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

Abstract

In the recent commentary by Pierce et al. titled ‘Gene therapy to cure haemophilia: Is robust scientific inquiry the missing factor?’,1 a group of national and international patient advocacy leaders laid out unanswered questions and uncertainties that remain for gene therapy in haemophilia. The authors called for more transparency from all those pursuing clinical trials, including meaningful research on the unanswered questions around safety, variability and durability of response. We agree with the premise of this article. Gene therapy will potentially provide people affected by haemophilia with the possibility to manage their disorder without regular factor infusions. Furthermore, it has the potential to improve treatment outcomes by reducing (subclinical) bleeding events while also offering potential improvements in the quality of patients’ lives. Despite this, there will be an undoubted need to pursue future work to address many of the clinical and academic unknowns. There are several efforts being undertaken to address the concerns raised in the article. As a proof point, a new consortium has been founded recently that aims to tackle a number of the very questions that Pierce et al. have raised. The IMI ARDAT (Accelerating Research and Development for Advanced Therapies) project,2,3 supported by the InnovativeMedicines Initiative (IMI) and led by Pfizer and the University of Sheffield, is a precompetitive €25.5 M 5-year public-private consortium that brings together the leading expertise of 34 academic, nonprofit, and private organizations, with the shared goal of helping to standardize and accelerate the development of advanced therapy medicinal products, with the aim of helping to bring these transformative treatments to patients sooner. The overarching goals of the ARDAT project are: (1) to develop improved standardized models for predicting product immunogenicity in humans, (2) to elucidate the molecular stability and metabolism of adeno-associatedvirus, including genome integration, and (3) tounderstand the clinical factors around preexisting immunity, as well as adaptive immune responses affecting product safety, efficacy, and persistence. Furthermore, engagement with regulators will ensure that the consortium-derived tools, methods, and data support regulatory harmonization and regulatory filings. Pierce et al. acknowledged that some uncertainty is unavoidable, and some questions cannot be fully answered prior to regulatory approval. As a consequence, the importance of long-term surveillance of those who receive gene therapy is paramount, and initiatives such as the World Federation of Hemophilia (WFH) Global Gene Therapy Registry are essential and will help to provide long-term clinical safety and efficacy data, while also addressing knowledge gaps. The WFH registry and initiatives like the ARDAT consortium demonstrate thevalueof collaborativeworkacrossmultiple stakeholders. This recognizes the importance of patients, clinicians, academia, industry, and regulators working together to address the unanswered questions and uncertainties highlighted by Pierce et al., andwill help to enable gene therapy to develop to its full potential.