Gene therapy shows promising results for hemophilia

In a packed auditorium with standing room-only audience, Glenn Pierce, MD, PhD, World Federation of Hemophilia (WFH) Medical Member gave a broad overview of gene therapy for hemophilia, including its history, the current state of the technology, and potential future developments. He started off by talking about the impact of various technologies on the treatment of hemophilia. “We’ve moved from on-demand to prophylactic treatment with ever-increasing durations (of efficacy), and now to 24/7 coverage with gene therapy and novel agents,” Pierce told the audience. “Gene therapy has redefined disruptive technology, resulting in outstanding companies losing their market share and the consequent competition between companies is intense. Therefore, caution is needed in the face of aggressive marketing campaigns.”

Pierce described the use of viral vectors to deliver genes into cells and discussed the main benefits and some of the drawbacks of the adeno-associated virus (AAV), the go-to vector for gene therapy. He went on to discuss two early-phase trials for gene therapy in hemophilia that have reported promising results. In the first trial, 10 male patients with hemophilia B and a high-specific-activity factor IX variant received gene transfer to date. Participants experienced sustained mean factor IX activity, a 96 per cent reduction in mean annualized bleeding rate (ABR), and a 99 per cent reduction in mean annualized infusion rate (AIR). In the second trial, nine male patients with severe hemophilia A experienced sustained and clinically relevant factor VIII activity levels 15 months following gene transfer. Furthermore, median ABR was reduced from 16.5 to 1.1, and mean AIR was reduced from 138.5 to zero.

Establishing an appropriate primary endpoint in pivotal gene therapy studies in hemophilia is also the subject of debate, with Pierce proposing that clotting factor activity is a more accurate and objective primary endpoint to evaluate efficacy, compared with ABR. This appears to be the viewpoint of the European Medicines Agency, but not the U.S. Food and Drug Administration.
Pierce discussed a framework for establishing a gene therapy knowledge base, including known unknowns, such as high variability of protein production and the consequences of integrating DNA into the genome.

As well as gene therapy, Pierce briefly touched upon gene editing and cell therapy, and showed data demonstrating the feasibility of these technologies. He added that disparities in access to treatment between developed and developing countries must be addressed.

Wrapping up his talk, Pierce stated, “Gene therapy is really exciting. Since 2015 we’ve seen therapeutic levels of factor IX and factor VIII being achieved in a small number of patients, and those levels have relieved them of their dependence on exogenous replacement therapy.” He emphasized the importance of continuing research in gene therapy, even once the technology is available in the clinic. “In gene therapy, we really need to continue research. There are far too many unanswered questions. We shouldn’t forget that this is an early technology.”

Mitch Semienchuk, Editor, Hemophilia World Online, wishes to thank Georghia Michael. PhD, for her contributions to this article.