From efficacy to experience: 52-week patient-reported outcomes with Mim8 in adolescents and adults with hemophilia A with or without inhibitors (FRONTIER2)

Abstract

Abstract Introduction Mim8 is a new-generation, bispecific antibody, activated factor VIII mimetic in clinical development for subcutaneous prophylaxis (PPX) in hemophilia A (HA) with or without factor VIII inhibitors. The phase 3 FRONTIER2 study (NCT05053139) demonstrated that Mim8 once every week (QW) or once every month (QM) significantly reduced the annualized bleeding rate for treated bleeds compared with continued on-demand treatment or previous clotting factor concentrate (CFC) PPX. Improvements in patient-reported outcomes (PROs) were observed during the 26-week main phase.Objective Assess PROs with Mim8 PPX over 52 weeks.Methods FRONTIER2 is an open-label, randomized trial in patients aged ≥12 years with HA, with or without inhibitors. Participants receiving on-demand treatment before the study were randomized to Mim8 PPX QW (Arm 2a) or QM (Arm 2b) for 52 weeks (main + extension), or to continue on-demand treatment (Arm 1) for 26 weeks (main) then switch to Mim8 QW or QM for another 26 weeks (extension). Participants on prior CFC PPX were randomized to Mim8 QW (Arm 3) or QM (Arm 4) for 52 weeks (main + extension). PROs were assessed at baseline, Week 26, and Week 52 using three instruments: the Hemophilia Treatment Experience Measure (Hemo-TEM; range 0–100; lower scores indicate lower burden, ≥8-point reduction defined as clinically meaningful improvement), the physical functioning domain of the Pediatric Quality of Life Inventory (PedsQL; range 0–100; higher scores indicate better functioning), and the Joint Pain Rating Scale (JPRS; range 0–10; lower scores indicate less pain). Additionally, the Patient Global Impression of Change (PGI-C) for pain and physical function and the Hemophilia Patient Preference Questionnaire (HPPQ) were assessed at Week 26 and Week 52. Changes were calculated from the start of Mim8 PPX (Week 0 for Arms 2a/2b/3/4; Week 26 for Arm 1).Results Comparable PRO results were observed across QW and QM dosing; therefore, results were pooled by previous treatment (Arm 1, Arms 2a/2b, Arms 3/4). A total of 281 participants were included in the full analysis set. Mean age was 32 (Arm 1), 32 (Arm 2a/2b), and 31 years (Arms 3/4). Most participants were male (99%) and weighed ≥45 kg (94%). This report includes 27 patients from China (Arm 1, n=1; Arms 2a/2b, n=2; Arms 3/4, n=24) absent from the prior 26-week abstract (Mancuso et al. ISTH 2024; LB01.5). At Week 52, mean changes in Hemo-TEM total scores from baseline were –16.0 in Arm 1 (n=13), –12.7 in Arms 2a/2b (n=29), and –9.7 in Arms 3/4 (n=182). Clinically meaningful improvement was achieved by 8/13 (62%), 16/29 (55%), and 84/182 (46%) respectively. At Week 52, a fairly strong or very strong preference for Mim8 over previous treatment was reported by 15/17 (88%) of participants in Arm 1, 39/40 (98%) in Arms 2a/2b, and 175/192 (91%) in Arms 3/4 as assessed by HPPQ. Mean changes in PedsQL physical function scores were +13.0 in Arm 1 (n=13), +17.6 in Arms 2a/2b (n=29), and +4.0 in Arms 3/4 (n=167). Improvements in PGI-C physical function were reported by 17/17 (100%) of participants in Arm 1, 36/40 (90%) in Arms 2a/2b, and 138/192 (72%) in Arms 3/4. Mean changes in JPRS joint pain scores were –1.8 in Arm 1 (n=13), –1.5 in Arms 2a/2b (n=29), and –0.4 in Arms 3/4 (n=184). Improvements in PGI-C pain intensity were reported by 15/17 (88%) of participants in Arm 1, 38/40 (95%) in Arms 2a/2b, and 115/192 (60%) in Arms 3/4.Discussion/Conclusion Mim8 PPX was associated with improvements across all assessed PROs over 52 weeks, including reduced treatment burden, improved physical function, decreased joint pain, and strong treatment preference. These findings are consistent with Week 26 results, indicating sustained patient-perceived benefits with continued Mim8 use. PROs were comparable between QW and QM dosing, supporting the flexibility of Mim8 tiered dosing. In Arms 3/4, the smaller magnitude of change may reflect a ceiling effect among participants on PPX at baseline. Patient preference data were highly favorable, including among participants already receiving PPX. These results support the long-term benefit of Mim8 in HA treatment, extending beyond bleed control. Consistent PRO improvements and strong patient preference highlight the potential for Mim8 to enhance the treatment experience and quality of life.