U.S. Cohort Study of Previously Untreated Patients with Congenital Hemophilia (ATHN 8: PUPs Study): Inhibitor Development and Treatment Characteristics

Background: Persons with hemophilia (PWH) are at risk of developing neutralizing inhibitors to factor product. While some risk factors for inhibitor development are known, mechanisms to delay or prevent this complication are less well understood. American Thrombosis and Hemostasis Network (ATHN) 8: U.S. Cohort Study of Previously Untreated Patients (PUPs) with Congenital Hemophilia (NCT03818529) is a longitudinal cohort study of PUPs with moderate or severe hemophilia A (HA) or B (HB) born between 1/2010 and 12/2021 and enrolled from participating ATHN-affiliated hemophilia treatment centers (HTCs). Through this study we sought to understand variables that contribute to inhibitor development.

Methods: At each HTC, data were entered for participants until 50 clotting factor exposure days (EDs), development of a confirmed neutralizing inhibitor, or study closure. The primary outcome was inhibitor development defined as a Bethesda Unit (BU) titer of >0.6 for HA or >0.3 for HB and a change in treatment. Secondary outcomes included diagnosis and treatment characteristics. Summary statistics were performed. For participants who met study endpoints at the time of enrollment, logistic regression analysis was utilized to evaluate birth cohort, race, hemophilia severity, genetic variant (for F8 gene only, classified as large structural changes >50 bp, other, and not sequenced), prophylaxis, and 5 or more consecutive EDs as risk factors for inhibitor development.

Results: The study enrolled 234 eligible male participants including 135 who had met study endpoints at the time of enrollment; 94 with 50 EDs and 41 with inhibitor. A total of 128 (128/234 = 55%) were White, non-Hispanic. Of 114 HA participants who met a study endpoint prior to enrollment, 38 (38/114 = 33%) developed an inhibitor (3 moderate, 35 severe). The median EDs prior to inhibitor development was 14 (min 1, max 75). Of 21 HB participants who met a study endpoint prior to enrollment, 3 (3/21 = 14%) developed an inhibitor, all with severe disease. The median EDs to inhibitor development was 9 (min 8, max 10).

Of the 234 eligible participants, 135 (135/234 = 58%) were on prophylactic treatment at any point. Of these, 33 (33/135 = 24%) received extended half-life (EHL) factor products (HA 20/114 = 17.5%; HB 13/21= 62%), while 14 (14/114 = 12%) with HA were receiving emicizumab. Over the course of the study, the rate of usage of emicizumab rose from 2% to 12% in participants with HA. Seventeen (17/39 = 44%) with HA were on prophylaxis at the time of inhibitor development, including 11 (11/39 = 28%) on standard half-life clotting factor, 1 (3%) on EHL clotting factor, and 0 on emicizumab. One participant with HB was on prophylaxis at the time of inhibitor development: none on standard half-life clotting factor, 1 (1/3 = 33%) on EHL clotting factor. Those who were on prophylaxis had decreased risk of confirmed inhibitor compared to those who were not (Odds ratio 0.24; 95% CI 0.09, 0.67).

89 participants with HA had F8 genetic testing completed, including 10 (11%) with large structural deletions. Large structural deletions were associated with higher inhibitor risk compared to other mutations in PUPs with HA at the time of inhibitor development (Odds Ratio = 5.32 vs. those with other mutations, 95% CI 1.27, 22.25). Race, ethnicity, birth cohort, and 5 or more consecutive EDs were not associated with inhibitor development.

Conclusion: In ATHN 8, inhibitor rates for PUPs with HA were consistent with published data and within the typical ED range. Prophylaxis appears to decrease the risk of inhibitor development. As expected, inhibitor development was associated with large structural deletions compared to other variant types in HA. Inhibitor occurrence was not associated with other traditional risk factors. For HB, the inhibitor rate was higher than most previous reports, which may be due to the small number of participants. For PUPs with HA, emicizumab prophylaxis increased over the course of the study period. These results support the use of prophylaxis as a prevention strategy for inhibitor development. Longitudinal follow-up is needed to determine if new treatment products (EHL clotting factor and emicizumab) are associated with changes in inhibitor rates or age at inhibitor development. Although ATHN 8 was closed to enrollment, PUPs will continue to be enrolled and followed in ATHN Transcends (NCT04398628), a natural history study including PUPs with hemophilia.

Carpenter:genentech: Honoraria. Guerrera:genentech: Consultancy; Hema Biologics: Consultancy; Kedrion: Consultancy; Novo Nordisk: Consultancy, Speakers Bureau; Biomarin: Speakers Bureau; Sanofi Genzyme: Speakers Bureau. Recht:Foundation for Women and Girls with Blood Disorders; Partners in Bleeding Disorders: Thrombosis and Hemostasis Societies of North America: Membership on an entity's Board of Directors or advisory committees; Bayer, Biomarin, CSL Behring, Genentech, Grifols, Hema Biologics, LFB, Novo Nordisk, Octapharma, Pfizer, Sanofi, Spark Therapeutics, Takeda, uniQure: Research Funding; Catalyst Biosciences, CSL Behring, Genentech, Grifols, Hema Biologics, Novo Nordisk, Pfizer, Sanofi, Takeda, uniQure: Consultancy; Oregon Health & Science University: Ended employment in the past 24 months; American Thrombosis and Hemostasis Network; Yale University School of Medicine: Current Employment. Sidonio, Jr.:Takeda: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Bayer: Honoraria; Novo Nordisk: Honoraria; Octapharma: Honoraria, Research Funding; Guardian Therapeutics: Honoraria; Pfizer: Honoraria; Biomarin: Honoraria; Spark: Honoraria; UniQure: Honoraria. Tarango:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Van den Berg:Takeda: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Octapharma: Consultancy, Research Funding; Biomarin: Consultancy; Tremeau Pharmaceuticals: Consultancy; Grifols: Consultancy; Guardian Therapeutics: Consultancy; Bayer: Consultancy; Novo Nordisk: Consultancy; Sanofi/Sanobi: Consultancy. Wang:BioMarin Pharmaceutical Inc.: Consultancy, Other: principal investigator; Bayer: Consultancy, Other: principal investigator; Bioverativ: Consultancy, Other: principal investigator; CSL Behring: Consultancy, Other: principal investigator; Novo Nordisk: Consultancy, Other: principal investigator; Genentech: Consultancy, Other: principal investigator; Takeda: Consultancy, Other: principal investigator; HEMA Biologics: Consultancy, Other: Clinical trial investigator; uniQure: Consultancy, Other: principal investigator; Pfizer/Spark: Consultancy, Other: principal investigator; Octapharma: Consultancy, Other: principal investigator. Thornburg:Biomarin Pharmaceuticals: Research Funding; Hema Biologics: Consultancy, Honoraria; Octapharma: Honoraria, Research Funding; Sanofi Genzyme: Consultancy, Honoraria; Cyclerion Therapeutics, Inc: Consultancy, Other: Data Safety Monitoring Board; Genentech: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BlueBird Bio: Consultancy, Other: Data Safety Monitoring Board.