BioMarin Presents Positive Safety and Efficacy Data for their Hemophilia A Gene Therapy

These data were presented by BioMarin at the American Society of Gene & Cell Therapy Virtual Meeting, which was held May 11-14, 2021

BioMarin recently reported key findings from preclinical studies of their investigational, gene therapy Roctavian (valoctocogene roxaparvovec), which was developed for the treatment of adults with severe hemophilia A. The findings were presented at the American Society of Gene & Cell Therapy (ASGCT) Virtual Meeting, which was held May 11-14, 2021.

Roctavian utilizes adeno-associated viruses (AAVs) as vectors to carry the genetic messaging that elicits production of the factor VIII (FVIII) protein that is deficient in people with hemophilia A. AAVs, which target the liver via a single intravenous injection, are designed to deliver this genetic material into living cells to sustained therapeutic effect.

Earlier studies have reflected substantial variability in the FVIII activity generated through treatment with Roctavian. Researchers therefore sought greater insights into the potential molecular-level factors contributing to these variations by studying responses to the therapy in mouse models.

The oral presentation, “Investigating Mechanisms of Variability of AAV5-hFVIII-SQ Expression in Mice,” described the study in which healthy male mice received a single dose of the therapy, which was delivered directly into the bloodstream. Investigators measured certain key markers including FVIII DNA, FVIII protein levels, and RNA – RNA is a molecule that acts as an intermediary, carrying  instructions from DNA for the production of proteins, including FVIII.

The authors explained that a significant correlation was found between the levels of liver AAV5 vector DNA and FVIII protein, suggesting vector uptake and processing in liver cells might “be an important contributing factor.”

Further, when higher doses of AAV5 were used, a strong correlation was observed between FVIII levels in the blood and levels of the liver Glucose-Regulated Protein (Grp78), a so-called chaperone protein responsible for folding and transporting other proteins out of cells. This suggests that “individuals who have a greater intrinsic ability to fold FVIII protein may secrete higher levels of mature protein into circulation,” explained the authors.

They also identified other elements that might impact FVIII gene expression including pre-dosing cholesterol levels, expression patterns of the AAV receptor, and DNA repair mechanisms.

A second research poster, “Rare Genomic Integrations of AAV5-hFVIII-SQ Occur Without Evidence of Clonal Activation or Gene-Specific Targeting,” shed light on potential safety concerns relevant to gene therapy, namely the permanent integration of the vector into the genome of recipients. This would represent an unintended outcome and raise concerns of therapy side- effects such as tumors or malignancies.

For this study, investigators collected liver samples and analyzed DNA from 12 male non-human primates, either 13- or 26- weeks post-treatment with Roctavian, which was administered at varying dose levels.

The results of their analysis were promising as 99.9% of the vectors used showed no signs of DNA integration. Further, these rare integration events occurred, on average, in less than one in 600 liver cells. According to the researchers, this frequency is in line with “expectations for AAV vectors and several orders of magnitude lower than the annual rate of natural mutations in humans.”

In addition, they found no evidence of cells with integrated DNA growing and expanding abnormally, “suggesting that individual integration sites were restricted to single cells or small groups of progeny cells.” Lastly, no pre-cancerous lesions, tumors, or malignancies were observed.

A third poster, “The Effect of Prophylactic Corticosteroid Treatment on Adeno-Associated Virus (AAV)-Mediated Gene Expression” suggested the potential utility of using corticosteroid hormone administration prior to gene therapy to prevent early, unwanted immune responses and promote AAV expression in mice.

“BioMarin is committed to furthering our scientific understanding of gene therapy through our experience developing valoctocogene roxaparvovec. This foundation of knowledge will help to inform the development of other gene therapies in our pipeline,” said Lon Cardon, PhD, Senior Vice President, Chief Scientific Strategy Officer at BioMarin. “The studies presented at ASGCT illustrate our continued quest to define who responds to treatment, why, and for how long. Vector catabolism remains the leading hypothesis as to why factor VIII expression evolves over time, highlighting pathways to improve patient outcomes.”

BioMarin is hoping to submit a marketing authorization application for Roctavian in the European Union in June 2021. The European Medicines Agency has already granted the company’s request for “accelerated assessment” of the therapy, ensuring a truncated review period. They also plan to submit a biologics license application in the U.S. as early as April 2022.

Source: Medical News Today, May 19, 2021

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