Intellia Therapeutics, Inc. · NASDAQ:NTLA
Intellia Therapeutics — Genome Engineering: The CRISPR-Cas Revolution at Cold Spring Harbor Laboratory (August 2018)
14 slides from Intellia Therapeutics's conference presentation, Aug 23, 2018
Slide 1: Development of NTLA-1001: LNP-CRISPR/Cas9 Genome Editing Therapeutic for ATTR
Development of NTLA-1001: First-in-Class, LNP-CRISPR/Cas9 Mediated Genome Editing Therapeutic for the Treatment of ATTR Yong Chang, Ph.D. August 23, 2018 Genome Engineering: The CRISPR-Cas Revolution at Cold Spring Harbor Laboratory 1
Slide 2: Intellia Therapeutics Legal Disclaimers – Forward Looking Statements
Intellia Therapeutics Legal Disclaimers – Forward Looking Statements This presentation contains “forward-looking statements” of Intellia of capital, expenses, future accumulated deficit and other 2018 financial Therapeutics, Inc. (“Intellia”) within the meaning of the Private Securities results; and
Slide 3: Hereditary Transthyretin Amyloidosis (hATTR) is a Rare Disease That's Typically Fatal if Untreated
Hereditary Transthyretin Amyloidosis (hATTR) is a Rare Disease That’s Typically 1 Fatal if Untreated Amyloidogenic TTR Cascade Liver TTR Tetramer TTR Monomer Misfolded State Amyloid Fibril Suppression of TTR stabilization Fibril degradation hATTR-PN amyloidogenic TTR (hereditary transthyretin amyloi
Slide 4: Intellia's Modular Lipid Nanoparticle (LNP) System Delivers CRISPR/Cas9 to Make an In Vivo Edit
Intellia’s Modular Lipid Nanoparticle (LNP) System Delivers CRISPR/Cas9 to Make an In Vivo Edit Intellia’s LNP delivery system includes Uptake a single guide RNA, mRNA encoding S.py Cas9 and a lipid formulation encapsulating these Editing in vivo requires cargo release, mRNA translation, RNP assembl
Slide 5: Editing Strategy Relies on Knockout Caused By Error-Prone NHEJ of a Double-Strand Break in Liver Cells
Editing Strategy Relies on Knockout Caused By Error-Prone Non-Homologous End Joining (NHEJ) of a Double-Strand Break in Liver Cells Chromosome 18: 31591726 to 31599011 signal Exon 2 peptide 1 Exon 2 Exon 2 CRISPR Double-Stranded Break alt start V30M 2 Exon 2 Exon 2 NHEJ Repair with Indels 3 KO via f
Slide 6: Durable Liver Editing and Knockdown of TTR Persists Months in Mice with no Histological Findings
Durable Liver Editing and Knockdown of TTR Persists 12 Months in Mice with no Histological Findings Single administration given at Day 1 Vehicle 3 mg/kg Day 7 12 Mos. No transformation or neoplastic changes observed across >100 mice over time up to 12 months post-edit 6
Slide 7: Mouse Multi-Dose Study: Repeat Low Dose of LNPs with CRISPR/Cas9 is Comparable to Single High Dose
Mouse Multi-Dose Study: Repeat Low Dose of LNPs with CRISPR/Cas9 is Comparable to Single High Dose 0.5 mg/kg 2 mg/kg 0.5 mg/kg 2 mg/kg veh. x1 x2 x3 x4 x1 veh. x1 x2 x3 x1 weekly monthly Serum TTR data reflects same trends Four weekly doses of 0.5 mg/kg is comparable to one 2 mg/kg dose 7
Slide 8: Lead Human TTR CRISPR/Cas9 LNPs Demonstrate On-Target Editing in Primary Human Hepatocytes In Vitro
Lead Human TTR CRISPR/Cas9 LNPs Demonstrate On-Target Editing, and Reduction of mRNA and TTR Protein in Primary Human Hepatocytes In Vitro 8
Slide 9: Top Human Guides Exhibit Robust, Dose-Responsive Liver Editing and Reduction of TTR in huTTR Mice
Top Human Guides Exhibit Robust, Dose-Responsive Liver Editing and Reduction of TTR in huTTR Mice 1 muTTR 2 X muTTR 3 huTTR ® huTTR VelociGene® is a registered trademark of Regeneron Pharmaceuticals, Inc. 9
Slide 10: Findings from huTTR V30M Mouse Model Study Recapitulate TTR Deposition Phenotype
Findings from huTTR V30M Mouse Model Study Recapitulate TTR Deposition Phenotype in Tissues and the Nervous System 1 muTTR 2 X muTTR 3 huTTR V30M huTTR V30M Homozygous for the human mutant V30M TTR transgene in a mouse Ttr-null background transgenic mice contain approximately ~47 copies of huTTR V30
Slide 11: CRISPR/Cas9 Decreasing Serum TTR in huTTR V30M Mouse Model Results in Decreased Amyloid Deposition
Decreasing Serum TTR by Editing the huTTR V30M Mouse Model Via CRISPR / Cas9 LNP Results in Dramatic Decreased Amyloid Deposition in Tissues Stomach Colon Sciatic Nerve DRG Control CRISPR/Cas9 LNP 11
Slide 12: Therapeutically Relevant Reduction of Serum TTR Protein Achieved in Initial NHP Studies
Therapeutically Relevant Reduction of Serum TTR Protein Achieved in Initial NHP Studies After a Single Dose with Lead Guide Candidate Liver Editing %TTR Protein Knockdown 34% Vehicle • mRNA improvement • LNP formulation • Cargo ratio • Guide chemistry High Dose Therapeutically (Improved) Relevant Ra
Slide 13: Acknowledgements
Acknowledgements • Intellia team: - Adam Amaral - Bo Han - Ellen Rohde - Naina Bhasin - Arti Kanjolia - Jessica Seitzer - Peter Bialek - Reynald Lescarbeau - Cindy Shaw - Carri Boiselle - John Leonard - Kevin Sloan - Tracy DiMezzo - Ivana Liric - Samantha Soukamneuth - Tanner Dirstine - Michael McCa
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