Fitusiran prophylaxis trumps standard care in preventing bleeds in haemophilia

Prophylactic use of the investigational antithrombin siRNA fitusiran significantly reduces bleeding events in people with severe haemophilia compared with on-demand treatment with clotting factor concentrates, according to the phase III ATLAS-A/B trial presented at ASH 2021.

Standard treatment for haemophilia involves frequent infusions of clotting factor concentrates to stave off bleeding. Although such therapy has substantially improved the outlook for patients with haemophilia, they still need to be careful to avoid contact sports that might lead to bleeding, especially when the levels of clotting factors turn low.

Fitusiran is a novel experimental siRNA therapeutic agent developed to target antithrombin in order to enhance the blood clotting potential and restore balance in haemostasis in patients with haemophilia. It is designed such that the drug maintains at a steady concentration from around 4 weeks onwards after therapy initiation — thereby helping to prevent spontaneous bleeds or bleeding after a minor injury.

“This is a new class of drugs that brings a high level of haemostasis, well beyond what we would have imagined,” said lead author Dr Alok Srivastava from Christian Medical College in Vellore, India.

Patients treated with fitusiran had significantly lower annualized bleeding rate (ABR) than those given factor concentrates on demand (median, 0.0 vs 21.8), which translates to a dramatic 90 percent reduction in the risk of bleeding annually (p<0.0001). Moreover, half of the patients in the fitusiran group (50.6 percent) did not experience any bleeds that required on-demand treatment with factor concentrates. [ASH 2021, abstract LBA-3]

“The convenience of this drug, and the high proportion of people who have zero or only a few bleeds, suggests we can really make a difference in the quality of life for people with severe haemophilia,” said Srivastava.

In the multinational, phase III, open-label study, 120 male patients aged ≥12 years with severe haemophilia A or B who were previously treated with on-demand concentrates and had yet to develop counteracting inhibitors were randomized 2:1 to treatment for 9 months with either subcutaneous fitusiran prophylaxis or on-demand factor concentrates for bleeding episodes.  

In addition to achieving the primary endpoint of lower ABR, secondary outcomes such as annualized spontaneous bleeding rate (AsBR; median, 0.0 vs 16.1; 91.7 percent reduction; p<0.0001) and annualized joint bleeding rate (AJBR; median, 0.0 vs 15.9; 90.3 percent reduction; p<0.0001) were also significantly reduced with fitusiran vs on-demand factor concentrates.

“This reduction in bleeding was associated with a meaningful improvement in health-related quality of life,” Srivastava reported.

Compared with the on-demand group, the fitusiran group experienced significantly better quality of life, as reflected in improvements in the transformed total and physical health score (least-squares mean difference, -7.07; p=0.0011 and -19.75; p<0.0001, respectively).

“With a monthly medication, haemophilia becomes easier to treat,” explained Srivastava. “You can reduce the number of times you have to receive intravenous injections, and the steady blood level of the drug means you can feel safer being more active and perhaps a little less fearful of bleeding in your daily activities.” 

Overall, 78.5 percent of patients in the fitusiran arm experienced at least one treatment emergent adverse event (TEAE) compared with 45 percent in the on-demand arm. Serious TEAEs occurred in 6.3 percent of the patients in the fitusiran arm — which included cholecystitis, cholelithiasis, asthma, and lower respiratory tract infection — compared with 12.5 percent in the on-demand arm.

None of the TEAEs were fatal, and there were no cases of thrombosis.

“With the aim of further enhancing the benefit-risk profile of fitusiran, a revised regimen with reduced dose and frequency is currently being evaluated in ongoing clinical studies,” stated  Srivastava, who also suggested that studies be done to guide the management of fitusiran-treated patients in special scenarios such as surgery or trauma.