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295 Efficacy and Safety of Apixaban for Pediatric Patients Requiring Anticoagulation for Treatment of Venous Thromboembolism

Program: Oral and Poster Abstracts
Type: Oral
Session: 332. Thrombosis and Anticoagulation: Clinical and Epidemiological: Thrombosis in Pregnancy and Childhood
Hematology Disease Topics & Pathways:
Bleeding and Clotting, Anticoagulant Drugs, Thromboembolism, Diseases, Thrombotic disorders, Treatment Considerations, Non-Biological therapies
Saturday, December 7, 2024: 4:00 PM

Joseph Driscoll1*, Sarah H. O'Brien, MD, MSc2, Jane W. Newburger3*, Lesley G. Mitchell4*, Susanne Holzhauer5*, Sanjay Ahuja, MD6, Agustin Rubio7*, Puneet Gaitonde8*, Anna Robertson1*, Martin Polinsky9*, Urszula Masiukiewicz1* and Leonardo R. Brandao, MD, MSc10

1Pfizer Inc., New York, NY
2Department of Pediatrics, Ohio State University, Columbus, OH
3Department of Cardiology, Boston Children’s Hospital, Boston, MA
4Department of Pediatrics, Division of Pediatric Hematology/Oncology, Stollery Children’s Hospital, University of Alberta, Edmonton, AB, Canada
5Department of Pediatric Hematology and Oncology, University of Medicine Berlin, Berlin, Germany
6Rainbow Babies and Children's Hospital, Cleveland, OH
7Seattle Children's Hospital, Seattle, WA
8Pfizer Inc., Cambridge, MA
9Bristol Myers Squibb, Lawrenceville, NJ
10Division of Haematology/Oncology, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada

Background: In children, the incidence of VTE was initially reported to be very low at 0.07–0.14 per 10,000 children; however, contemporary data revealed a higher incidence for hospitalized children: ≥ 106 per 10,000 admissions (Andrew M et al. Blood 1994;83:1251–7, van Ommen CH et al. J Pediatr 2001;139:676–81, O’Brien SH et al. Pediatrics 2022;149:e2021054649). Pediatric evidence-based VTE treatment guidelines recommend unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or vitamin K antagonists (VKAs) as standard of care (SOC), acknowledging the gap surrounding the use of direct oral anticoagulants, such as apixaban, in children (Monagle P et al. Chest 2012;141[suppl 2]:e737S–e801S, Monagle P et al. Blood Adv 2018;2:3292–3316). The safety and efficacy profile of apixaban in adults with VTE has been established (Agnelli G et al. N Engl J Med 2013;368:699–708 and 2013;369:799–808). This study assessed the efficacy, safety, and pharmacokinetics/pharmacodynamics (PK/PD) of apixaban in pediatric patients (pts) requiring anticoagulation for the treatment of VTE.

Methods: In this 12-week, open-label, active-controlled descriptive study (NCT02464969), pediatric pts (aged < 18 years) with image-confirmed VTE were randomized 2:1 to receive apixaban dosed according to a fixed-dose, body weight tiered (mg/kg) regimen by age group (birth to 27 days, 28 days to < 2 years, 2 to < 12 years, 12 to < 18 years), or SOC prescribed per local practice (VKA, LMWH, and UFH). The primary efficacy endpoint was image-confirmed and adjudicated recurrent VTE defined as contiguous progression or non-contiguous new thrombus (new), including deep vein thrombosis (DVT), pulmonary embolism (PE), other thrombosis, paradoxical embolism, and VTE-related mortality. The primary safety endpoint was adjudicated major bleeding and clinically-relevant non-major bleeding (CRNMB). Secondary endpoints included new or recurrent symptomatic/asymptomatic DVT, PE, VTE other than DVT or PE, stroke, index event status, minor bleeding events, and apixaban PK/PD (plasma concentration and anti-Factor Xa activity [AXA] of apixaban). Pts who discontinued anticoagulation completed end-of-treatment and safety visits. The study was not powered and used descriptive statistics.

Results: Overall, 229 pts were randomized (full analysis set: apixaban n = 155, SOC n = 74). In total, 26 pts (11.4%) discontinued treatment (apixaban n = 17, SOC n = 9) and 4 (1.7%) were not treated (apixaban n = 3, SOC n = 1). The majority of pts were female (55.9%) and White (76.4%); median (range) age was 14.2 (0.04–18.0) years. Baseline demographics were comparable between treatment arms. Primary efficacy endpoint: in the apixaban group, 4 (2.6%, 95% CI 0.8–6.7) pts had ≥ 1 symptomatic or asymptomatic recurrent VTE event compared with 2 (2.7%, 95% CI 0.2–9.9) pts in the SOC group; no pts had VTE-related death. Primary safety endpoint: no pts in either treatment group had major bleeding events. In the apixaban group, 2 (1.3%, 95% CI 0.1–5.0) pts had CRNMB compared with 1 (1.4%, 95% CI 0.0–8.1) in the SOC group. The overall safety profile of apixaban was similar to SOC based on the incidence of treatment-emergent adverse events (AEs) and serious AEs. No clinically meaningful treatment differences in hematology and clinical chemistry laboratory parameters were observed. Day 14 pre-dose and corresponding post-dose median apixaban concentrations were similar across age groups at the administered doses. AXA was linearly correlated to apixaban concentrations across all age groups and body-weight tiers.

Conclusions: In this active-controlled descriptive study in children from birth to < 18 years of age with acute VTE, treatment with apixaban resulted in a low risk of VTE recurrence and comparable risk of major and CRNMB events compared to SOC therapy. No new safety signals were observed in apixaban-treated pts. The safety profile was generally consistent with that reported in adult VTE studies. PK/PD findings demonstrated linear correlation and were consistent across age and body-weight tiers.

Study support: This study was sponsored by Pfizer and Bristol Myers Squibb.

Acknowledgments: We thank the Study B0661037 investigators and patients for their participation. Editorial and medical writing support were provided by Caudex, a division of IPG Health Medical Communications, New York, NY, USA, and were funded by Pfizer and Bristol Myers Squibb.

Disclosures: Driscoll: Pfizer: Current Employment, Current equity holder in publicly-traded company. O'Brien: Pharmacosmos: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; iECURE: Other: Ad hoc DSMB member. Newburger: Pfizer: Other: Chair, Independent Events Adjudication Committee, Research Funding; Bristol Myers Squibb: Other: Chair, Independent Events Adjudication Committee for trial of apixaban. Co-Chair, Data Safety Monitoring Committee for trial of mavacamten. Mitchell: Bristol Myers Squibb: Research Funding. Holzhauer: Bayer AG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sobi: Consultancy, Honoraria; Böhringer Ingelheim: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Current equity holder in publicly-traded company, Honoraria. Ahuja: US FDA: Honoraria, Other: Member of the Blood Products Advisory Committee; Case Western Reserve University: Patents & Royalties: Patent for US 11,408,844 issued; XaTek: Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; BioMarin: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Governor’s Office, State of Ohio: Other: Membership on Rare Disease Advisory Council for the State of Ohio. Rubio: Bristol Myers Squibb: Current equity holder in publicly-traded company, Research Funding. Gaitonde: Pfizer: Current Employment, Current equity holder in publicly-traded company. Robertson: Pfizer Research and Development UK: Current Employment. Polinsky: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Masiukiewicz: Pfizer: Current Employment, Current equity holder in publicly-traded company. Brandao: Pfizer/Bristol Myers Squibb: Research Funding; AstraZeneca: Other: Ad board meeting on andexanet alfa (Feb. and Jun. 2023/ISTH – Montreal/QC, Canada.

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