Introduction

Fitusiran is a synthetic small interfering RNA (siRNA) molecule directed against antithrombin that is used as prophylaxis against bleeding episodes in patients with hemophilia A or B. Fitusiran has been linked to mild-to-moderate ALT elevations during therapy and to rare cases of acute liver injury with jaundice. It has also been associated with cholelithiasis and cholecystitis.

Background

Fitusiran (fit” ue sir’ an) is a synthetic, double-stranded, small interfering RNA (siRNA) directed against antithrombin, which results in an increase in coagulability and decrease in bleeding episodes in patients with hemophilia. The two major forms of hemophilia, hemophilia A and B, are genetic X-linked disorders due to deficiency in coagulation factors VIII (hemophilia A) or IX (hemophilia B). Both forms of hemophilia are rare, hemophilia A occurring in approximately 1:5,000 and hemophilia B in 1:25,000 live male births. Both disorders are characterized by frequent episodes of bleeding occurring spontaneously or with minor trauma that can result in disability and early mortality. The current standard therapy of hemophilia A and B is use of intravenous factor VIII or IX infusions for acute bleeding episodes and prophylactic replacement therapy using infusions every 1 to 2 weeks. However, despite coagulation factor prophylaxis, bleeding episodes still occur particularly in patients who develop neutralizing antibodies (inhibitors). Fitusiran reduces bleeding episodes by inhibition of antithrombin, a liver produced protein which acts as a natural anticoagulant, terminating the coagulation cascade induced by thrombin. Fitusiran is a double-stranded RNA conjugated with N-acetyl-galactosamine which is taken up by the asialoglycoprotein receptor found only on hepatocytes. Within hepatocytes, the double-stranded siRNA is cleaved into smaller fragments and separated into single strands that bind and silence the mRNA of antithrombin. In animal models of hemophilia, fitusiran reduced antithrombin levels and improved hemostasis. In placebo-controlled trials of fitusiran in patients with hemophilia A or B with and without inhibitors, single injections of fitusiran resulted in dose related reductions in antithrombin. With monthly or every other month dosing, the annualized rates of bleeding episodes decreased by an average of 70% and a proportion of patients had no bleeding episodes. Fitusiran was approved for use in the United States for patients with hemophilia A or B with or without inhibitors in 2025. Current indications are limited to adults and children 12 years of age or older. Fitusiran is available in solution in single-dose pre-filled pens of 50 mg (in 0.5 mL) and in single dose vials of 20 mg (in 0.2 mL) under the brand name Qfitlia. The recommended initial dose regimen is 50 mg subcutaneously once every 2 months with monitoring of antithrombin levels and dose adjustment to maintain antithrombin levels at 15%-35% of normal. Fitusiran is generally well tolerated with few side effects attributable to the drug, the product label listing only viral and bacterial infections. Less common, but more severe side effects include thrombotic events and acute and recurrent gallbladder disease and its complications which can lead to cholecystectomy.

Hepatotoxicity

Hemophilia A and B are rare, and the pivotal trials of fitusiran were conducted in rather small numbers of patients for limited periods of time, so the full spectrum of hepatotoxicity may not be fully known. Nevertheless, in the registration-controlled trials using the highest doses of fitusiran [80 mg every month], serum aminotransferase elevations arose above 3 times the upper limit of normal (ULN) in 17% to 32% of treated patients versus none of the controls. Levels above 5 times ULN were rare, but one patient developed elevations with jaundice and required discontinuation which resulted in prompt resolution. This high rate of ALT elevations was not seen with the currently recommended lower dose regimen. Using an initial dose of 50 mg every two months followed by dose adjustments to maintain antithrombin levels of 15% to 35%, ALT elevations above 3 times ULN arose in only 3.4% of patients, and there were no instances of clinically apparent liver injury or jaundice with ALT elevations. Since approval of fitusiran, there have been no reports of drug-induced liver injury, but its clinical use has been limited. Thus, fitusiran appears to be capable of causing clinically apparent acute liver injury, but the frequency, clinical features, and severity of such episodes have not been defined.

The increased risk for gallbladder disease associated with fitusiran therapy is not well understood, but 17% of patients treated with the 80 mg dose given monthly vs none of the controls developed symptomatic cholecystitis, cholangitis, or choledocholithiasis. Some patients developed pancreatitis, and a proportion required cholecystectomy. Again, this adverse event was less frequent in patients receiving the currently recommended regimen of 50 mg every two months with dose adjustments, occurring in only 4% of patients, only one of whom required cholecystectomy. Patients with acute cholecystitis or cholangitis can have accompanying elevations in liver tests. For this reason, it is important to rule out gallbladder disease as a cause when elevations in liver associated enzymes are found.

Likelihood score: D (possible cause of clinically apparent liver injury).

Mechanism of Injury

The cause of hepatic injury and gallbladder disorders from the fitusiran is unknown. Fitusiran is metabolized endo- and exo-nucleases and is not a substrate of cytochrome P450 enzymes. Serum aminotransferase elevations rarely occur with other siRNA therapeutic agents. One possibility is that the suppression of antithrombin activity may result in hepatocellular injury by an unknown mechanism or that the mRNA suppression may not be completely specific for antithrombin and effect synthesis of other essential proteins.

Outcome and Management

The liver injury associated with fitusiran therapy has been mild, rarely associated with jaundice or symptoms, and rapidly resolving with discontinuation or even dose adjustment. In prelicensure clinical trials, patients were followed carefully for evidence of liver injury and current recommendations are that liver tests be monitored regularly, at least monthly for six months after the initial dose or after any dose increase, and as clinically indicated thereafter. Temporary interruption or discontinuation is recommended for significant and persistent serum aminotransferase elevations or any elevations with jaundice or symptoms.

Drug Class: Genetic Disorder Agents

Other Therapeutic siRNA Agents: Givosiran, Patisiran, Golodirsen, Eteplirsen