CSL's Garadacimab Pediatric Data Supports Filing, But Open-Label Design and Lack of Figures Weaken Competitive Stance

CSL's Andembry Shows Promise in Paediatric HAE Phase IIIb Study

CSL announced positive topline results from an open-label Phase IIIb study (NCT05819775) of its hereditary angioedema (HAE) therapy, Andembry (garadacimab), in paediatric patients aged two to 11. The subcutaneous factor-XIIa-targeting therapy demonstrated treatment responses across the study population, with the majority of patients remaining free of swelling attacks over the 12-month trial. Andembry's safety profile was consistent with previous studies. These results support CSL's plan to file for label expansion into the paediatric population for Andembry in the first half of its fiscal year, aiming to strengthen its position in the competitive HAE market against therapies like Takhzyro and Orladeyo.

• The open-label Phase IIIb study (NCT05819775) evaluated Andembry in HAE patients aged two to 11 years. While full efficacy details are pending, CSL reported that the subcutaneous factor-XIIa-targeting therapy elicited treatment responses across the study population, with most patients remaining free of swelling attacks throughout the 12-month trial duration.
• Andembry demonstrated a safety profile consistent with prior studies, indicating good tolerability in the paediatric population. Based on these positive topline results, CSL plans to submit for an expanded approval of Andembry for children aged two to 11 years with HAE during the first half of its fiscal year, aiming to broaden its market reach.
• The HAE market is increasingly competitive, with existing therapies like Takeda's Takhzyro (a blockbuster subcutaneous therapy) and BioCryst's Orladeyo (the first oral therapy for paediatric HAE prevention). CSL's Andembry, if approved for this paediatric population, would further extend the company's presence in HAE, complementing its C1 esterase inhibitors, Berinert and Haegarda.

Why Paediatric HAE Patients Need New Treatment Options

Recent literature highlights that despite the availability of long-term prophylaxis (LTP) and on-demand treatments for hereditary angioedema (HAE), significant unmet needs persist. Challenges in treatment adherence, disease control, and access continue to place a substantial burden on patients, underscoring the need for improved management strategies, particularly for vulnerable subpopulations.

• Suboptimal Treatment Adherence and Effectiveness: Real-world data reveal significant gaps in treatment utilization, with suboptimal adherence to subcutaneous long-term prophylaxis (mean medication possession ratio of 73%) and high discontinuation rates of 46-48%. Furthermore, 57% of patients do not treat every HAE attack, and the mean time to treatment is 2.4 hours, often due to perceived attack severity or lack of on-demand medication availability.

• Persistent Disease Burden and Inadequate Control: Despite available therapies, a large portion of the patient population experiences poor disease control, with 48% of physicians reporting that their patients fail to achieve the WAO/EAACI goal of a normalized life. This translates to a high disease burden, characterized by frequent attacks, significant impairment to quality of life and mental health, and substantial annualized treatment-related expenditures averaging over $209,000 per patient.

• Systemic Barriers in Diagnosis and Access: Significant delays in diagnosis, averaging a decade from first symptoms, often lead to patients undergoing unnecessary procedures. Post-diagnosis, considerable access barriers remain, including gaps in non-expert physician knowledge, treatment costs, and reimbursement challenges for LTP. These issues are exacerbated by pronounced geographic disparities in access to on-demand treatment, such as 72.2% availability in South Africa versus 100% in Hong Kong.

• Identification of High-Need Patient Populations: Specific patient cohorts demonstrate higher unmet needs, including individuals with HAE with normal C1-inhibitor (HAE-nC1-INH), who tend to be less well-controlled and experience more emergency department visits. The pediatric and adolescent population also requires focused attention, as the median age of symptom onset is 13 years, and younger patients are noted to be less likely to carry on-demand treatment.

Andembry's Place in the Evolving HAE Treatment Landscape

Over the past five years, the treatment landscape for Hereditary Angioedema (HAE) has significantly advanced, moving decisively towards highly effective, targeted long-term prophylactic (LTP) therapies. The approvals of lanadelumab, a monoclonal antibody targeting plasma kallikrein, and berotralstat, the first oral plasma kallikrein inhibitor, established a new standard of care. Clinical data from studies like EMPOWER and real-world evidence have consistently shown that these agents substantially reduce attack rates and improve quality of life. The landscape evolved further with the 2025 approval of garadacimab, a monoclonal antibody that inhibits activated Factor XII (FXIIa). Data from the pivotal Phase 3 VANGUARD trial and its open-label extension demonstrated that garadacimab reduced the mean monthly attack rate by up to 95%, with over 60% of patients remaining attack-free, all while maintaining a favorable long-term safety profile.

The late-stage clinical pipeline promises to further refine HAE management with additional novel mechanisms and formulations. For on-demand treatment, sebetralstat, an oral plasma kallikrein inhibitor, has shown rapid absorption and a median time to symptom relief of under two hours in Phase 3 trials, positioning it as a convenient, effective option for acute attacks. For prophylaxis, donidalorsen, an antisense oligonucleotide designed to reduce prekallikrein, demonstrated sustained attack rate reductions of over 90% and clinically meaningful quality-of-life improvements with monthly or bi-monthly subcutaneous dosing in the OASISplus study. Another promising oral agent, deucrictibant, a bradykinin B2 receptor antagonist, showed significant attack rate reductions of up to 85% in its Phase 2 CHAPTER-1 trial, providing the first clinical evidence for this prophylactic mechanism.

Beyond the development of new agents, the therapeutic paradigm has expanded to address related conditions and prioritize patient-centric outcomes. Retrospective studies have supported the use of FDA-approved HAE medications, such as recombinant human C1-esterase inhibitor (rhC1-INH) and lanadelumab, for patients with HAE with normal C1-INH levels (HAE-nl-C1INH), who previously failed on traditional therapies. Across recent clinical trials for nearly all agents, a strong emphasis has been placed on patient-reported outcomes, with data consistently showing clinically meaningful improvements in Angioedema Quality of Life (AE-QoL) and Angioedema Control Test (AECT) scores. This focus underscores a treatment goal that has evolved beyond mere attack reduction to achieving well-controlled disease and enabling a normalization of patient lives.