(MED-TH-07.2) Non-factor replacement

The development of factor replacement therapy (FRT) in the management of haemophilia has been remarkable, marked by the evolution of the therapeutic landscape from blood and blood products to plasma-derived concentrates, recombinant concentrates, and, more recently, recombinant products with improved pharmacokinetics (extended half-life products). However, FRT has several unmet needs, including 1) a high treatment burden (due to the necessity for intravenous administration), 2) unfavourable pharmacokinetics of replacement therapy (peaks and troughs), 3) immunogenicity (with inhibitor prevalence of up to 30% in haemophilia A and 11% in haemophilia B), 4) inadequate bleed protection (only one-third of patients receiving factor replacement prophylaxis achieve zero bleeds), and 5) deteriorating musculoskeletal outcomes (largely due to breakthrough bleeds). Non-factor therapies (NFTs) were developed to address these unmet needs. The NFTs developed to date include anti-activated protein C, anti-tissue factor pathway inhibitors, anti-thrombin therapy, and factor FVIII mimetics. Several NFTs have completed phase 3 clinical trials. Using data from these trials, we describe how non-factor therapies may be able to fulfil the unmet needs of factor replacement therapy. The potential impact of NFTs includes a significant reduction in treatment burden (all NFTs are administered subcutaneously), steady-state haemostasis (no peaks and troughs in the pharmacokinetics of NFTs), improvements in zero bleed rates (many NFTs boast zero bleed rates of over 50%), and very low annual bleed rates (many NFTs have a median yearly bleed rate of zero). Ongoing analyses of NFT data suggest that these improvements translate into enhanced quality of life and better musculoskeletal outcomes for individuals with haemophilia. Therefore, NFTs may represent the optimal care for haemophilia.