Metagenomi Therapeutics (MGX) Study Update summary

Program overview and study rationale

• MGX-001 is a gene editing therapy for Hemophilia A, aiming for a one-time curative treatment by integrating the Factor VIII gene into hepatocytes at a safe harbor site.

• The approach addresses limitations of AAV gene therapies, such as loss of expression and unsuitability for pediatric patients, by ensuring permanent gene integration and use of an endogenous promoter.

• The therapy is designed for both adults and children, with potential pharmacoeconomic and outpatient administration benefits.

• MGX-001 consists of an LNP delivering a novel nuclease and an AAV delivering the Factor VIII donor DNA template.

• The program is on track for an IND filing in 2026, with ongoing engagement with regulatory agencies and manufacturing preparations.

Preclinical study design and results

• In non-human primate studies, single intravenous doses of AAV and LNP delivered the FVIII donor template and nuclease, with liver biopsies assessing gene integration at Day 7.

• Durable Factor VIII expression was observed in all animals over 12 months, with levels of approximately 82%, 41%, and 9%, correlating with gene integration rates of 0.7% to 2.9%.

• Factor VIII activity remained consistent from 3–6 months to 9–12 months, supporting the potential for a lifelong cure.

• Safety data showed only moderate, transient transaminase elevations, no significant changes in albumin or bilirubin, and no adverse clinical observations; NHPs remained healthy with normal weight gain.

• The study used an older gene construct; the clinical candidate incorporates a bioengineered Factor VIII and improved nuclease for enhanced efficacy.

Optimization and future directions

• Key optimizations include a novel Type V CRISPR nuclease, mRNA sequence enhancements, guide RNA modifications, and a bioengineered B domain deleted Factor VIII construct.

• Safety measures include orthogonal specificity assays, liver-targeted LNPs, and codon optimization to minimize immunogenicity.

• Ongoing and planned studies include dose response in NHPs, long-term durability follow-up, and further engagement with hemophilia experts and advocacy groups.

• The platform may be leveraged for additional therapies targeting secreted protein disorders by swapping the gene of interest.

• Clinical development will start in adults, with pediatric studies planned as more data become available.