Type: Oral
Session: 322. Hemophilia A and B: Clinical and Epidemiological: Beyond Efficacy of Hemostatic Agents in Hemophilia: Exploring Pharmacokinetics, Dosing Regimens, and Special Populations
Hematology Disease Topics & Pathways:
Adult, Clinical trials, Research, Epidemiology, Clinical Research, Pediatric, Study Population, Human
Fitusiran, a subcutaneous investigational siRNA therapeutic, lowers antithrombin (AT) to increase thrombin generation and rebalance hemostasis in people with hemophilia A/B (PwHA/B), irrespective of inhibitor status. For PwHA/B receiving fitusiran, the bleed management guidelines (BMG) recommend reduced doses and frequencies of clotting factor concentrates (CFC) or bypassing agents (BPAs) to treat breakthrough bleeding. In three phase 3 trials of fitusiran, (ATLAS-INH [NCT03417102], ATLAS-A/B [NCT03417245], ATLAS-PPX [NCT03549871]), the majority of breakthrough bleeds were successfully managed with only one infusion of reduced dose CFC or BPA. This current analysis compared a subset of participants receiving the fitusiran antithrombin-based dosing regimen (AT-DR) in ATLAS-OLE (NCT03754790) to their previous CFC/BPA prophylaxis in the ATLAS-PPX study and reports on CFC/BPA utilization in this subgroup.
Methods
Analysis included males aged ≥12 years with severe hemophilia A or B, with or without inhibitors, who received ≥1 dose of fitusiran in ATLAS-PPX and then continued AT-DR in the ATLAS-OLE study. CFC/BPAs were used for the management of breakthrough bleeds during both periods and for SOC prophylaxis during the CFC/BPA period, with BPAs (activated prothrombin complex concentrate [aPCC] or recombinant activated factor VII [rFVIIa]) used to treat PwH with inhibitors, and FVIII and FIX CFC for PwH without inhibitors. Annualized weight-adjusted CFC/BPA consumption, number of treated bleeds, and infusions per bleed were assessed in the fitusiran efficacy period and in the CFC/BPA prophylaxis period.
Results
Data from 67 participants (PwHA, n=52; PwHB, n=15) receiving CFC/BPA prophylaxis and 69 participants (PwHA, n=52; PwHB, n=17) receiving fitusiran prophylaxis were included in the analysis. Overall in the participants receiving fitusiran prophylaxis, 33.3% of participants with inhibitors (Cohort A) and 66.7% without inhibitors (Cohort B) were enrolled. The AT-DR demonstrated a substantial reduction in mean annualized bleeding rate (ABR) versus BPA prophylaxis (70% reduction, p=0.0002) and was comparable with CFC prophylaxis (p=0.61). Annualized mean weight-adjusted consumption of CFCs and BPAs and number of infusions per breakthrough bleed were lower with fitusiran AT-DR versus CFC/BPA prophylaxis. The mean (SD) total weight-adjusted dose per bleed for participants without inhibitors and with inhibitors was reduced during fitusiran prophylaxis as compared to the CFC/BPA prophylaxis period (FVIII/FIX (45.3 [41.8] IU/kg and 73.6 [54.7] IU/kg, respectively) vs FVIII/FIX (12.0 [6.0] IU/kg and 22.3 [10.8] IU/kg, respectively) and aPCC/rFVIIa (207.8 [373.5] U/kg and 637.3 [1090.8] ug/kg, respectively during the BPA prophylaxis period versus 50.1 [32.2] U/kg and 86.5 [85.8] ug/kg. In order to treat a bleed while on fitusiran prophylaxis, participants without inhibitors required a median (Q1, Q3) of 1.0 (1.0, 1.0) infusions of reduced dose FVIII and FIX, whereas participants with inhibitors required 1.0 (1.0, 2.0) infusions of reduced dose aPCC and rFVIIa. Overall, participants required fewer infusions for the management of breakthrough bleeds with fitusiran AT-DR (with inhibitors=57, without inhibitors=148) versus those who received CFC (total=189) or BPA (total=465) prophylaxis.
Conclusion
Fitusiran prophylaxis was associated with a meaningful reduction in the number of infusions and substantially lower doses of CFCs/BPAs required to treat breakthrough bleeds as compared to SOC prophylaxis. Consumption was reduced on fitusiran based AT-DR. These results support the hemostatic capacity of fitusiran prophylaxis which led to a reduction in the number of bleeds and the amount of CFC/BPA required for the management of breakthrough bleeding events. These data further support the modeled factor equivalency of 20-40% in both PwHA and PwHB on fitusiran prophylaxis.
Disclosures: Pipe: Apcintex, ASC Therapeutics, Bayer, Be Bio, BioMarin, CSL Behring, HEMA Biologics, Freeline, LFB, Metagenomi, Novo Nordisk, Pfizer, Poseida Therapeutics, Precision Bioscience, Regeneron, Roche/Genentech, Sanofi, Takeda, Spark Therapeutics, UniQure: Consultancy; Siemens, YewSavin: Research Funding; Scientific Advisory Board GeneVentiv, Equilibra Bioscience: Membership on an entity's Board of Directors or advisory committees. Kavakli: BioMarin: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees. Matsushita: CSL: Honoraria; Pfizer: Consultancy; Novo Nordisk: Consultancy, Honoraria, Research Funding; Chugai: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Honoraria; Sysmex: Honoraria; Takeda: Consultancy, Honoraria; JB Pharma: Honoraria; KM Biologics: Honoraria; Sanofi: Honoraria. Tran: Sanofi, Takeda, Roche and CSL Behring: Other: Grants or contracts . Zulfikar: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; CSL Behring: Consultancy; Novo Nordisk: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy; Genveon: Consultancy; Shire, Roche, Sobi, Bayer and BioMarin: Consultancy, Membership on an entity's Board of Directors or advisory committees. Menapace: Sanofi: Current Employment, Current equity holder in publicly-traded company. Puurunen: Sanofi: Current Employment, Current equity holder in publicly-traded company. Hu: Sanofi: Current Employment, Current equity holder in publicly-traded company. Shen: Sanofi: Current Employment, Current equity holder in publicly-traded company. Kaddi: Sanofi: Current Employment, Current equity holder in publicly-traded company. Salinas: Shire, Biogen, Genentech, Bayer, Pfizer and CSL Behring: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biomarin, Sanofi, Bayer and Genentech: Speakers Bureau.