Establishing the appropriate primary endpoint in haemophilia gene therapy pivotal studies

Over the past decade, the annualized bleeding rate (ABR) has been used as the primary endpoint in prelicensure studies of new factor VIII and IX products. We propose that for gene therapy trials, clotting factor activity is a more accurate and objective primary endpoint to assess efficacy than ABR. This recommendation is timely, anticipating that several gene therapy programs are likely beginning discussions with regulatory agencies around the design of their Phase 3 pivotal trials. Although ABR has served the community well as a primary endpoint in protein replacement trials, where dosing regimens that manage peaks and troughs need to be established, we believe it is not the appropriate endpoint for future pivotal studies in haemophilia gene therapy. Treatment advances, such as gene therapy, bring the prospect of greater efficacy and improved outcomes for people living with haemophilia. ABR alone does not have the capacity or sensitivity to distinguish the improved outcomes and efficacy possible with gene therapies.1 As we move closer to achieving a cure for haemophilia, we need a drug evaluation standard that can directly measure the effect of the applied gene therapy. Factor VIII and factor IX activity levels have long been established as direct measures of severity of haemophilia (reviewed in Ref. 2). Factor levels are a direct manifestation of the gene defect, as they are directly linked to the pathophysiology of the disease. Patients with mild (>5%), moderate (1%-5%) and severe (<1%) disease have distinct and separable phenotypes based upon activity levels.3-5 These are measured by bleeding rates, severity of bleeding, severity of sequelae including joint damage and risk of mortality. The natural history of progressive crippling in haemophilia based on clotting factor levels is well established. While there is interlaboratory variability in the assays, the use of centralized testing in clinical studies obviates this concern.6, 7 ABR has a major subjective component, in that the patient or the physician needs to distinguish a bleeding episode from arthritic pain. False positive and false negative rates between the patient's perceptions of joint bleeding and arthritis compared with concurrent ultrasound evaluation are high.8 The current joint disease status of a patient is largely based on his treatment history and has a large influence on the accurate reporting of ABR. Recently, the FDA has affirmed its intention to focus more on outcomes important to patients. In Prescription Drug User Fee Act (PDUFA) V, FDA committed to a new initiative called Patient-Focused Drug Development with the goal of obtaining the patient perspective on certain disease areas during the 5-year period of PDUFA V. This information was deemed a critical aspect of decision making by the FDA as it establishes the context in which the regulatory decision is made.9, 10 Further, the National Hemophilia Foundation-McMaster treatment guidelines on care models for haemophilia specifically reviewed outcomes important to assessing care. Outcomes such as bleeding and bleeding rate were considered important, but judged not important enough to be included in the final list of patient important outcomes.11 Greater patient involvement can drive the development of innovative medicines that deliver more relevant and impactful patient outcomes.12 In 2016, for the first time, therapeutic levels of FVIII and FIX activity expected to abrogate all bleeding events were achieved through gene therapy.13, 14 The establishment, through in vivo delivery of the clotting factor gene, of long-term, normal or near-normal circulating clotting factor activity levels, absent the peaks and troughs of protein replacement therapy, has underlying scientific validity since breakthrough bleeding occurs more frequently as clotting factor levels approach troughs.15 Changing patients with severe or moderate disease to mild or normal phenotype makes ABR a useful secondary endpoint and clotting factor levels a more informative primary endpoint. The availability of a new gene delivery modality which abrogates peaks and troughs, frequent repeat infusions, adherence issues and permits assumption of a normal lifestyle are all important to establish as secondary endpoints. Success or failure of gene therapy studies should be based on the establishment of safety, and clotting factor activity as the primary endpoint. We call upon regulatory agencies to consider their scientific positions on this fundamental issue prior to the initiation of licensure studies. GFP is a consultant for BioMarin and St. Jude Children's Research Hospital. BOM has served on an advisory board for Freeline. SWP is a consultant for Dimension Therapeutics, uniQure and Bayer. MWS is a consultant for Spark and Bayer. All authors wrote and edited the paper.

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