Metagenomi Therapeutics (MGX) 2024 Wells Fargo Healthcare Conference summary

Technology platform and differentiation

• Utilizes metagenomics to discover novel, highly efficient, and specific programmable nucleases with small size for versatile delivery.

• Expanded toolbox includes base editors, prime editors, and CRISPR-associated transposases for diverse gene editing applications.

• AI-driven protein engineering enhances activity and packaging of base editors, achieving up to 80% editing efficiency in AAV.

• RNA-mediated integration enables large, high-fidelity gene insertions, with demonstrated integration of up to 1,000 base pairs in human cells.

• Differentiation from first-generation CRISPR-Cas includes higher specificity, smaller enzyme size, and broader genome targetability.

Lead program in hemophilia A (Hem A)

• Lead candidate MGX-001 uses a two-component system: LNP-delivered nuclease and AAV-delivered donor DNA for targeted integration at albumin intron one.

• Non-human primate data show durable Factor VIII expression (9–82% of normal) maintained for 12 months, with plans to extend follow-up.

• Integration at a native promoter ensures persistent expression, addressing durability challenges seen in gene therapy like Roctavian.

• Lower AAV and LNP doses targeted for improved safety and commercial viability; enhancements in mRNA and protein design support this.

• IND-enabling studies are underway, with IND filing targeted for 2026 and positive initial FDA interactions reported.

Safety, variability, and clinical translation

• Durability study showed only moderate, transient transaminase elevations and no long-term safety concerns in primates.

• Variability in Factor VIII expression is present but less intra-subject variability than gene therapy; manufacturing and bioengineering improvements aim to reduce this.

• Wide therapeutic window in hemophilia A allows for functional cure even with expression variability.

• Dose response studies and further safety assessments planned for later in the year.