Intellia Therapeutics, Inc. · NASDAQ:NTLA

Intellia Therapeutics — Technical Presentation (May 2019)

14 slides from Intellia Therapeutics's technical presentation, May 2, 2019

  1. Slide 1: CRISPR/Cas9-Mediated Gene Knockout to Address Primary Hyperoxaluria

    CRISPR/Cas9-Mediated Gene Knockout to Address Primary Hyperoxaluria Anette Hübner, Ph.D. American Society of Gene and Cell Therapy 22nd Annual Meeting May 2, 2019 1 Disclosure: Employee of Intellia Therapeutics, Inc.

  2. Slide 2: Intellia Therapeutics’ Legal Disclaimer

    Intellia Therapeutics’ Legal Disclaimer This presentation contains “forward-looking statements” of Intellia Therapeutics, Inc. (“Intellia”) within the meaning of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, but are not limited to, express or implied

  3. Slide 3: Intellia's Modular Non-Viral Delivery of CRISPR/Cas9 Addresses Disease at the Genetic Level

    Intellia's Modular Non-Viral Delivery of CRISPR/Cas9 Addresses Disease at the Genetic Level Lipid Nanoparticles (LNPs) Key Advantages of LNP Delivery • Large cargo capacity for CRISPR/Cas9 AAAA Ldha gRNA • Transient expression Cas9 mRNA Cas9 • Scalable synthetic manufacturing Hao1 gRNA • Redosing ca

  4. Slide 4: Renal Failure and Systemic Disease Often Result from Oxalate Overproduction Associated with PH1

    Renal Failure and Systemic Disease1 Often Result from Oxalate Overproduction Associated with Primary Hyperoxaluria Type 1 (PH1) Retinal Oxalosis Primary Hyperoxaluria Type 1 (PH1) Cardiomyopathy Rare disease with prevalence of ~1-3 per million;1 Potentially ~1,000 patients in U.S.* Nephrocalcinosis

  5. Slide 5: In People with PH1, Surplus Oxalate Combines with Calcium to Form Insoluble Deposits

    In People with PH1, the Production of Surplus Oxalate Combines with Calcium to Form Insoluble Deposits AGXT AGXT mutations produce nonfunctional AGT protein Oxalate 1 over- 2 production HAO1 LDHA Kidney Stones Potential to treat PH1 with either: 1. CRISPR/Cas9-mediated knockout of LDHA* or 2. CRISPR

  6. Slide 6: CRISPR-Mediated Knockout of LDHA Disrupts LDHA Protein Production

    CRISPR-Mediated Knockout of LDHA Disrupts LDHA Protein Production Oxalate regulated LDHA Oxalate levels are reduced upon LDHA knockout Treatment Hypothesis 1 for PH1 Patient* 6 *Graphic depicts CRISPR-mediated LDHA knockout in PH1 patient only, although this treatment approach addresses all three fo

  7. Slide 7: In Vivo Ldha Gene Editing Levels Correlate with Urinary Oxalate Decrease in PH1 Mouse Model

    In Vivo Ldha Gene Editing Levels Following Single Dose of CRISPR/Cas9 LNPs Correlate with Urinary Oxalate Decrease in PH1 Mouse Model1 Increased Editing and Reduction in Lead Guide2 Achieved Robust Editing Urinary Oxalate Are Dose-Responsive3 Control 0.25 mg/kg 0.5 mg/kg 1 mg/kg R² = 0.93 2 mg/kg 7

  8. Slide 8: 63% Oxalate Reduction Sustained for At Least 15 Weeks Following Single Dose

    63% Oxalate Reduction Sustained for at Least 15 Weeks, Following Single Dose of CRISPR/Cas9 LNPs at 1 mg/kg in PH1 Mouse Model Ldha Knockout Results in Sustained Oxalate Reduction Therapeutic range (>30% oxalate reduction)1 Normal range (wildtype mouse) (80 - 122 ug oxalate / mg creatinine)2 8 1Neph

  9. Slide 9: CRISPR-Mediated Knockout of Ldha Reduces LDHA Protein Production; Effect Sustained 15 Weeks

    CRISPR-Mediated Knockout of Ldha Reduces LDHA Protein Production; Effect Sustained for at Least 15 Weeks in PH1 Mouse Model LDHA Protein Reduction Control Correlates with Indel Frequency Control Control 0.3 mg/kg 1 mg/kg LDHA LNP (1mpk) LDHA LNP (1mpk) 9 *Western Blot quantification

  10. Slide 10: CRISPR-Mediated Knockout of HAO1 Disrupts Glycolate-to-Glyoxylate Conversion, Addressing PH1

    CRISPR-Mediated Knockout of HAO1 Disrupts Glycolate-to-Glyoxylate Conversion, Addressing PH1 Oxalate regulated regulated HAO1 HAO1 knockout results in reduction of oxalate precursor, glyoxylate Treatment Hypothesis 2 for PH1 Patient 10

  11. Slide 11: 57% Oxalate Reduction Sustained for At Least 15 Weeks Following Single Dose

    57% Oxalate Reduction Sustained for at Least 15 Weeks, Following Single Dose of CRISPR/Cas9 LNPs at 1 mg/kg in PH1 Mouse Model Hao1 Knockout Results in HAO1 Protein Reduction Correlates Sustained Oxalate Reduction with Indel Frequency Control 0.3 mg/kg 1 mg/kg Therapeutic range (>30% oxalate reducti

  12. Slide 12: Key Takeaways

    • Modularity of Intellia's platform enables independent, one-time therapeutic approaches for PH1 by swapping guide alone Key • Editing of Ldha or Hao1 gene each results in therapeutically Takeaways relevant reduction of oxalate (>30% oxalate reduction1) in PH1 mouse model: • Ldha knockout: 63% Urina

  13. Slide 13: Acknowledgements

    Acknowledgements Intellia team Sean Burns Reynald Lescarbeau Cindy Shaw Vinita Doshi Jonathan Nolasco Sam Soukamneuth Zachary Dymek Shobu Odate Walter Strapps John Finn Matthew Roy Arvind Subramanian Noah Gardner Jessica Seitzer Vaughn Walker Arti Kanjolia Ruchi Shah Kristy Wood Elisabeth Krumm Univ

  14. Slide 14: Intellia Therapeutics

    Inte:iia THERAPEUTICS

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