Intellia Therapeutics : In vivo CRISPR/Cas9 editing of KLKB1 in patients with HAE

In vivo CRISPR/Cas9 editing of KLKB1 in patients with HAE

Hilary Longhurst1, Lauré M. Fijen2, Karen Lindsay1, Carri Boiselle3, James Butler3, Adele Golden3, David Maag3, Joseph Vogel3, Yuanxin Xu3, and Danny M. Cohn2

1Auckland District Health Board and University of Auckland, New Zealand 2Amsterdam University Medical Centers, University of Amsterdam, the Netherlands 3Intellia Therapeutics, Cambridge, MA, U.S.

Session V: Bradykinin Symposium, Berlin, Germany

16 September 2022

Clinical Trial Registration # NCT05120830

This study and medical writing support for this presentation is funded by Intellia Therapeutics

Targeting KLKB1 gene expression for long-term prophylaxis of HAE attacks

Factor XII Factor XIIa

KLKB1 gene	Prekallikrein	Kallikrein

HMW Kininogen B Bradykinin

B

NTLA-2002	Vascular leakage

Knocking out KLKB1 gene

1 is intended to prevent production of kallikrein

2	Reducing kallikrein levels
	balances bradykinin production

3	Reducing bradykinin
prevents HAE attacks

Kallikrein is a clinically validated therapeutic target for preventing HAE attacks

	HAE, Hereditary Angioedema
2 This presentation includes data for an investigational product not yet approved by regulatory authorities	Adapted from Zuraw BL. Hereditary angioedema. N Engl J Med. 2008;359:1027-1036

Lipid nanoparticle

NTLA-2002 is a novel, investigational CRISPR/Cas9-basedin vivo gene editing therapy

NTLA-2002

Uptake in

Hepatocytes

	Complementary
	sequence to
CAPILLA RY	KLKB1 gene
	Streptococcus
	pyogenes (Spy)
	Cas9 mRNA

Endosomal release

KLKB1-specific sgRNA

NTLA-2002

LDL receptors

Endocytosis

of LNP

Endosome Cas9-sgRNA ribonucleotide protein

HEPATOCY TE			Target-specific
		20-nt sequence
Translation of
Cas9-sgRNA
Cas9 mRNA	Endogenous DNA repair
	enters nucleus
	through non-homologous
			end joining leads to indels
			in KLKB1 that prevent
	Complementary	production of Kallikrein protein
NUCLEUS	Kallikrein
	Noncomplementary
			protein
	Targeted
	DNA editing

3 This presentation includes data for an investigational product not yet approved by regulatory authorities

LNP, Lipid Nanoparticle; sgRNA, Single Guide RNA

NTLA-2002 global Phase 1/2 study design:

Two-part,multi-center study of NTLA-2002 in adults with HAE Types I and II

Today's interim data cover

the first six patients

(Data cut-off: 27 July 2022)

Intervention: Single dose administered via an intravenous (IV) infusion

PRE-TREATMENT REGIMEN

Day -1: Oral dexamethasone 8 mg (or equivalent)

Day 1: IV dexamethasone 10 mg (or equivalent), IV or oral H1 and H2 blocker, C1-INH

PHASE 1 Open-label,single-ascending dose

75 mg (n=3)

25 mg (n=3)

50 mg* (dosing complete)

PRIMARY OBJECTIVES

Evaluate safety & tolerability

OTHER OBJECTIVES

PK, PD, clinical efficacy (attacks)

PHASE 2

Expansion study to confirm recommended dose

Randomized	Dose 1 (n=10)
Placebo Arm (n=5)
	Dose 2 (n=10)

PRIMARY OBJECTIVES

Clinical efficacy (attacks through week 16)

OTHER OBJECTIVES

PD, safety & tolerability, PK, QoL

*Minimum of 3 subjects and maximum of 6 patients per cohort

4 This presentation includes data for an investigational product not yet approved by regulatory authoritiesH1, Histamine Receptor 1; H2, Histamine Receptor 2; C1-INH, C1 Esterase Inhibitor; PK, Pharmacokinetics; PD, Pharmacodynamics

Key eligibility criteria (Phase 1)

INCLUSION

• Documented diagnosis of Type I or Type II HAE
• At least 3 investigator-confirmed HAE attacks within 90 days prior to screening
• Access to acute therapies to treat HAE attacks
• Concurrent therapy with standard-of- care long-term prophylaxis allowed

EXCLUSION

1. Concomitant use of ecallantide or lanadelumab

1. Known hypersensitivity or prior infusion- related reaction to LNP components

1. History of cirrhosis, Hepatitis B, Hepatitis C or HIV

5 This presentation includes data for an investigational product not yet approved by regulatory authorities