Intellia Therapeutics, Inc. · NASDAQ:NTLA

Intellia Therapeutics — The International Liver Congress 2022

17 slides from Intellia Therapeutics's conference presentation, Jun 24, 2022

  1. Slide 1: In vivo CRISPR/Cas9 editing of the TTR gene with NTLA-2001 – dose selection considerations

    In vivo CRISPR/Cas9 editing of the TTR gene with NTLA-2001 in patients with transthyretin amyloidosis – dose selection considerations Ed Gane, Jörg Täubel, Björn Pilebro, Marianna Fontana, Justin Kao, Michael L. Maitland, Mark Stroh, Jessica Seitzer, Jonathan Phillips, Kristy Wood, Yuanxin Xu, Carri

  2. Slide 2: Transthyretin (ATTR) amyloidosis

    Transthyretin (ATTR) amyloidosis Rare, progressive, fatal disease • Caused by accumulation of amyloid deposits composed of misfolded transthyretin (TTR) protein • ATTR amyloidosis consists of two forms of the disease: hereditary and wild type • Rate of new diagnoses is increasing Hereditary ATTR amy

  3. Slide 3: Potential for gene editing to address unmet need for ATTR amyloidosis

    Potential for gene editing to address unmet need for ATTR amyloidosis • Therapy in ATTR amyloidosis is directed at reducing the circulating amyloid-forming protein – Gene silencing therapy knocks serum TTR down by ~80% and benefits neuropathy in ATTRv1 • Greater TTR knockdown is expected to achieve

  4. Slide 4: NTLA-2001 is a novel, investigational CRISPR/Cas9-based in vivo gene editing therapy

    Lipid nanoparticle NTLA-2001 is a novel, Complementary TTR-specific sgRNA sequence to investigational CAPILLARY TTR gene CRISPR/Cas9-based in vivo Streptococcus gene editing therapy pyogenes (Spy) NTLA-2001 Cas9 mRNA NTLA-2001 Uptake in LDL receptors Hepatocytes Endosomal release Endocytosis of LNP

  5. Slide 5: Non-human primates: Durable, >95% TTR reduction after single dose of NTLA-2001

    Non-human primates: Durable, >95% TTR reduction after single dose of NTLA-2001 proportion of baseline, % (mean ± SD) 120 Control (n=3) 100 1.5 mg/kg (n=3) TTR protein production, 3.0 mg/kg (n=3) 80 6.0 mg/kg (n=3) 60 40 20 0 0 40 80 120 160 200 240 280 320 360 Day 5 This presentation includes data f

  6. Slide 6: In Vitro: No detectable off-target editing with pharmacologic concentration of sgRNA

    In Vitro: No detectable off-target editing with pharmacologic concentration of sgRNA 100 EC90 80 On target Editing frequency (%) Sequence 1 60 Sequence 2 40 Sequence 3 Sequence 4 20 Sequence 5 Sequence 6 2.5 Sequence 7 2.0 1.5 1.0 0.5 0 0.007 0.021 0.063 0.191 0.574 1.724 5.172 15.517 sgRNA concentr

  7. Slide 7: NTLA-2001 Phase 1 Study: Polyneuropathy Arm

    NTLA-2001 Phase 1 Study: Polyneuropathy Arm Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv-PN) Today's interim data presentation covers longer-term safety, PD and PK data across all four dose levels in Part I PART I – DOSING COMPLETE PART II – ONGOING Single-Ascending Dose Single Do

  8. Slide 8: Patient demographics & characteristics

    Patient demographics & characteristics Parameter 0.1 mg/kg 0.3 mg/kg 0.7 mg/kg 1.0 mg/kg All patients n=3 n=3 n=3 n=6 n=15 Age, years 54 53 51 61 55 median (min, max) (50, 63) (46, 64) (19, 58) (49, 70) (19, 70) Sex, n (%) Male 1 (33%) 3 (100%) 2 (67%) 3 (50%) 9 (60%) Female 2 (67%) – 1 (33%) 3 (50%

  9. Slide 9: NTLA-2001 was generally well tolerated across all dose levels through the follow-up period

    NTLA-2001 was generally well tolerated across all dose levels through the follow-up period • Across all dose levels, the most frequent adverse events* were headache, infusion-related reactions, back pain, rash† and nausea – Majority of adverse events were mild in severity with 73% (n=11) of patients

  10. Slide 10: Majority of adverse events were mild in severity

    Majority of adverse events were mild in severity 0.1 mg/kg 0.3 mg/kg 0.7 mg/kg 1.0 mg/kg All Patients n=3 n=3 n=3 n=6 n=15 Parameter Gr. 1 Gr. 2 Gr. 3 Gr. 1 Gr. 2 Gr. 3 Gr. 1 Gr. 2 Gr. 3 Gr. 1 Gr. 2 Gr. 3 Gr. 1 Gr. 2 Gr. 3 Patients with at least one TEAE 3 – – 3 – – 2 – 1* 3 2 1† 11 2 2 Headache 2 –

  11. Slide 11: Minor, transient changes in AST and ALT levels observed post NTLA-2001 infusion

    Minor, transient changes in AST and ALT levels observed post NTLA-2001 infusion AST Levels Over 6 Months ALT Levels Over 6 months 100 100 0.1 mg/kg 0.1 mg/kg 90 0.3 mg/kg 90 0.3 mg/kg 0.7 mg/kg 0.7 mg/kg 80 80 1.0 mg/kg Aspartate Aminotransferase (U/L) – AST 1.0 mg/kg Alanine Aminotransferase (U/L)

  12. Slide 12: Dose-dependent reductions in serum TTR, reaching a mean reduction of 93% at 1.0 mg/kg

    Dose-dependent reductions in serum TTR, reaching a mean reduction of 93% at 1.0 mg/kg Mean (SE) % TTR reduction by dose level at day 28 00 =–10 12 -10mo. –20 = -20 9 mo. –30 –40% TTR reduction (%) -30 (n=3) –40 -40 –52% (n=3) –50 -50 –60 -60 –70 -70 –87% –86% –80 -80 (n=3) (n=3) –93% –90 -90 (n=6) –

  13. Slide 13: Higher doses demonstrated rapid and deep serum TTR reduction sustained through 6-12 months

    Higher doses demonstrated rapid and deep serum TTR reduction sustained through 6-12 months Mean (SE) % TTR reduction by dose level 0 0.1 mg/kg (n=3*) -10 0.3 mg/kg (n=3) 0.7 mg/kg (n=3) -20 1.0 mg/kg (n=6†) TTR reduction (%) -30 -40 -50 -60 -70 -80 -90 87% 89% 93% 93%†† -100 1 2 4 6 9 12 Months * n=

  14. Slide 14: NTLA-2001 declines rapidly from peak and then exhibits a secondary peak and log-linear phase

    NTLA-2001 declines rapidly from peak and then exhibits a secondary peak and log-linear phase Mean plasma concentration-time profiles of LP01 following single dose IV infusion of NTLA-2001 NTLA-2001 comprises LP01, an ionizable lipid, additional lipids and the RNA 14 This presentation includes data f

  15. Slide 15: Simulations identified NTLA-2001 80mg as the fixed dose equivalent to 1.0 mg/kg

    Simulations identified NTLA-2001 80mg as the fixed dose equivalent to 1.0 mg/kg Model-predicted distribution of NTLA-2001 AUC (mg*h/mL) following 1.0 mg/kg and 80 mg by indicated weight quartile 1.0 mg/kg 80 mg 5 5 AUC (mg/mL*hr) 4 AUC (mg/mL*hr) 4 3 3 2 2 1 1 0 0 48-72 72-81 81-90 90-146 48-72 72-8

  16. Slide 16: Deep, consistent and durable TTR reductions following single administration of in vivo CRISPR-based gene editing

    Deep, consistent and durable TTR reductions following single administration of in vivo CRISPR-based gene editing • Mean TTR reduction sustained at all doses tested through 6-12 months • At 1.0 mg/kg, mean reduction of 93% at day 28 was sustained through 6 months • NTLA-2001 was generally well tolera

  17. Slide 17: Acknowledgements

    Acknowledgements ▪ We express our gratitude to the patients who participated in this study, their families and the research staff at New Zealand Clinical Research, Richmond Pharmacology and Umeå University. ▪ We thank the Charles River Laboratory, Altasciences, Precision for Medicine, PPD, and QPS f

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