Patients with Alpha-1 Antitrypsin Deficiency Liver Disease Show Improvement After Six Months of Experimental Treatment


Arrowhead Pharmaceuticals recently announced positive twenty-four-week biopsy results from four patients who participated in the first cohort of the Phase II clinical trial of ARO-AAT.

ARO-AAT is Arrowhead’s investigational RNA therapeutic. It is a therapy for a rare liver disease that is caused by Alpha-1 antitrypsin deficiency.

About Alpha-1 Antitrypsin Deficiency

A deficiency in alpha-1 antitrypsin (Alpha-1) may result in liver disorders in children, infants, or adults. Adults are also at risk of lung disease from Alpha-1.

The disease causes the production of massive amounts of abnormal alpha-1 antitrypsin protein (AAT) by the liver. About eighty-five-percent of AAT does not pass through the liver causing scarring and liver damage.

In addition, when the blood is deficient in AAT, the lungs are susceptible to air pollution and cigarette smoke. Researchers are working to find treatment for the disease.

About Phase II (AROAAT2002)

Phase II AROAAT2002 is an open-label trial investigating ARO-AAT Arrowhead’s therapeutic RNA interference (RNAi). RNAi is a cellular mechanism that silences a gene using the gene’s own DNA sequence.

The first cohort consisted of four patients who received 200 mg ARO-AAT in weeks one, four, and sixteen.

In an open-label trial, as opposed to a blinded or masked trial, both the researchers and study participants are informed if the patient is receiving a drug or a placebo.

About the Trial Results

The trial results show improvement in biomarkers, which are molecules that indicate a normal or abnormal condition or disease. A decrease was evident in alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), serum biomarkers of liver injury.

ALT is generally detected in the liver. If it is elevated, the cause may be intrahepatic disease. If GGT is elevated, it is also possibly due to liver disease.

The four trial participants exhibited reductions in GGT and ALT of fifty-eight and sixty-six percent respectively.

Results of the AROAAT2002 trial were studied twenty-four weeks after the initial treatment. The researchers found that all four patients had a decrease in intra-hepatic Z-AAT and serum of up to ninety-five and ninety-three percent respectively. (The source article and results may be accessed here.)

Dr. Javier Martin, CMO of Arrowhead, indicated that the results of the trial exceeded their expectations. He said that while the company anticipated significant reductions in the Z-AAT monomer, there were also improvements in critical biomarkers, Z-AAT polymer decreases, and reductions in GGT and ALT.

Note that a monomer is a molecule that may be bonded to other molecules and form a polymer.

Dr. Martin said that the company is working with the FDA and other agencies to further streamline the program.

Dr. Pavel Strnad, a principal trial investigator from Aachen, Germany, commented that the trial results indicate that ARO-AAT has the potential to reduce liver injuries. Dr. Strnad added that since there were no major adverse lung events during treatment, it was an indication that the RNAi reduction of Z-AAT in the liver did not affect lung function negatively.

The doctor was pleased that his patients have agreed to remain with the study for a twelve-month extension.

AROAAT2002 (NCT03946449)

The NCT03946449 Phase 2 study will enroll the next three cohorts for a total of sixteen patients with AATD-related liver disease and use liver fibrosis as a baseline. The study is investigating the participant’s response to Arrowhead Pharmaceutical’s ARO-AAT. Eligibility requirements include a biopsy prior to the onset of dosing and a biopsy at the end of the study. Assessments will be conducted at six, twelve, eighteen, and twenty-four months of continuous ARO-AAT treatment.

As of August 2019, Arrowhead has also been evaluating ARO-AAT in the Phase 2/3 SEQUOIA trial.



Rose Duesterwald

Rose Duesterwald

Rose became acquainted with Patient Worthy after her husband was diagnosed with Acute Myeloid Leukemia four years ago. He was treated with a methylating agent While he was being treated with a hypomethylating agent, Rose researched investigational drugs being developed to treat relapsed/refractory AML.

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