PB0662 - Clinical Study of Adenovirus-Associated Viral Vector-Mediated Gene Therapy of Human Factor VIII in Severe and Moderately Severe Hemophilia A

Background: Hemophilia A is a rare congenital, monogenic, X-linked bleeding disorder caused by mutations in the coagulation factor VIII (fVIII) gene. Standard of care for hemophilia A includes prophylactic fVIII replacement therapy primarily using plasma-based or recombinant fVIII concentrates as an intravenous (IV) bolus or as treatment for bleeding episodes. Despite treatments available, patients may experience progressive joint disease due to repeated hemarthroses as well as the development of fVIII inhibitors, that render replacement therapy ineffective. As hemophilia has a well-known genetic background, it became an ideal target for gene therapy.

Aims: ASC Therapeutics has developed ASC618, a highly potent and minimally sized vector containing a hepatic combinatorial bundle promoter, liver-specific codon optimization, and a highly expressing bioengineered human fVIII (ET3) transgene, designed to express fVIII protein for the treatment of patients with severe and moderately severe hemophilia A, potentially providing a long-term solution or even functional cure for people living with this disease (Pipe, 2021; https://www.tandfonline.com/doi/full/10.1080/14712598.2022.2002842).

Methods: In the prospective clinical study (NCT04676048; https://www.asctherapeutics.com/en/company-news/asc-therapeutics-receives-ind-clearance-from-the-u-s-food-and-drug-administration-for-asc618-second-generation-gene-therapy-for-hemophilia-a/), the safety, tolerability and preliminary efficacy of ASC618 will be assessed (see Figure 1). The decision of dose escalation vs. dose expansion in each cohort will be based on fVIII levels and safety evaluations such as Liver Function Tests, enzyme-linked immunospot (ELISpot), bleeding episodes and AEs. Following the infusion, patients will be closely monitored for fVIII levels and ALT/AST for up to 5 years post-infusion

Results: Preclinical work demonstrated that in the C57Bl/6 murine model, the cynomolgus monkey, and the humanized liver mouse model (FRG-KO), ASC618 was well tolerated at all doses evaluated with no toxicologically significant microscopic findings (Veselinovic 2020).

Conclusion(s): ASC618 will be evaluated in this clinical program for its potential to provide durable therapeutic benefit, reduce treatment burden on patients and significantly improve their quality of life.