Benzinga | Jun 28, 2021 09:56AM EDT

Arrowhead Pharma Early Saturday Highlighted Presentation Of Added Interim 48-Week Liver Biopsy Results From Ongoing Study For Its Investigational RNA Interference Therapeutic Being Co-Developed With Takeda

Arrowhead Pharmaceuticals Inc. (NASDAQ:ARWR) today presented additional positive interim 48-week liver biopsy results from the ongoing AROAAT2002 study, an open-label Phase 2 clinical study of ARO-AAT, the company's second generation investigational RNA interference (RNAi) therapeutic being co-developed with Takeda Pharmaceutical Company Limited ("Takeda") as a treatment for the rare genetic liver disease associated with alpha-1 antitrypsin deficiency (AATD), at The International Liver Congress - The Annual Meeting of the European Association for the Study of the Liver (EASL).

The results demonstrate that, in the AROAAT2002 study, investigational ARO-AAT treatment led to improvements in multiple measures of liver health, including fibrosis, with substantial and sustained reductions in the level of mutant AAT protein (Z-AAT). In addition, ARO-AAT treatment was generally well tolerated after up to 1 year of treatment.

Javier San Martin, M.D., chief medical officer at Arrowhead, said: "We believe the interim results that were presented today at EASL represent an important breakthrough for the field and are encouraging for patients with alpha-1 liver disease, who currently have no available treatment options other than liver transplant. The data indicate that treatment with investigational ARO-AAT, being developed in collaboration with Takeda as TAK-999, resulted in substantial, sustained, and consistent reductions in the production of the toxic mutant Z-AAT protein, which has been identified as the cause of progressive liver disease in patients with alpha-1 antitrypsin deficiency. This reduction over 6 and 12 months led to multiple important signals associated with healing of patients' liver disease. Importantly, we believe ARO-AAT is the first investigational therapy to show this type of benefit in patients with alpha-1 liver disease. We want to thank all the investigators and patients for their participation in the study, and we look forward to the availability of additional results from this study and from our ongoing SEQUOIA study of ARO-AAT, which we anticipate will reach full enrollment during the third quarter of 2021."

Pharmacodynamics and Efficacy

After 24 weeks (cohort 1, n=4) and 48 weeks (cohort 2, n=5) of treatment with investigational ARO-AAT in the AROAAT2002 study, the following results were observed:

* Serum Z-AAT levels decreased in all patients

* Median decrease in intra-hepatic Z-AAT levels were: Total Z-AAT -80.1% (range -72 to -97%) Monomer -90% (range -79 to -97%) Polymer -81% (range* -42 to -97%) *Excluding 1 subject in cohort 1 that had very low Z-AAT polymer levels at baseline that increased at week 24

* Histological globule burden was reduced in all nine patients, with two achieving full resolution (total aggregate globule burden score=0)

* Six of the nine patients (2/4 after 24 weeks and 4/5 after 48 weeks) achieved a 1 or greater stage improvement in Metavir fibrosis stage, with no worsening of fibrosis in the other three patients Two patients had baseline F4 fibrosis (cirrhosis), with one patient achieving a two-stage improvement to F2 and the other patient achieving a one-stage improvement to F3

* Multiple biomarkers of liver health improved, including liver stiffness (FibroScan), liver enzymes alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), and PRO-C3, a marker of collagen formation

Safety and Tolerability

In AROAAT2002, investigational ARO-AAT demonstrated an acceptable safety profile and was generally well tolerated after up to 1 year of treatment. There were no treatment-emergent adverse events leading to drug discontinuation, dose interruptions, or study withdrawal. Lung function was assessed throughout the study and there were no clinically meaningful changes in percent predicted forced expiratory volume in 1 second (ppFEV1). Three serious adverse events (SAEs) were reported, but none were considered related to the study drug. All SAEs were moderate in severity and all resolved.

AROAAT2002 (NCT03946449) is a pilot open-label, multi-dose, Phase 2 study to assess the response to investigational ARO-AAT in 16 patients with AATD associated liver disease and baseline liver fibrosis. All eligible participants receive a pre-dose biopsy and an end of study biopsy. Treated participants will also be offered the opportunity to continue treatment in an open-label extension (OLE). Including the OLE, interim assessments will be made after 6 months, 12 months, 18 months, and 24 months of treatment with ARO-AAT.

Presentation Details

Title: ARO-AAT an investigational RNAi therapeutic demonstrates improvement in liver fibrosis with reduction in intra-hepatic Z-AAT burden

Authors: Pavel Strnad, et al.

Type: Late-Breaking Oral Presentation

Date and Time: June 26, 2021 at 12:15 CEST

A copy of the presentation materials may be accessed on the Events and Presentations page under the Investors section of the Arrowhead website.