MICA: An open label dose-escalation study of a novel adeno-associated viral vector for gene transfer in subjects with haemophilia A

Haemophilia A is a bleeding disease in males due to very low levels of coagulation factor VIII (FVIII) in the blood. The major effect on health in severely affected patients is spontaneous (in the absence of trauma or injury) repeated bleeds into joints like the knee, hip, ankles and elbows, cause joint damage and chronic disability. Rarely, the disease causes death due to bleeding into the brain or other important organs. The current treatment is intravenous injection of FVIII clotting factor protein concentrates, in response to bleeding. Regular injection of FVIII clotting factor protein concentrates three times a week prevents spontaneous bleeds and joint damage. This study plans to use a virus called adeno-associated virus (AAV), which in nature causes no disease, and can be engineered to deliver the human FVIII gene (AAV8-HLP-codop-hFVIII-V3) to the liver, where FVIII is normally made. We have recently used this type of AAV vector for gene therapy of haemophilia B, a related condition with identical clinical manifestation, except that it arises because of low levels of a different protein called factor IX. In this study stable expression of FIX at levels 1-6% of normal were observed in all 10 participants without long lasting toxicity, resulting in significant patient benefit. Following extensive preclinical studies, a single dose of AAV vector containing a novel more potent human clotting factor VIII variant (AAV8-HLP-codop-hFVIII-V3) will be administered into a peripheral vein of adult patients with severe Haemophilia A. We propose to test three dose levels: 2e11, 6e11 and 2e12 vector genomes per kg body weight, which is the same dose range tested in the Haemophilia B clinical trial. The main objective will be to establish the safety and to do so we have established a comprehensive monitoring plan which includes an array of clinical and laboratory tests. Enrolment of each subject will proceed only after the previous subject has been observed for at least 28 days for acute toxicity. Enrolment will be suspended if serious adverse toxicity is observed in one subject. The other objective is to determine the dose of vector that results in expression of FVIII at more than 5% in peripheral blood. This level of expression can significantly reduce the frequency of severe bleeding episodes. The reason why human studies are critical is because our haemophilia B gene therapy trial, as well as other gene therapy studies in the field, have shown that animal models are poor predictors of outcome in humans. Successful Haemophilia A gene therapy will transform the treatment paradigm for this disease and will also support the development of gene therapy for other diseases affecting the liver including lysosomal storage disorders and hepatocellular carcinoma.