decided to enroll in an ongoing open label extension study (NCT04739059), in which all participants are receiving garadacimab once per month. That study is expected to conclude in 2025.
According to study researchers, these findings “support the use of garadacimab as a potential prophylactic [preventive] therapy for the treatment of hereditary angioedema in adolescents and adults.”
“The development of garadacimab reflects our commitment to providing life changing medicines for patients with HAE and for the physicians who treat them,” Milch said