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Arrowhead Preclinical Data Demonstrates RNAi Therapy Prevents and Reverses Alpha-1 Liver Disease at The International Liver Congress™

April 12, 2019 Off By BusinessWire

PASADENA, Calif.–(BUSINESS WIRE)–lt;a href="https://twitter.com/search?q=%24arwr&src=ctag" target="_blank"gt;$arwrlt;/agt; lt;a href="https://twitter.com/hashtag/ILC2019?src=hash" target="_blank"gt;#ILC2019lt;/agt;–Arrowhead Pharmaceuticals Inc. (NASDAQ: ARWR) today presented
preclinical data at The International Liver Congress™ 2019 (ILC), the
annual meeting of the European Association for the Study of the Liver
(EASL), demonstrating that sustained reduction of mutant Z-AAT protein
by RNA interference (RNAi) substantially reversed the alpha-1
antitrypsin deficiency (AATD) disease phenotype in the PiZ mouse model.
Arrowhead has completed a Phase 1 clinical trial of ARO-AAT, the
company’s second generation subcutaneously administered RNAi therapeutic
being developed as a treatment for AATD-related liver disease. Pending
regulatory clearance, Arrowhead intends to initiate an adaptive Phase
2/3 trial with the potential to serve as a pivotal registrational study.

Bruce Given, M.D., chief operating officer and head of R&D at Arrowhead,
said: “The results presented today at EASL from a long-term term
preclinical study of our prior generation compound, ARC-AAT, suggest
that RNAi holds great promise for the treatment of patients with
AATD-associated liver disease. It is particularly encouraging that we
were able to prevent liver damage and reverse existing damage in the PiZ
mouse model that harbors the human Z-AAT gene and recapitulates many
features of AATD liver disease. This gives us added confidence in the
ARO-AAT clinical candidate as we embark on a Phase 2/3 clinical study,
which has the potential to be registrational.”

In the study presented at ILC, PiZ mice were treated with ARC-AAT for 33
weeks. Measurements of plasma Z-AAT levels, Z-AAT protein accumulation
in the liver, and expression of genes previously implicated in liver
injury and development of fibrosis were taken. In addition, histological
evaluations of globules and inflammation and an ultrastructural
evaluation of the liver by electron microscopy were performed.

Key results include the following:

Sustained RNAi reduction of Z-AAT substantially reversed the AATD
disease phenotype:
- Deeply reduced monomeric Z-AAT protein in the liver
- Reduced polymeric Z-AAT in the liver
- Prevented the dramatic increase in globule size seen in
  age-matched control PiZ mice
- Improved abnormal endoplasmic reticulum morphology
- Prevented inflammation
- Prevented/reduced expression of fibrosis, redox-regulation,
  stress, apoptosis and autophagosome-associated genes
- Resulted in abundance of healthy mitochondria

Poster Presentation Details:

Reduction of hepatic Z-alpha1 antitrypsin by RNA interference (RNAi)
prevents and reverses liver disease including hepatic mitochondrial
injury in the PiZ mouse

Presentation Reference: FRI-446
Session: Poster: Rare liver diseases (including pediatric and genetic)
Session Date and Time: April 12, 2019 at 9:00 a.m. to 5:00 p.m. CET
Authors: Christine Wooddell, et al.

Additional details, including the presentation abstract, can be found on
the ILC website at https://ilc-congress.eu/.
A copy of presentation materials can be accessed by visiting the Events
section under the Investors tab of the Arrowhead website.

About Arrowhead Pharmaceuticals

Arrowhead Pharmaceuticals develops medicines that treat intractable
diseases by silencing the genes that cause them. Using a broad portfolio
of RNA chemistries and efficient modes of delivery, Arrowhead therapies
trigger the RNA interference mechanism to induce rapid, deep, and
durable knockdown of target genes. RNA interference, or RNAi, is a
mechanism present in living cells that inhibits the expression of a
specific gene, thereby affecting the production of a specific protein.
Arrowhead’s RNAi-based therapeutics leverage this natural pathway of
gene silencing.

For more information, please visit www.arrowheadpharma.com,
or follow us on Twitter @ArrowheadPharma.
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please visit http://ir.arrowheadpharma.com/email-alerts.

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