Haemophilia, state of the art and new therapeutic opportunities, a regulatory perspective

Abstract

Haemophilia A and B are rare bleeding disorders. Over the past decades, they have been transformed from debilitating diseases to manageable conditions in the Western world. However, optimizing haemophilia care remains challenging in developing countries. Several challenges and unmet needs remain in the treatment of the haemophilia limiting the QoL of patients. These challenges are now being addressed by extended half-life recombinant factors, rebalancing and substitution therapies. Gene therapy and genome editing show promise for a definite clinical cure. Here, we provide an overview of new therapeutic opportunities for haemophilia and their advances and limitations from a regulatory perspective. The database on human medicines from the European Medicines Agency (EMA) was used and data from rare disease (orphan) designations and EPARs were retrieved for the analysis. Clinical trial databases were used to query all active studies on haemophilia. Gene therapy medicinal products based on AAV and lentiviral vectors are in development and clinical trials have reported substantial success in ameliorating bleeding tendency in haemophilia patients. The prospect of gene editing for correction of the underlying mutation is on the horizon and has considerable potential. With regard to the benefit of the gene therapy medicinal products, more long-term efficacy and safety data are awaited. We are entering an era of innovation and abundance in treatment options for those affected by bleeding disorders, but issues remain about the affordability and accessibility to patients.

Keywords: gene therapy; haemophilia; marketing authorization; orphan designation; orphan drugs; rebalancing therapy; replacement therapy.

FIGURE 1

ODs for the treatment of haemophilia A and B (n = 41)

FIGURE 2

Haemophilia ‘active’ ODs classification according to MOA (n = 26)

FIGURE 3

Mechanisms of action of novel nonfactor therapeutics for haemophilia. Haemostatic nonfactor agents in varying phases of development include substitution therapies (Emicizumab) for FVIII, which can restore Factor Xa generation, and rebalancing therapies, which knock down or disrupt the natural anticoagulants (small interfering RNA to AT and PS, monoclonal antibodies to TFPI), to augment haemostasis