2020-10-10| Asia-Pacific

Takeda Collaborates with Arrowhead to Overcome Inherited Disorder via RNAi Therapy

by Judy Ya-Hsuan Lin
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By Judy Ya-Hsuan Lin

Alpha-1 antitrypsin deficiency (AATD) is a disease that presently has no cure, and the only way-out is the transplantation. Unfortunately, some patients do not survive this long wait. AATD has inflicted 180,000 people worldwide, among which there are 1 in 3000-5000 people in the U.S. and 1 in 2500 people in Europe affected.

On October 8th, Osaka-based Takeda Pharmaceuticals and Pasadena, California-based Arrowhead Pharmaceuticals, announced a partnership for Arrowhead’s ARO-AAT, a Phase 2 investigational RNA interference (RNAi) therapy in development to treat Alpha-1 antitrypsin (AAT)-associated liver disease (AATLD).

Four years ago, Arrowhead suffered a blow when placed under a clinical hold by the FDA. In early November 2016, several non-human primate deaths were reported while testing its Hepatitis B candidate ARC-520. In another couple of weeks, this candidate was rejected, leaving Arrowhead falling hard and dipping under $90 million as well as ending that year with $1.55 a share (barely $8 a share, at its peak in August 2016).

However, since 2018, Arrowhead began to rise steadily when Johnson & Johnson paid $175 million and committed $1.6 billion for the second attempt on the Hepatitis B candidate. The data from the second attempt presented at the Digital International Liver Congress showed that 39% of patients who received three doses of the drug had sustained reductions in a key biomarker for Hepatitis B, indicating the therapy’s potentially long-lasting effects.



AATD is an inherited disorder in which individuals with the homozygous PiZZ genotype have a severe deficiency of functional AAT, causing pulmonary and liver disease. The protein AAT is mainly synthesized and secreted by liver hepatocytes to inhibit enzymes that can break down normal connective tissue. The mutant protein caused by a single amino acid substitution results in improper protein folding, leading to ineffective secretion and severe accumulation of globules that eventually induce fibrosis, cirrhosis, and increased risk of carcinoma in the liver.

The signs and symptoms of the condition and the age at which they appear to vary among individuals. People with AATD usually develop the first signs and symptoms of lung disease between ages 20 and 50. The earliest symptoms are shortness of breath following mild activity, reduced ability to exercise, and wheezing. Other signs include unintentional weight loss, recurring respiratory infections, fatigue, and rapid heartbeat upon standing. Individuals with AATD often develop emphysema, damages to the small air sacs in the alveoli, causing difficulty to breathe, hacking coughs, and a barrel-shaped chest.


Clinical Study

ARO-AAT demonstrated its potential to reduce mutant alpha-1 antitrypsin protein production, the cause of AATLD progression. According to Arrowhead’s interim results of its ongoing Phase 2 study released in mid-September, after 24 weeks of treatment, all four participants experienced up to 93% of reduction in serum and 95% reduction in total intra-hepatic Z mutant-AAT, the most common disease variant. A 66% maximum reduction in ALT and a 58% maximum reduction in GGT in all four patients; both biomarkers indicate a decrease in liver damages.

“These data are very encouraging and suggest that ARO-AAT may rapidly ameliorate liver injury. It is particularly reassuring to see the decrease in liver enzymes, which suggests that elevations are related to proteotoxic stress that could be addressed with AR-AAT therapy rather than reflecting co-morbidities,” trial investigator Pavel Strnad, M.D., of the University Hospital Aachen in Germany, said in a statement.

“In addition, no major lung events have occurred in this study to date, which indicates that RNAi-based reduction of Z [mutant]-AAT in the liver has not negatively affected lung function during the treatment period. I am pleased that all my patients have opted to continue on study for the 12-month extension, and I am eager to follow their progress.”


Collaboration Agreement

Takeda and Arrowhead will co-develop and commercialize ARO-AAT under a 50/50 profit-sharing structure. Takeda will lead the global commercialization strategy and receive an exclusive license to commercialize ARO-AAT, while Arrowhead receives tiered royalties of 20-25% on net sales. Arrowhead will also receive an upfront payment of $300 million and milestones of up to $740 million. Therefore, Arrowhead will obtain up to a total of $1.04 billion. Their collaboration brought the shares of Arrowhead up to 1.5% on the Nasdaq by the afternoon of October 8th’s trading and Takeda shares up to 1.5% on the New York Stock Exchange.

Editor: Rajaneesh K. Gopinath, Ph.D.

Related Article: Takeda Established Capabilities to Engine Cell Therapy Manufacturing



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