ViewPoints Interview: Arrowhead’ Dr. Christopher Anzalone Shares Insights on the Data of ARO-AAT Presented at EASL 2021

 ViewPoints Interview: Arrowhead’ Dr. Christopher Anzalone Shares Insights on the Data of ARO-AAT Presented at EASL 2021

In an interview with PharmaShots, Dr. Christopher Anzalone, President and CEO at Arrowhead shared his views on the interim 48-week data from the P-II AROAAT2002 study evaluates the safety and PD effects of ARO-AAT for the treatment of liver disease due to AATD


  • The P-II AROAAT2002 study evaluated the safety & PD effects of ARO-AAT in 16 patients with liver disease caused by AATD. The therapy is being co-developed in collaboration with Takeda
  • The results showed an improvement in multiple measures of liver health including fibrosis, substantial and sustained reductions in the level of the toxic mutant Z-AAT protein. The therapy was generally well tolerated with an acceptable safety profile @1yrs. of treatment
  • Additionally, the therapy also showed an improvement in multiple biomarkers including liver stiffness, liver enzymes & markers of collagen formation, no treatment-emergent AEs leads to drug discontinuation, dose interruptions, or study withdrawal

Tuba: Discuss the clinical data of the P-II AROAAT2002 study in detail, including the data presented at EASL International Liver Congress?

Dr. Anzalone: AROAAT2002 (NCT03946449) is a pilot open-label, multi-dose, multi-cohort Phase 2 study to evaluate the safety and pharmacodynamic effects of investigational ARO-AAT on clinically relevant biomarkers of liver disease in participants with alpha-1 antitrypsin deficiency (AATD) – associated liver disease. Between the three cohorts, patients will receive 18 or 24 months of treatment with ARO-AAT, including an optional extension phase.

To date, we’ve announced results from nine patients, four from cohort one and five from cohort two. Two of the four patients from cohort one and four of the five patients from cohort two achieved a one or greater stage improvement in the Metavir fibrosis stage, with no worsening of fibrosis in the other two patients. The two patients who demonstrated improvements from cohort one were both deemed cirrhotic (F4) when the study began and one patient experiencing a dramatic two-stage improvement (F4 to F2). The three remaining patients showed no signs of fibrosis worsening.

Beyond fibrosis score, the patient-level data presented at EASL demonstrated remarkably consistent responses across all patients in several additional metrics. All nine patients experienced a decrease in the accumulation of mutant protein in the liver and serum and all nine patients showed improvements in important indicators of liver health such as liver stiffness, liver enzymes, and markers of collagen formation. Additionally, the drug was found to be generally safe and well-tolerated after one year of treatment in all patients.

These results strongly support further clinical development of ARO-AAT.

Tuba: Highlight the importance of this data for patients with liver disease.

Dr. Anzalone: AATD-associated liver disease is a devastating, rare condition for which there are no approved therapies. The only available treatment for these patients is liver transplantation. These data highlight the potential of ARO-AAT to potentially address the lack of treatment options and potentially prevent liver damage in these patients. 

Tuba: What is ARO-AAT? Discuss its importance in Liver disease associated with alpha-1 antitrypsin deficiency (AATD)

Dr. Anzalone: ARO-AAT is an investigational RNA interference (RNAi) therapy in Phase 2 development to treat AATD-associated liver disease. ARO-AAT is a potential first-in-class therapy designed to reduce the production and accumulation of a mutant protein, which is the cause of AATD-associated liver disease. 

RNAi therapies work by “silencing” genes and preventing the formation of proteins for which they code. We believe that by stopping the production and accumulation of the mutant protein, we could potentially halt liver disease progression and improve liver health through innate liver cell regeneration and repair in patients with AATD-associated liver disease.

Tuba: Tell us more about Alpha-1 Antitrypsin-Associated Liver Disease. What is its epidemiology?

Dr. Anzalone: AATD is a rare genetic disorder associated with liver and pulmonary disease in children and adults. The protein, alpha-1 antitrypsin (AAT), is primarily synthesized and secreted by the liver. Its function is to inhibit enzymes that can break down normal connective tissue. The most common disease variant, the Z mutant, results in improper folding of the protein. The misfolded mutant protein cannot be effectively exported and accumulates in the liver triggering continuous liver injury, leading to fibrosis, cirrhosis, and increased risk of liver cancer.

Individuals homozygous for the Z mutation have severe deficiency of functional AAT, leading to pulmonary disease and liver disease. The lung disease is frequently treated with AAT augmentation therapy which supplements a functional version of the enzyme to support healthy lung function. However, augmentation therapy does not ameliorate liver disease, and for patients with AATD-associated liver disease, a transplant is currently the only available cure.

Tuba: Give an overview of the company’s pipeline?

Dr. Anzalone: We have a broad pipeline that leverages the modular design of our TRiM™ RNAi platform. Currently, we are focused on our clinical programs for cardiometabolic, pulmonary, oncology, and liver diseases. We are also focused on bringing the potential of RNAi therapeutics to tissues outside the liver and are exploring programs targeting multiple tissues and diseases throughout the body. 

Tuba: Are you planning to evaluate the ARO-AAT in other rare genetic disorders?

Dr. Anzalone: ARO-AAT is an RNAi therapeutic which is tailored to target a specific gene, alpha-1 antitrypsin (AAT). While this therapeutic is only designed for patients with AATD, we are developing a robust pipeline of other candidates targeting other genes in both rare and high prevalence disorders using our Targeted RNAi Molecule, or TRiM, platform technology. 

Tuba: How this novel therapy validates the potential of the company’s RNAi platform?

Dr. Anzalone: Our TRiM platform is designed to enable tissue-specific targeting while being structurally simple. Targeting has been core to Arrowhead’s development philosophy and the TRiM™ platform builds on more than a decade of work on actively targeted drug delivery vehicles. 

The platform comprises a high-affinity targeting ligand, various linkers and chemistries, and a highly potent RNAi trigger with sequence-specific stabilization chemistries.

Since our targeting technology is modular, we believe that we can apply our platform to a range of indications so long as there is a clear genetic basis. 

 Tuba: Are you expecting FTD, BTD from the US FDA, and other regulatory authorities for your therapies?

Dr. Anzalone: We recently received Breakthrough Therapy Designation from the U.S. FDA which marks a major milestone for both the company and the patient community who is desperately in need of new treatment options. ARO-AAT was also previously granted Orphan Drug designation and Fast Track designation from the FDA, and Orphan Designation from the European Commission. We are continuing to explore other special designations in the US and abroad to expedite our clinical program.

Tuba: Are you open to more collaborations to advance your therapies?

Dr. Anzalone: We believe that our modular approach can be applied to almost any disease with a clear genetic basis. We are continuing to explore partnerships and collaborations with other leading biotech and pharmaceutical companies to bring the potential of RNAi to new patient populations.

Source: Eat This, Not That

About Author: Dr. Christopher Anzalone is a President, CEO, and Director of Arrowhead. He was an NIH-supported postdoctoral fellow in Reproductive Endocrinology at the Smithsonian Institution’s Conservation and Research Center. Dr. Anzalone holds a Ph.D. in Biology from UCLA and a B.A. in Government from Lawrence University

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Tuba Khan

Tuba Khan is Senior Editor at PharmaShots. She is curious, creative, and passionate about recent updates and innovation in the Life sciences industry. She covers Biopharma, MedTech, and Digital health segments. Tuba also has an experience of digital and social media marketing and runs the campaigns independently. She can be contacted on

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