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Fitusiran cut bleeding in both hemophilia A and B with a monthly infusion compared with patients who had on-demand bypassing agents (BPAs), results from two phase III trials showed.

In both trials -- , which evaluated fitusiran in patients with inhibitors, and which evaluated the therapy in those without inhibitors – the number of bleeding events in patients on fitusiran was reduced by about 90% compared with patients treated with on-demand BPAs.

ATLAS-INH was featured during a plenary session at the , and ATLAS-A/B was presented during a late-breaking abstract session at the meeting.

"What we have with fitusiran is the first of what many people would call a cross-segment prophylactic strategy," said ATLAS-A/B co-author Steven Pipe, MD, medical director of the Pediatric Hemophilia and Coagulation Disorders Program and the Special Coagulation Laboratory of the University of Michigan in Ann Arbor, during an ASH press briefing. "This is going to have the same efficacy, and that's being realized in the trials, in hemophilia A or hemophilia B, with inhibitors and without inhibitors."

Fitusiran is a novel, investigational prophylactic drug based on the small interfering RNA molecule, which targets antithrombin to restore thrombin generation and rebalance hemostasis in hemophilia patients.

The primary endpoint of both trials was the annualized bleeding rate (ABR) in patients with hemophilia A or B with or without inhibitors on fitusiran prophylaxis compared with those on standard-of-care on-demand BPA. Secondary endpoints were spontaneous ABR, joint ABR, and quality of life, measured by the Hemophilia Quality of Life Questionnaire for Adults (), frequency of bleeding events during the onset period, and tolerability.

ATLAS-INH

ATLAS-INH included patients ages 12 or older with hemophilia A or B, with inhibitors, who were receiving on-demand treatment with BPAs. Patients were randomized on a 2:1 basis to receive monthly 80 mg subcutaneous fitusiran prophylaxis (with use of on-demand BPAs for the treatment of breakthrough bleeds) or to continue with on-demand BPA. There were more patients with hemophilia A than B in both groups -- 29 and nine, respectively, in the fitusiran group; and 16 and three in the BPA group.

Guy Young, MD, of Children's Hospital Los Angeles at the University of Southern California, who presented the data, reported that the observed median ABR for all, spontaneous, and joint bleeding events was 16.8, 13.4, and 11.7, respectively, for BPA patients, and 0.0 for each of those bleeding events in the fitusiran arm.

The estimated mean ABR for all bleeding events was 1.67 (95% CI 1.01-2.74) in the fitusiran arm and 18.07 (95% CI 10.60-30.81) in the BPA arm, for a rate ratio of 0.09 (95% CI 0.04-0.19, P<0.0001).

"This is just not a statistically significant endpoint, but it's definitely a clinically meaningful and important endpoint as well," said Young.

In addition, he reported:

• The estimated mean observed ABR for spontaneous bleeds was 0.87 (95% CI 0.49-1.55) in the fitusiran arm and 15.68 (95% CI 9.28-26.47) in the BPA arm, for a rate ratio of 0.06 (95% CI 0.03-0.12, P<0.0001)

• The estimated mean observed ABR for joint bleeds in the fitusiran arm was 1.35 (95% CI 0.80-2.28) and 13.76 (95% CI 7.95-23.81) in the BPA arm, for a rate ratio of 0.10 (95% CI 0.05-0.21, P<0.0001)

• A total of 25 of the 38 patients (65.8%) in the fitusiran arm did not have any observed bleeds, compared with one of 19 patients (5.3%) in the BPA arm during the 9-month phase of the study

ATLAS-A/B

Atlas-A/B included 79 patients in the fitusiran arm and 40 in the on-demand BPA arm; 93 had hemophilia A (62 in the fitusiran arm and 31 in the BPA arm) and 27 had hemophilia B (18 in the fitusiran arm and nine in the BPA arm), reported Alok Srivastava, MD, of Christian Medical College in Vellore, India.

Other major findings included:

• The median observed ABR for all bleeding events was 0.0 (IQR 0.0-3.4) in the fitusiran arm and 21.8 (IQR 8.4-41.0) in the BPA arm, with an estimated ABR reduction in the fitusiran arm versus the BPA arm of 89.9% (95% CI 84.1%-93.6%, P<0.0001); 40 patients (50.6%) in the fitusiran arm had no bleeds requiring on-demand factor concentrates

• The median observed ABR for spontaneous bleeding events was 0.0 (IQR 0.0-1.7) in the fitusiran arm and 16.1 (IQR 3.4-27.6) in the BPA arm, with an estimated reduction in the fitusiran arm compared with the BPA arm of 91.7% (95% CI 85.9%-95.1%, P<0.0001)

• The median observed ABR for joint bleeding events was 0.0 (IQR 0.0-3.4) in the fitusiran arm and 15.9 (IQR 4.2-33.5) in the BPA arm, with an estimated ABR reduction in the fitusiran arm versus the BPA arm of 90.3% (95% CI 83.9%-94.1%, P<0.0001).

Safety and Quality of Life

Treatment-emergent adverse events (TEAEs) of special interest in ATLAS-INH included 11 instances of elevated alanine transaminase (ALT) or aspartate transaminase in the fitusiran arm. All were mild to moderate in severity, and none of these patients discontinued the study drug as a result of these elevations, said Young.

Thromboembolic events occurred in two patients, with one patient who had a suspected vessel thrombosis possibly related to fitusiran who was discontinued from the study.

In ATLAS-AB, TEAEs in the fitusiran arm included cholelithiasis in two patients, and cholecystitis, lower respiratory tract infection, and asthma in one patient each. In the fitusiran arm two patients had TEAEs that resulted in discontinuing the drug (cholecystitis and increased ALT), Srivastava said, adding that no TEAEs of thrombosis were reported.

Regarding quality-of-life measurements from baseline to end of study (based on the Haem-A-QoL tool in which a negative score suggests improvement), ATLAS-INH patients in the fitusiran arm had a total score of -15.27 compared with -0.42 in the BPA on-demand arm, and physical health score- of 30.67 of -1.34.

Quality-of-life scores in ATLAS-A/B were comparable.

"That's not surprising," Young said. "If you only have to dose once a month subcutaneously and you're not bleeding, of course your quality of life is going to improve, and these are just the numbers that underlie that and prove that."

"What we are able to achieve with fitusiran is that steady state hemostatic re-balancing, which means 24-7, 365 days a year, the patient has the same hemostatic balance restoration, which I think liberates them for more spontaneity in their day-to-day activities, [and not be] wedded to the timing of their infusions," Pipe explained. "I think it has the opportunity to really transform the day-to-day lives of patients going forward."