PB1315 - Weight-band dosing with Mim8: using modelling to support a streamlined approach to haemophilia A treatment

Background: Mim8 is a novel, next-generation FVIIIa mimetic bispecific antibody in Phase 3 development for subcutaneous treatment of haemophilia A with/without FVIII inhibitors. Currently marketed haemophilia treatments require dose calculations based on body weight (BW) and vial strength, with potential for wastage. Mim8 has a long half-life, wide target exposure range and limited inter-individual variability, suggesting suitability for a simplified weight-band dosing approach.

Aims: To predict safety and efficacy of Mim8 using a weight-band dosing strategy in a population ranging from children to adults, using pharmacokinetic/pharmacodynamic (PK/PD) modelling.

Methods: Population PK and PK/PD models for treated bleeds were developed using data from 129 participants (healthy or with haemophilia A) exposed to Mim8 in Phase 1/2 studies, with baseline BW as the most significant covariate for exposure. Virtual paediatric and adult/adolescent Phase 3 populations were generated (mean BW, kg: 30 and 77). To optimise doses and weight-bands, trial simulations were run with a variety of ranges, to ensure ≥95% reduction in relative bleed risk from baseline and sustained maximum exposure below the exposure cap defined in Phase 1/2 studies. Individual typical PK and bleed risk profiles were simulated ensuring all weights within the bands would be covered by the pre-defined criteria.

Results: Based on PK/PD simulations, five dose presentations cover an optimised matrix of three dosing regimens and three weight-bands (Table).
The median, upper 95th percentile of the virtual population, and all individual typical PK profiles were predicted to be < 18 µg/mL (average plasma concentration: 5–7 µg/mL), across all dosing regimens (Figure). A >97% relative reduction in bleed risk from baseline was predicted for all regimens.

Conclusion(s): Based on the optimised weight-bands and dosing regimens, population PK and PK/PD simulations suggest maintenance of Mim8 target exposure levels, with a high reduction in bleed risk for all BWs and regimens used in Mim8 Phase 3 studies.