Intellia Therapeutics, Inc. · NASDAQ:NTLA
Intellia Therapeutics — Technical Presentation (June 2021)
17 slides from Intellia Therapeutics's technical presentation, June 2021
Slide 1: 2021 PNS Annual Meeting
2021 PNS ANNUAL MEETING Virtually Anywhere
Slide 2: In vivo CRISPR/Cas9 Editing of the TTR Gene by NTLA-2001 in Patients with Transthyretin Amyloidosis
In vivo CRISPR/Cas9 Editing of the TTR Gene by NTLA-2001 in Patients with Transthyretin Amyloidosis Julian D. Gillmore1, Jorg Taubel2, Justin Kao3, Marianna Fontana1, Michael L. Maitland4, Jessica Seitzer4, Daniel O’Connell4, Jonathan Phillips4, Kristy Wood4, Yuanxin Xu4, Adam Amaral4, Adam P. Boyd4
Slide 3: Disclosures
Disclosures • JDG: Expert adviser for Alnylam Pharmaceuticals, Eidos Therapeutics, Ionis Pharmaceuticals Inc., and Intellia Therapeutics Inc.
Slide 4: Potential for gene editing to address unmet need for hATTR/ATTRv amyloidosis
Potential for gene editing to address unmet need for hATTR/ATTRv amyloidosis • Therapy in amyloidosis is intended to reduce or stabilize precursor protein, in ATTR amyloidosis = transthyretin (TTR) – Gene silencing therapy (patisiran) knocks serum TTR down by ~80% (mean) and benefits neuropathy in A
Slide 5: NTLA-2001 is a novel CRISPR/Cas9-based in vivo gene editing therapy
NTLA-2001 is a novel CRISPR/Cas9-based in vivo gene editing therapy NTLA-2001 Complementary TTR sequence to sgRNA TTR gene Streptococcus pyogenes (Spy) Cas9 mRNA Lipid nanoparticle sgRNA; single guide RNA; TTR, transthyretin
Slide 6: NTLA-2001 delivers sgRNA and Cas9 into the nucleus, which precisely edit and inactivate the TTR gene
NTLA-2001 delivers sgRNA and Cas9 into the nucleus, which precisely edit and inactivate the TTR gene Cas9/sgRNA Ribonucleoprotein induces Endogenous DNA repair via nonhomologous end ribonucleoprotein unwinding of chromosomal DNA, joining results in introduction of indels into TTR enters nucleus then
Slide 7: 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 (%) 60 Sequence 1 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
Slide 8: NHP: Durable, >95% TTR reduction after a single dose
NHP: Durable, >95% TTR reduction after a single dose 120 Production of baseline level (%) 100 Control (n = 3) 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 NHP; non-human primate, TTR, transthyretin
Slide 9: First-in-human: Two-part phase 1 study of NTLA-2001
First-in-human: Two-part phase 1 study of NTLA-2001 Population: Adults with ATTRv with polyneuropathy Part I Part II Single-ascending dose Single-dose expansion cohort Primary objectives Intervention: • Evaluate safety, Single dose Administer tolerability, PK and PD administered recommended dose sel
Slide 10: NTLA-2001 first-in-human study: Demographics
NTLA-2001 first-in-human study: Demographics 0.1 mg/kg dose 0.3 mg/kg dose 0.1 mg/kg dose 0.3 mg/kg dose Parameter Parameter (n = 3) (n = 3) (n = 3) (n = 3) Age, years Clinical scores, n Median (min, max) 54 (50, 63) 53 (46, 64) Polyneuropathy disability score 1 3 3 Sex, n NYHA Functional 3 3 Male 1
Slide 11: NTLA-2001 generally well tolerated in acute phase (N=6): all AEs Grade 1 with no serious AEs
NTLA-2001 generally well tolerated in acute phase (N=6): all AEs Grade 1 with no serious AEs 0.1 mg/kg 0.3 mg/kg Preferred Term (n = 3) (n = 3) Subjects with at least one TEAE 2 1 Headache 2 Diarrhea 1 Nausea 1 Infusion-related reaction 1 Skin abrasion 1 Vertigo positional 1 Foreign body sensation i
Slide 12: No liver findings or coagulopathy based on laboratory testing
No liver findings or coagulopathy based on laboratory testing Liver function Coagulation 50 40 18 ULN 36 ULN 40 32 16 28 30 ALT (u/L) 14 AST (u/L) PT (sec) 24 ULN 20 20 12 16 12 10 10 8 0 4 8 BL 4 7 14 28 BL 4 7 14 28 BL 4 7 14 28 Time (Days) Time (Days) Time (Days) Individual patients Mean Referenc
Slide 13: Dose-dependent serum TTR reduction after NTLA-2001
Dose-dependent serum TTR reduction after NTLA-2001 Change in serum TTR in individual patients B at 0.1 mg/kg (n = 3) 0 Change in serum TTR from baseline (%) –20 –40 47% 52% –60 56% –80 –100 0 7 14 21 28 Day TTR, transthyretin
Slide 14: Dose-dependent serum TTR reduction after NTLA-2001
Dose-dependent serum TTR reduction after NTLA-2001 Change in serum TTR in individual patients Change Changeininserum serum TTR in in TTR individual patients individual patients at 0.1 mg/kg (n = 3) atat0.3 mg/kg (n = 3) 0.3 mg/kg (n = 3) B B 0 0 Change in serum TTR Change in serum TTR from baseline
Slide 15: Average TTR reduction of 87% for 0.3 mg/kg: Predicted to result in clinical benefit for patients
Average TTR reduction of 87% for 0.3 mg/kg: Predicted to result in clinical benefit for patients Dose 0.1 mg/kg 0.3 mg/kg 0 Mean percent reduction in –20 serum TTR (%) –40 52% 87% –60 87% –80 –100 Bars represent standard deviation. TTR, transthyretin
Slide 16: Conclusions: In vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001
Conclusions: In vivo CRISPR/Cas9 editing of the TTR gene by NTLA-2001 • A single systemic administration of NTLA-2001 in patients with ATTRv amyloidosis-PN caused a profound reduction in serum TTR protein concentrations – Effect of NTLA-2001 was dose-dependent – 0.1 mg/kg: 52% mean reduction in TTR
Slide 17: Acknowledgements
Acknowledgements • We thank the patients who participated in this trial, and their families • We thank New Zealand Clinical Research and Richmond Pharmacology for contract research assistance, and Charles River Laboratory, Altasciences, Precision for Medicine, PPD, and QPS for serum TTR ELISA measur
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