Mim8 Prophylaxis Beyond Bleeding: Investigating Multifaceted, Patient-Reported Outcomes for Hemophilia A in the FRONTIER2 Study

Introduction

Beyond hemostatic efficacy, patient-reported outcomes (PROs) appear critical for evaluating patient experience and disease burden with new hemophilia treatments. Mim8 (denecimig) is a factor VIIIa mimetic bispecific antibody in development for subcutaneous prophylaxis (PPX) of hemophilia A (HA) and HA with inhibitors (HAwI). In the phase 3 FRONTIER2 study (NCT05053139), Mim8 demonstrated hemostatic efficacy by reducing annualized bleeding rate (ABR) for treated bleeds compared with on-demand treatment and vs previous clotting factor concentrate (CFC) PPX (Mancuso et al. ISTH 2024; LB01.5).

Aims

To investigate Mim8 once every week (QW) and once every month (QM) PPX for PROs assessing patient physical functioning, treatment burden and joint pain intensity.

Methods

FRONTIER2 is an open-label, randomized controlled study for male and female patients (aged ≥12 years) with HA/HAwI of any severity. Patients receiving on-demand treatment before enrollment were randomized to continued on-demand treatment or Mim8 PPX QW or QM for 26 weeks. Patients on CFC PPX continued PPX for 26 weeks and were then randomized to Mim8 PPX QW or QM for 26 weeks. The following PROs were prespecified secondary outcomes: physical function domain of the Pediatric Quality of Life Inventory™ (PedsQL; 0-100, higher domain scores denote better physical functioning), Hemophilia Treatment Experience Measure (Hemo-TEM; 0-100, lower scores denote less treatment burden) and Joint Pain Rating Scale (JPRS; 1-10, lower scores denote less intense pain). Supportive PROs included the Hemophilia Patient Preference Questionnaire (HPPQ) and Patient Global Impression (PGI) scales: Change in Pain Intensity, and Severity and Change in Physical Function. Data are reported as mean [SD] scores at baseline (randomization) and mean [SD] change from baseline scores at Week 26. A post hoc ANCOVA model was used to analyze changes from baseline to Week 26 for prior on-demand arms, with treatment, inhibitor status and historical ABR as factors and baseline as a covariate. Estimated treatment differences (ETD) and p-values are provided for two-sided 2.5% tests of no difference.

Results

Of 254 randomized patients (17, 21 and 20 in prior on-demand arms and 98 in each prior CFC PPX arm), 246 completed 26-week treatment. Overall 26% were adolescents, 2% female and 83% had severe HA. HAwI patients represented 47% of prior on-demand arms and 2% of prior CFC PPX arms.

Physical functioning (PedsQL) baseline scores for prior on-demand arms were 50.5 [18.6] to 59.2 [22.2]. Scores increased with Mim8 PPX (Mim8 QW 14.2 [22.0], Mim8 QM 20.8 [20.3]) and decreased with on demand (−5.5 [17.8]). ETD (95% CI) vs on demand was 19.9 (4.9, 34.9; p=0.0108) for Mim8 QW and 27.3 (12.6, 41.9; p=0.0006) for Mim8 QM. Baseline scores for prior CFC PPX arms were 71.8 [21.1] and 75.2 [21.5] and increased with Mim8 QW (1.9 [13.1]) and Mim8 QM (2.1 [10.1]).

Treatment burden (Hemo-TEM) baseline scores were 29.0 [19.4] for the on-demand arm and 15.3 [12.4] to 18.4 [15.6] for Mim8 arms. Scores for prior on-demand arms decreased by −9.9 [13.4] with Mim8 QW, −11.2 [11.6] with Mim8 QM and −2.2 [14.1] with on demand. ETD (95% CI) vs on demand was −13.0 (−20.2, −5.8; p=0.0009) for Mim8 QW and −16.6 (−23.8, −9.4; p<0.0001) for Mim8 QM. Prior CFC PPX arms had decreases of −10.8 [15.5] with Mim8 QW and −10.0 [10.5] with Mim8 QM. Clinically meaningful score decreases (≥8 points) were reported for 33% (on demand), 38% (Mim8 QW) and 60% (Mim8 QM), and in prior CFC PPX arms for 49% (Mim8 QW) and 48% (Mim8 QM) of patients.

Joint pain intensity (JPRS) baseline scores were 5.0 [2.4] for the on-demand arm and 2.8 [2.5] to 3.1 [2.4] for Mim8 arms. Scores for prior on-demand arms decreased by −0.5 [3.4] for Mim8 QW, −1.8 [2.8] for Mim8 QM and −0.8 [2.4] for on demand; decreases for prior CFC PPX arms were −0.1 [2.4] for Mim8 QW and −0.3 [1.9] for Mim8 QM.

Similar improvements were reported with Mim8 for all PGI scales. HPPQ scores showed a strong patient preference for Mim8.

Conclusion

Mim8 PPX improved physical functioning and reduced treatment burden compared with on-demand treatment and baseline. Among patients previously receiving CFC PPX, physical functioning improved to a lesser extent. Joint pain intensity was not severe at baseline in all arms and did not change notably with Mim8 PPX. These findings demonstrate the holistic benefits of Mim8 beyond bleed protection and provide insights into opportunities for individualized care.

Hermans:LFB: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novo Nordisk: Consultancy, Honoraria; Sobi: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria; Regeneron: Consultancy, Honoraria; BioMarin: Consultancy, Honoraria; CSL Behring: Consultancy, Honoraria; Octapharma: Consultancy, Honoraria. Ay:BMS, Pfizer, Daiichi-Sankyo, Bayer, Sanofi, Novo Nordisk, CSL Behring, Sobi, Roche: Honoraria, Speakers Bureau. Escuriola:Biotest: Consultancy, Honoraria, Other: Travel; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Sobi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Roche/Chugai: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Octapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; LFB: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; CSL Behring: Consultancy, Honoraria, Other: Travel; BioMarin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel; Bayer Healthcare: Consultancy, Honoraria, Other: Travel. Kampmann:AbbVie, Novo Nordisk, Roche, Takeda: Consultancy; CSL Behring, BioMarin, Novo Nordisk: Other: Advisory Boards; AbbVie, Bayer, BioMarin, CSL Behring, Novo Nordisk, Sobi: Other: Speaker fees; BioMarin: Speakers Bureau. Medom Meldgaard:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company. Rakhmatullin:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company. van Vulpen:Novo Nordisk: Research Funding; Griffols: Research Funding. Wang:BioMarin, Sanofi, CSL Behring, Genentech, Hema Biologics, Takeda, Vega Therapeutics: Consultancy; ApcinteX, Bayer, Be Biopharma, BioMarin, CSL Behring, Genentech, Novo Nordisk, Pfizer, Regeneron, Vega Therapeutics, Takeda: Other: Sponsored research studies. Susen:Lille University: Current Employment; BioMarin, Bioverativ, CSL Behring, CorWave, Roche-Chugai, Sanofi, Shire/Takeda, Siemens Healthineers, Sobi, Stago, LFB: Other: Research Support/P.I.; BioMarin, LFB, Sanofi, Sobi: Consultancy; BioMarin, CSL Behring, LFB, Roche, Novo Nordisk, Sanofi, Sobi, Takeda: Other: Scientific Advisory Board.

Mim8 is an investigational drug, currently being evaluated in phase 3 clinical trials for the management of hemophilia A with and without inhibitors, and is not yet approved in any country worldwide.