Uncertainty in an era of transformative therapy for haemophilia: Addressing the unknowns

Abstract

Haemophilia is at the dawn of a new era in therapeutic management, one that can generate greater protection from bleeding and a functional cure in some individuals. Prior advances in protein engineering and monoclonal antibody technology have facilitated therapeutic options to maintain decreased risk of bleeding and less burdensome treatment. The use of gene transfer, first proposed in 1971 for monogenic diseases, is emerging as an effective long‐term treatment for a variety of diseases. Transfer of functional factor VIII (FVIII) and factor IX (FIX) genes has witnessed a series of advances and setbacks since the first non‐clinical experiments in animals were initiated nearly 30 years ago. More recently, multiyear therapeutic levels of FVIII and FIX activity have been achieved in human clinical trials, translated into meaningful clinical benefit and a functional cure. While clinical progress has been definitive, many questions remain unanswered as prelicensure phase 3 clinical trials are underway. These unanswered questions translate into a state of uncertainty about the known unknowns and unknown unknowns intrinsic to any new therapeutic platform. Accepting this modality as a means to functionally cure haemophilia also means accepting the uncertainty regarding the biology of viral vector‐mediated gene transfer, which remains inadequately understood. Gene therapy is a far more complex biological ‘drug’ than small molecule and protein drugs, where manufacturing processes and the drugs themselves are now well characterized. Extent of community acceptance of uncertainty and acknowledgement of the need for an uncompromising drive for answers to the unknowns will characterize the introduction of this first generation of gene therapy for haemophilia to the wider patient population in both resource‐rich and resource‐poor countries.

Reimbursing the value of gene therapy care in an era of uncertainty

“…A new disruptive technology for the treatment for haemophilia is near 34‐36 . This innovation should be rewarded, but not at the cost of limiting access and speed of access to these treatments.…”

Impact of humanitarian aid linked prophylaxis in Côte d'Ivoire (Ivory Coast)

“…14 positive incremental progress measured year over year, both globally and within countries. 1,[15][16][17][18] Over the long term, some form of genetic therapy may be a likely successor to the humanitarian aid programme, 19 and may result in a cure or partial cure to alleviate the misery and death of severe and severely moderate haemophilia in resource constrained countries.…”

“…Over the long term, some form of genetic therapy may be a likely successor to the humanitarian aid programme, 19 and may result in a cure or partial cure to alleviate the misery and death of severe and severely moderate haemophilia in resource constrained countries. Much work is required on the technology and advocacy fronts before this vision becomes reality.…”

Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor?

“…8 These issues demostrate that the knowledge of the biology of AAV gene therapy has not kept pace with advancing clinical studies. 2 We ask, do we have a safe, reliable product to give us the sustained cure we are awaiting? Perhaps, not quite.…”

“…From our earliest memories, we, all men born with severe haemophilia, have dreamed of a cure. We witnessed many false starts beginning in the 1990s through the 2000s 2 until the first hint of effectively ameliorating our phenotypes appeared 3 . Development of the FIX Padua mutation, offering fivefold to sevenfold higher specific activity, and recent FVIII trials have allowed the possibility that the severe haemophilic phenotype really could be changed to mild or even normal 4,5 …”