In the phase III ATLAS-PPX trial, the subcutaneous investigational siRNA* therapeutic fitusiran significantly cut bleeding events compared with factor/bypassing agent (BPA) prophylaxis in people with haemophilia A or B with and 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, 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 when looking at it from the standpoint of the mean, 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. “When you look at the lead-in period when patients are on factor prophylaxis, ABR typically falls around 3 or 4. So 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 were cut in half with fitusiran vs factor/BPA (mean estimated AjBR** reduction, 51.5 percent; p=0.0242), as were 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

There were two suspected or confirmed thromboembolic events reported with fitusiran, which were considered adverse events of special interest (AESIs). One was a cerebrovascular accident; the other, a suspected thrombosis of the papilla 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 because of this, 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

ATLAX-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 hemostatic 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, and this was for both patients with and without inhibitors. These resulted in meaningful improvements in QoL,” he concluded.

*siRNA: Small interfering RNA

**AjBR/AsBR: Annualized joing bleeding rate/annualized spontaneous bleeding rate

***Muscle, internal, skin/mucosa treated bleeds

^#ALT/AST: Alanine aminotransferase/Aspartate aminotransferase

^##WFH: World Federation of Hemophilia