Arrowhead Pharmaceuticals : EASL 2022 AROAAT2002

Reduction of Intra-hepaticZ-AAT Synthesis by Fazirsiran Decreases Globule Burden and Improves Histological Measures of Liver Disease in Adults with Alpha-1 Antitrypsin Deficiency

Pavel Strnad1, Mattias Mandorfer2, Gourab Choudhury3, William Griffiths4, Christian Trautwein1, Rohit Loomba5, Romil Saxena6, Thomas Schluep7, Ting Chang7, Min Yi7, Bruce D. Given7, James C. Hamilton7, Javier San Martin7, Jeffery H. Teckman8

1 Department of Internal Medicine III, University Hospital, Rwth Aachen, Aachen, Germany; 2 Division of Gastroenterology & Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; 3 Respiratory Medicine, University of Edinburgh, Edinburgh, United Kingdom; 4 Department of Hepatology, Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, United Kingdom;

5 University of California at San Diego, Division of Gastroenterology, San Diego, USA;

6 Emory University School of Medicine, Atlanta, USA; 7 Arrowhead Pharmaceuticals, Inc, Pasadena, USA; 8 Pediatrics, Saint Louis University School of Medicine, St. Louis, USA

Background

• Alpha-1antitrypsin (AAT) deficiency is caused by mutations in the SERPINA1 gene leading to loss-of-function pulmonary disease and gain of-function liver disease.1
• 95% of severe cases are due to homozygous substitution of a single amino acid, Glu342Lys (PIZZ).1
• PiZZ homozygosity occurs in ~1 in 2,500 to 3,500 of Caucasians.1,2
• A third of adults with PIZZ may have clinically significant liver fibrosis.2,3

1 Strnad P, et al. N Engl J Med 2020;382:1443-55;2 Alpha-1 Foundation:https://www.alpha1.org/Alpha1/wp-

content/uploads/2019/09/HealthcareProvidersBrochure-1.pdf;3 Clark VC, et al. J Hepatol2018;69:1357-64.	3

Accumulation of Hepatotoxic Z-AAT Protein Causes Liver Disease in Alpha-1 Antitrypsin Deficiency (AATD)

	Plasma membrane
	Cytoplasm
	Autophagic
Proteosomal	degradation
(UPR)
degradation
(ERAD)

Ubiquitin

	Lysosome
Z-AAT monomer	Autophagosome
Z-AAT polymer

Inflammation	Chronic
and apoptosis	regeneration

SERPINA1		Hepatocellular
mutation		injury
	PASD globules	 Liver impairment
		 Fibrosis and cirrhosis
Nucleus	Endoplasmic reticulum	 End-stage liver disease
4

Fazirsiran (ARO-AAT) Inhibits Z-AAT Expression to Allow Clearance of Polymers and Globules and Improvement in Liver Health

	Plasma membrane
	Cytoplasm
	Autophagic
Proteosomal	degradation
(UPR)
degradation
(ERAD)

	Ubiquitin	Lysosome	Inflammation	Chronic
ARO-AAT
			and apoptosis	regeneration
	Z-AAT monomer	Autophagosome
	Z-AAT polymer
SERPINA1		Hepatocellular
mutation	PASD globules	injury	 Liver impairment
			 Fibrosis and cirrhosis
Nucleus	Endoplasmic reticulum		 End-stage liver disease
		5