Fazirsiran is an investigational RNA interference (RNAi) therapeutic currently under development. It is designed to address certain genetic conditions at their source and is being developed through the collaborative efforts of Arrowhead Pharmaceuticals and Takeda Pharmaceuticals USA. Fazirsiran is undergoing clinical trials.
The Condition Fazirsiran Addresses
Fazirsiran is being developed to treat liver disease associated with Alpha-1 Antitrypsin Deficiency (AATD), a genetic disorder affecting approximately 1 in 2,500 to 5,000 people in the United States and Europe. This disorder arises from mutations in the SERPINA1 gene, which is responsible for producing the alpha-1 antitrypsin (AAT) protein. The most common variant is the Z mutant allele, leading to the production of a misfolded AAT protein known as Z-AAT.
The liver is the primary site where the AAT protein is synthesized and secreted. However, the Z-AAT protein cannot be efficiently transported out of liver cells (hepatocytes). Instead, it accumulates within the endoplasmic reticulum of these cells, forming abnormal globules. This retention and aggregation of the misfolded protein triggers intracellular injury, including endoplasmic reticulum stress, and cell death.
Over time, this continuous cellular damage and inflammation can lead to progressive liver disease. This damage initiates hepatic fibrosis, or scarring of the liver. As fibrosis progresses, it can result in severe conditions such as cirrhosis, where healthy liver tissue is replaced by scar tissue, and an increased risk of hepatocellular carcinoma, a type of liver cancer.
How Fazirsiran Works
Fazirsiran leverages a natural biological process known as RNA interference (RNAi) to address the underlying cause of liver disease in AATD. RNAi is a cellular mechanism that can intercept and silence specific “instructions” within a cell before they can be fully carried out. In a cell, genes contain blueprints, which are copied into messenger RNA (mRNA) molecules. These mRNA molecules then carry instructions to cellular factories to build proteins.
In the context of AATD, the mutated SERPINA1 gene produces a faulty mRNA that carries the instructions for making the abnormal Z-AAT protein. Fazirsiran is designed as a small interfering RNA (siRNA) molecule. These siRNA molecules are delivered to the liver cells, where they recognize and bind to the specific mRNA carrying the instructions for producing the Z-AAT protein.
Once bound, the siRNA triggers the degradation of this harmful mRNA before the Z-AAT protein can be made. This action prevents the creation of the misfolded Z-AAT protein at its source within the hepatocytes. By reducing the production of this toxic protein, fazirsiran aims to alleviate the burden on liver cells, potentially halting or slowing the progression of liver damage caused by Z-AAT accumulation.
Clinical Trial Outcomes
Clinical studies have provided encouraging data regarding fazirsiran’s effects on liver disease associated with AATD. In a Phase 2 study, patients receiving fazirsiran demonstrated significant reductions in the levels of the mutant Z-AAT protein in both serum and liver tissue. Patients treated with fazirsiran experienced a median reduction of 94% in total liver Z-AAT.
Dose-dependent reductions in serum Z-AAT concentration were also observed, with declines of 74%, 89%, and 94% at week 48 for 25 mg, 100 mg, and 200 mg doses, respectively. This reduction in Z-AAT accumulation was further supported by a decrease in hepatic globule burden, a histological measure of Z-AAT accumulation within liver cells, which improved from a mean score of 5.9 at baseline to 2.3 after treatment.
Beyond protein reduction, fazirsiran treatment was associated with improvements in liver enzyme concentrations, such as alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), which are indicators of liver health. Regression of liver fibrosis, or scarring, was observed in a portion of trial participants. In one study, 50% of fazirsiran-treated patients showed at least a one-point improvement in METAVIR liver fibrosis stage. These outcomes indicate a potential for the drug to not only halt but also reverse some of the liver damage caused by AATD.
Administration and Safety Profile
Fazirsiran is administered through subcutaneous injection, meaning it is given just under the skin. In clinical trials, the typical dosing frequency has involved initial doses on day 1 and week 4, followed by injections every 12 weeks. This allows for a relatively infrequent dosing schedule, which can improve patient convenience.
Fazirsiran has generally been well tolerated in clinical studies. The adverse events reported were generally balanced between fazirsiran and placebo groups. Common side effects observed included arthralgia, or joint pain, and increased concentrations of blood creatinine kinase. There were no dose-dependent increases in the frequency or severity of these adverse events. No adverse events led to the discontinuation of treatment in the trials, and pulmonary function tests remained stable over the study period.