2021 ASH blockbuster Fitusiran preventive treatment of patients with type A or type B hemophilia patients with the efficacy and safety of the first batch of results announced

The annual American Society of Hematology (ASH) annual meeting is one of the largest and most comprehensive international academic conferences in the field of hematology in the world
.

This year, the 63rd ASH Annual Conference will be held offline and online from December 11th to 14th
.

A study by Professor Alok Srivastava's team from India was selected for the Late-Breaking Abstracts (LBA) section of this year's ASH Annual Conference.
The editor will organize its main content as follows for the reference of readers
.

Research background Hemophilia is a rare bleeding disorder characterized by the lack of FVIII or FIX, which leads to ineffective blood clot formation due to thrombin generation disorders
.

fitusiran is a subcutaneously injected siRNA preparation that targets antithrombin to improve the thrombin generation potential of hemophilia patients and rebalance the hemostatic function, regardless of the inhibitor status
.

Professor Alok Srivastava’s team conducted a phase III study (ATLAS-A/B; NCT03417245), which explored fitusiran prophylactic treatment versus coagulation factor concentrate on-demand (OD) treatment for hemophilia A or B without inhibitors Efficacy and safety of patients
.

Research Methods This phase III, multi-country, multi-center, randomized, open-label study evaluated the efficacy and safety of fitusiran in the treatment of male patients with severe hemophilia A or B who are ≥12 years old and without inhibitors.
These patients have previously Receive OD treatment
.

Eligible patients randomly receive 80 mg SC fitusiran (fitusiran group) or coagulation factor concentrate OD for bleeding episodes (OD group) at a 2:1 ratio.
The treatment period is 9 months
.

The primary end point is the annual bleeding rate (ABR) during the efficacy period (day 29 to day 246 after the first use of fitusiran), and the secondary endpoints include the annualized spontaneous blood rate (AsBR) and annualized joint bleeding rate (AJBR) during the efficacy period.
And health-related quality of life during the treatment period (HRQoL; assessed by Haem-A-QoL)
.

The safety and tolerability were evaluated throughout the study
.

Research results 120 patients were randomly assigned (80 in the fitusiran group; 40 in the OD group); 79 patients (98.
8%) in the fitusiran group and 37 patients (92.
5%) in the OD group completed the study
.

Ninety-three patients had hemophilia A (62 cases in fitusiran group, 31 cases in OD group), and 27 patients had hemophilia B (18 cases in fitusiran group, 9 cases in OD group)
.

The baseline demographic characteristics of the two groups were similar
.

The median ABRs of the fitusiran group and the OD group were 0.
0 (IQR, 0.
0-3.
4) and 21.
8 (IQR, 8.
4-41.
0), respectively; 40 patients (50.
6%) in the fitusiran group did not need to be treated with coagulation factor concentrate OD Bleeding
.

Compared with the OD group, the estimated ABR of the fitusiran group was significantly reduced (decrease by 89.
9% [95% CI, 84.
1%-93.
6%], P<0.
0001)
.

The median AsBR of the fitusiran group and the OD group were 0.
0 (IQR, 0.
0-1.
7) and 16.
1 (IQR, 3.
4-27.
6), respectively.
Compared with the OD group, the estimated AsBR of the fitusiran group was significantly reduced (91.
7% [95% CI] , 85.
9%-95.
1%], P<0.
0001)
.

The median AJBR of the fitusiran group and the OD group were 0.
0 (IQR, 0.
0-3.
4) and 15.
9 (IQR, 4.
2-33.
5), respectively.
Compared with the OD group, the estimated AJBR of the fitusiran group was significantly reduced (a decrease of 90.
3% [95% CI , 83.
9%-94.
1%], P<0.
0001)
.

 Compared with the OD group, the fitusiran group's total score and physical fitness score after conversion were also significantly improved (LS mean difference was -7.
07[95%CI, -11.
23 to -2.
90], P=0.
0011; -19.
75[95%CI , -27.
00 to -12.
50], P<0.
0001)
.

79 patients who received fitusiran treatment and 40 patients in the OD group were included in the safety analysis
.

Overall, 62 patients (78.
5%) in the fitusiran group and 18 patients (45%) in the OD group experienced ≥1 "treatment period" adverse events (TEAE)
.

In the 5 patients (6.
3%) of the fitusiran group, a total of 5 "treatment period" serious adverse events (TESAE) were reported, and in the 5 patients (12.
5%) of the OD group, a total of 9 TESAEs were reported
.

TESAEs in the fitusiran group included cholelithiasis (2 cases, 2.
5%), cholecystitis, lower respiratory tract infections, and asthma (1 case each, 1.
3%)
.

Two patients (2.
5%) in the fitusiran group developed TEAEs (cholecystitis and elevated alanine aminotransferase) that caused the discontinuation of fitusiran
.

No thrombosis occurred and no fatal TEAE was reported
.

Research conclusions This phase III study met all key primary and secondary endpoints
.

Specifically, compared with OD treatment, the monthly 80mg SC fitusiran preventive treatment showed that the ABR, AsBR and AJBR of patients with severe hemophilia A or B without inhibitors were significantly reduced (about 90% each)
.

The reduction in bleeding is associated with a meaningful improvement in HRQoL
.

The reported TESAE is generally consistent with the previously determined risk of fitusiran
.

In order to further improve the benefit-risk profile of fitusiran, clinical studies are currently underway to evaluate the dose reduction and frequency revision protocol
.

Reference source: Alok Srivastava, et al.
2021 ASH.
Abstract LBA-3.
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