PB0190 - Structural, functional and carcinogenicity as essential liver biomarkers for gene therapy of hemophilia A

Background: Hemophilia A is a rare congenital, monogenic, X-linked bleeding disorder caused by mutations in the gene for coagulation factor VIII (fVIII). Despite available treatments, patients may experience progressive joint disease due to repeated hemarthroses as well as the development of fVIII inhibitors, which may render replacement therapy ineffective. Therefore, hemophilia is an ideal candidate for gene therapy, targeting the hepatocyte as a fVIII biofactory, implying that the liver structure, function, and carcinogenicity must be thoroughly assessed.

Aims: ASC Therapeutics has developed a second-generation, highly potent and minimally sized vector (AAV8) containing a hepatic combinatorial bundle promoter, liver-specific codon optimization, and a highly-expressing bioengineered human fVIII transgene (ASC618). This cassette is 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 (reviewed in https://www.tandfonline.com/doi/full/10.1080/14712598.2022.2002842).

Methods: In a prospective clinical study (NCT04676048; IND-cleared by the FDA), the safety, tolerability, and preliminary efficacy of ASC618 will be assessed. In addition to safety and preliminary efficacy, sensitive, specific, and standardized biomarkers will be used to evaluate the relationship between them and ASC618. These biomarkers will include (1) structural biomarkers, such as fibroscan and ultrasound, to assess the structure of the liver, (2) functional biomarkers, such as standard circulating liver enzymes, Enhanced Liver Fibrosis, GRP78/BiP and microRNA and (3) carcinogenicity biomarkers, such as the GALAD index, Virscan, and cell-free DNA.

Results: The prospective clinical study will assess these biomarkers in hemophilia A patients.

Conclusion(s): The ASC618 gene therapy clinical program aims to evaluate overall safety with a focus on liver structure, function and carcinogenicity, with efficacy endpoints assessing its potential to provide durable therapeutic benefits, reduction of the treatment burden and significant improvement of quality of life of patients.