Slide 1: EDIT-401: Transformative In Vivo CRISPR Gene Editing Approach to Lower LDL Cholesterol
EDIT-401: Transformative In Vivo CRISPR Gene Editing Approach to Lower LDL Cholesterol Jenny Xie, PhD Vice President, In Vivo Discovery Editas Medicine May 14, 2026
Slide 2: Editas' differentiated in vivo gene editing upregulation strategy
Editas’ differentiated in vivo gene editing upregulation strategy Functional Upregulation Other Differentiated use of CRISPR nuclease-based technology Approaches Edit Edit Coding Non-Coding, Regulatory • Treats diseases by Regions Regions increasing the level of disease mitigating Knockdown of prote
Slide 3: EDIT-401: A potential best-in-class, in vivo, gene editing medicine to reduce LDL-C
EDIT-401: A potential best-in-class, in vivo, gene editing medicine to reduce LDL-C Robust preclinical efficacy Potential one-time Compelling preclinical data data with a ≥90% mean treatment designed for supporting rapid progression to reduction of LDL-C1 lifelong benefit human proof-of-concept LDL-
Slide 4: Atherosclerotic cardiovascular disease is a serious disease with significant opportunity for a transformative therapy
Atherosclerotic cardiovascular disease is a serious disease with significant opportunity for a transformative therapy to reduce LDL-C ASCVD is driven by cholesterol-rich plaque accumulation in the arteries • ASCVD is the primary cause of morbidity and mortality globally, including in patients with h
Slide 5: Therapeutic strategy of LDLR upregulation for LDL-C reduction is informed by human genetics
Therapeutic strategy of LDLR upregulation for LDL-C reduction is informed by human genetics Seven Icelandic family members were identified as carriers of partial LDLR 3' UTR deletion1 Plasma LDL-C levels1 Impact on carriers1 3' UTR deletion carriers LDL-C: • 0.35–1.87 mmol/L (13–72 mg/dL) n = 101,85
Slide 6: CRISPR/Cas9 and dual gRNA-based strategy with LNP delivery creates a potent approach to LDLR upregulation
CRISPR/Cas9 and dual gRNA-based strategy with LNP delivery creates a potent approach to LDLR upregulation for LDL-C reduction Functional edits increase LDLR protein • CRISPR/Cas9 nuclease and dual expression and LDL-C uptake gRNAs disrupt negative regulatory elements in the 3' UTR, increasing LDLR p
Slide 7: Comprehensive in vitro screening of LDLR regulatory regions and editing cargos identified optimal strategy
Comprehensive in vitro screening of LDLR regulatory regions and editing cargos identified optimal therapeutic strategy Step 1: Identification of target region for Step 2: Identification of Region 3 lead guide pair for optimal LDLR protein increase LDLR protein increase based on potency LDLR protein
Slide 8: EDIT-401 achieved LDL-C reduction by LDLR upregulation in livers of NHPs
EDIT-401 achieved LDL-C reduction by LDLR upregulation in livers of NHPs EDIT-401: CRISPR/Cas9 mRNA, and dual gRNAs for LDLR upregulation encapsulated in a GalNAc LNP administered to NHPs EDIT-401 induces upregulation of LDLR in hepatocytes in livers of NHPs Vehicle control EDIT-401 Liver (20x) LDLR
Slide 9: EDIT-401 achieved >90% mean LDL-C reduction by upregulating LDLR
EDIT-401 achieved >90% mean LDL-C reduction by upregulating LDLR EDIT-401: CRISPR/Cas9 mRNA, and dual gRNAs for LDLR upregulation encapsulated in a GalNAc LNP administered to NHPs Single dose of EDIT-401 • >90% mean LDL-C reduction Vehicle (n=3) 1.5 mg/kg (n=3) 2 mg/kg (n=2) 3 mg/kg (n=2) 4 mg/kg (n
Slide 10: EDIT-401 displayed dose-dependent and durable LDL-C reduction
EDIT-401 displayed dose-dependent and durable LDL-C reduction EDIT-401: CRISPR/Cas9 mRNA, and dual gRNAs for LDLR upregulation encapsulated in a GalNAc LNP administered to NHPs Single dose of EDIT-401 Vehicle 1.0 mg/kg 1.5 mg/kg 2.0 mg/kg 3.0 mg/kg (n=4) (n=4) (n=8) (n=4) (n=4) 40 • Dose-dependent L
Slide 11: EDIT-401 enables increase in LDLR protein levels needed to achieve ≥90% LDL-C reduction in NHPs
EDIT-401 enables increase in LDLR protein levels needed to achieve ≥90% LDL-C reduction in NHPs LDL-C reduction correlated with LDLR protein upregulation (% change from baseline) 0 R2 = 0.8926 -20 • A ≥6-fold mean increase in -40 LDLR protein in liver resulted LDL-C -60 in ≥90% LDL-C reduction in NH
Slide 12: Therapeutic strategy requires only a moderate level of functional editing to demonstrate ≥90% LDL-C reduction
EDIT-401 therapeutic strategy requires only a moderate level of functional editing to demonstrate ≥90% LDL-C reduction in NHPs LDL-C reduction correlated with functional editing (% change from baseline) 0 R2 = 0.9436 -20 • Approximately 10%–40% functional editing can lead to -40 LDL-C the LDLR prote
Slide 13: Highest delivery of EDIT-401 observed in liver as compared to non-target tissues
Highest delivery of EDIT-401 observed in liver as compared to non-target tissues (assessed by editing levels) Single dose of EDIT-401 at 1.5 mg/kg, D29 Non-target tissue editing 25 Vehicle EDIT-401 1.5 mg/kg • Low editing detected in 20 adrenal gland, spleen and ovary of NHP Percent indel 15 • No si
Slide 14: EDIT-401 demonstrates high delivery in hepatocytes and undetectable cargo in oocytes
EDIT-401 demonstrates high delivery in hepatocytes and undetectable cargo in oocytes at therapeutically relevant dose of 1.5 mg/kg 24hr ISH 24hr IHC Day 29 IHC Liver (20x) Liver (20x) Cas9 mRNA Nuclei Cas9 Protein Nuclei Ovary (30x) * * oocyte oocyte LDLR Protein Nuclei Cas mRNA Detected by Positivi
Slide 15: Wild-type and Ldlr+/- mice have similar liver exposure and biomarker reduction upon EDIT-401(mu)
Wild-type and Ldlr+/- mice have similar liver exposure and biomarker reduction upon administration of EDIT-401(mu) Similar Cas9 mRNA liver exposure in WT and Similar dose correlation with LDL-C reduction Ldlr+/− mice in WT and Ldlr+/- mice 100 10000 WT 0.05 mg/kg WT WT 0.2 mg/kg Ldlr+/- WT 1.0 mg/kg
Slide 16: EDIT-401 murine surrogate achieved durable ≥90% mean LDL-C reduction in WT and Ldlr+/- mice
EDIT-401 murine surrogate achieved durable ≥90% mean LDL-C reduction in WT and Ldlr+/- mice with high baseline LDL-C WT and Ldlr+/− mice on high-fat diet administered a LDLR protein fold-regulation in liver single dose of EDIT-401 murine surrogate 500 WT vehicle 15 12x WT edited 400 Ldlr+/- vehicle
Slide 17: EDIT-401 differentiated mechanism of action to reduce LDL-C
EDIT-401 differentiated mechanism of action to reduce LDL-C EDIT-401 therapeutic strategy for LDLR upregulation • Disruption of negative regulatory elements of the LDLR gene increases the stability of the mRNA, enabling ≥6-fold increase in LDLR protein in preclinical models • This amplification appr
Slide 18: Summary and conclusions
Summary and conclusions • EDIT-401 combines Editas' drug development expertise and Genevant LNP to deliver a differentiated therapeutic strategy of functional LDLR upregulation • A single dose of EDIT-401 achieved ≥90% mean LDL-C reduction with ≥6-fold mean increase in LDLR protein in the NHP liver,
Slide 19: Acknowledgments
Acknowledgments Thank you to our research team and collaborators for their contributions • P Wrighton1 • M Thakkar1 • M Seth1 • HT Phan2 • J Newmark1 • L Agosto1 • E Kaye1 • N Chander2 • B Diner1 • MP Thompson1 • B Steward1 • M Kazemian2 • V Soman1 • P Amin1 • J Bochicchio1 • K Lam2 • A Apte1 • W Zh
Slide 20: Thank you!
Thank you! 20