Three experts on gene therapy in hemophilia presented during the final session on day one of the 10th World Federation of Hemophilia Global Forum held in Montreal on November 7, 2017. The session, Unmet needs and unfinished business in gene therapy, was chaired by David Lillicrap, MD.
Known knowns and known unknowns on the path to a cure
The focus of the presentation by Glenn Pierce, MD, PhD was gene therapy as a long-term solution for hemophilia. Pierce gave an overview of the implications for efficacy, safety, and success for this rather complex technique. Although therapeutic levels of factor VIII (FVIII) and factor IX (FIX) have been achieved in early-stage clinical trials, good manufacturing practice is lacking and a great deal of work is needed before these products can be commercialized. Pierce reiterated the importance of thorough research to address known knowns, such as vector integration into the liver and acute subclinical liver toxicity, and to address known unknowns, such as long-term efficacy, safety, and the consequences of integration. Pierce concluded that research into gene therapy should not stop with the initiation of clinical trials.
How to judge the efficacy of gene therapy trials
In her presentation, Marijke van den Berg, MD, PhD, said that gene therapy is within reach and is expected to deliver a cure for hemophilia A and B in the near future. Sustainable FVIII and FIX levels (>10%) have been reached, and the impact on annual bleeding rate is dependent on joint status at the start of gene therapy. Van den Berg discussed the most appropriate outcomes for gene therapy trials. Primary outcomes should reflect clotting factor activity measured as sustainable levels (>5%) of FVIII and FIX. Important secondary outcomes are annual bleeding rate, factor usage, and health-related quality of life.
Gene therapy in the developing world
Alok Srivastava, MD, drew on examples of hematopoietic stem cell transplantation for thalassemia major to describe a cost-compatible gene therapy solution for people with hemophilia in developing countries. Srivastava also described the adeno-associated virus (AAV)-based gene therapy trial ongoing in India with collaborations in the U.S.A., and the strategies used to improve factor protein expression. He emphasized the importance of collaborations with regulatory reviewers and also patient groups to increase awareness and share information on gene therapy. Srivastava said that a gene therapy for hemophilia may be just a few years away, but that there is always room for improvement, such as the possibility of using lentivirus vector gene therapy to overcome the obstacles associated with AAV technology.