Fitusiran cuts bleeding in haemophilia patients regardless of inhibitor use

In the phase III ATLAS-PPX trial, the investigational siRNA* therapeutic fitusiran significantly cut bleeding events compared with factor/bypassing agent (BPA) prophylaxis in patients with haemophilia A or B with or without inhibitors.

“In the factor/BPA prophylaxis group, the observed median annualized bleeding rate (ABR) was 4.4, while with fitusiran, the median was zero,” said Dr Guy Young from the Children’s Hospital Los Angeles in Los Angeles, California, US.

Looking at estimated mean ABR, the values for the respective factor/BPA and fitusiran cohorts were 7.5 and 2.9, translating to a 61-percent reduction in estimated ABR in favour of fitusiran, Young said. The p value was 0.0008. [EHA 2023, abstract S303]

Among those with inhibitors who had BPA prophylaxis, median ABR was 6.5.

For those without inhibitors on factor prophylaxis, median ABR was 4.4. “Looking at the lead-in period when patients are on factor prophylaxis, ABR typically falls around 3 or 4. This is representative of what you would expect with factor prophylaxis,” noted Young.

Only 17 percent of patients on factor/BPA prophylaxis experienced zero treated bleeds whereas with fitusiran, the rate was 63 percent. There were also more fitusiran than factor/BPA recipients with ≤3 bleeds (89 percent vs 66 percent).

 

Joint and spontaneous bleeds, antithrombin levels

Joint bleeds decreased by half with fitusiran vs factor/BPA (mean estimated AjBR** reduction, 51.5 percent; p=0.0242), as did spontaneous bleeds (mean estimated AsBR** reduction, 55.6 percent; p=0.0129). Median ABRs were 0 for other clinically relevant bleeds*** in the fitusiran efficacy period.

Among those with inhibitors, mean reduction in antithrombin levels was sustained at –81 to –88 percent. In the noninhibitor group, the rates were nearly similar (–82 to –90 percent). “[These show that] the mechanism of action of fitusiran is not dependent upon whether you have an inhibitor or not,” said Young.

 

Safety, QoL

Adverse events of special interest (AESI) with fitusiran included one cerebrovascular accident and one suspected case of thrombosis of the papillae of the eye. Young underlined that there is a risk of increasing thrombosis when lowering antithrombin.

Another AESI with fitusiran was ALT/AST^# elevations (25 percent), but this remained stable or dropped over time, and patients did not discontinue the drug or withdrew from the study, noted Young. “While this is an adverse effect we have to keep an eye on, it did not result in damage to the patients, at least in the short term.”

Cholecystitis and cholelithiasis (7.5 percent for both) were also AESIs that shall be monitored, according to Young.

Fitusiran also led to greater absolute reductions from baseline total (least squares mean [LSM] change, –7.62 vs –3.07; p=0.0039) and physical health scores (LSM change, –9.60 vs –6.00; p=0.3008) than factor/BPA. “In the Haem-A-QoL tool, negative numbers are better … These suggest QoL improvements with fitusiran relative to factor/BPA prophylaxis,” said Young.

 

Findings align with guidelines

ATLAS-PPX comprised 80 males with severe haemophilia A or B who have had prior factor/BPA prophylaxis for ≥6 months (n=50 without inhibitors). All participants continued their factor/BPA for 6 months. Following which, 65 participants switched to once-monthly fitusiran 80 mg (n=46 without inhibitors). About three-quarters had haemophilia A.

Historically, haemophilia treatment relied upon regular IV infusions of missing clotting factor VIII or IX. Today, the WFH^## guidelines recommend regular administrations of a haemostatic agent/s with the goal of preventing bleeding and improving QoL. [Haemophilia 2020;26:1-158]

“In our study, fitusiran prophylaxis resulted in a statistically significant reduction in bleeding events compared with factor/BPA prophylaxis in patients with or without inhibitors. These resulted in meaningful improvements in QoL,” he concluded.