INTRODUCTION: Hemophilia B is a rare, X-linked disorder caused by F9 gene mutations, leading to deficient or dysfunctional clotting factor IX and bleeding complications. Emerging therapies including extended half-life products, non-factor therapies, and gene therapies are improving disease and treatment burden, using metrics such as annualized bleeding rate (ABR) to assess effectiveness. Understanding potential differences in ABR data in clinical trials and real-world studies may provide perspective on treatment effectiveness and patient experiences. These endpoints are essential for understanding the burden and unmet needs for patients with hemophilia B. The objective of this study was to conduct a systematic literature review and meta-analysis to summarize bleeding events in people with hemophilia B.

METHODS: A systematic search of MEDLINE, Embase, and Cochrane was conducted on the Ovid platform, as well as a bibliographic review, search of ClinicalTrials.gov, WHO ICTRP, and conferences. Included studies evaluated patients of any age or severity with inherited hemophilia B without inhibitors receiving prophylactic standard or extended half-life factor IX replacement therapies. Data from the lead-in phase of gene therapy trials and non-factor therapies where patients received factor IX replacement therapies were also included. Annualized bleeding rate (ABR) was analyzed as total ABR (specified as treated and untreated) and treated ABR where possible as reported by the included studies. ABR was also analyzed for treated and unspecified ABR for studies that did not specify bleeding events as total or treated. Meta-analysis used a random-effects model to account for heterogeneity across included studies.

RESULTS: The search yielded 5,727 citations and a total of 66 studies were included in the meta-analysis (19 clinical trials and 44 observational studies). Six of the 19 clinical trials included patients <12 years, 9 trials included patients ≥12 years, of which 2 were gene therapy trials that included adults (≥18 years) only, and 4 trials included patients of any age. Eighteen trials included patients with moderately severe to severe disease and 1 trial included patients with any disease severity. Four of the 44 observational studies included patients <12 years, 13 included patients ≥12 years, of which 9 included adults (≥18 years) only, and 27 studies included patients of any age. Sixteen studies included patients with moderately severe to severe disease, 10 included patients with severe disease only, 18 included patients of any disease severity.

In 19 clinical trials including 862 patients, only 2 reported the total ABR, both of which were from the lead-in phases or studies of gene therapy trials (4.19 and 4.41). Eleven trials reported treated ABR [combined mean 2.26 (95% confidence interval (CI) 1.47, 3.46)]. The combined mean for treated or unspecified ABR was 2.44 (95% CI 1.83, 3.24; 19 trials). The combined mean for treated ABR among patients <12 years and ≥12 years, was 0.82 (95% CI 0.31, 2.15; 3 trials) and 3.16 (95% CI 2.48, 4.02; 7 trials), respectively. The combined mean for treated or unspecified ABR among patients <12 years and ≥12 years, was 1.93 (95% CI 0.95, 3.90; 7 trials) and 3.17 (95% CI 2.66, 3.78; 9 trials), respectively.

In 44 observational studies representing 2,426 patients, no study specified ABR as total and only 3 specified ABR as treated. In the analysis combining all 44 studies, the combined mean for treated or unspecified ABR was 2.27 (95% CI 1.89, 2.73). The combined mean for treated or unspecified ABR among patients <12 years and ≥12 years, was 2.80 (95% CI 1.01, 7.80; 6 studies), 2.15 (95% CI 1.55, 2.97; 15 studies) respectively.

CONCLUSIONS: Significant advancements have been made in treating hemophilia B. The results from this meta-analysis reflect these positive developments, but also highlight unmet needs, with many patients experiencing over 2 bleeding events per year. In clinical trials, bleeding events were generally specified as treated or total. In contrast, in most observational studies (over 90%), bleeding events were not clearly defined. The lack of consistent ABR definitions coupled with variability in follow-up times raises concerns about generalizability and reproducibility, complicating the application of findings to clinical decision-making. Further analyses are needed to explore other sources of heterogeneity such as age, factor IX replacement type, and follow-up time.

This content is only available as a PDF.
2025
Sign in via your Institution