Fitusiran prophylaxis superior to on-demand treatment for severe hemophilia
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Once-monthly fitusiran prophylaxis improved outcomes compared with on-demand treatment for patients with severe hemophilia A or B without inhibitors, according to study results presented at ASH Annual Meeting and Exposition.
The prophylactic regimen conferred significant benefit with regard to annualized bleeding, spontaneous bleeding and joint bleeding rates, results of the randomized phase 3 ATLAS-A/B study showed.
“Despite recent developments in hemophilia treatment, unmet needs exist for patients regarding prevention of bleeds, reduction of treatment burden and improvement in quality of life,” Alok Srivastava, MD, FRACP, FRCPA, FRCP, head of the department of hematology and Centre for Stem Cell Research at Christian Medical College, Vellore, in India, told Healio. “With its novel mechanism of action, fitusiran has the potential to provide an effective, constant and consistent hemostatic effect through a subcutaneous, prophylactic, therapeutic option for people with both hemophilia A or B without inhibitors with much less frequent dosing.”
Fitusiran (Sanofi) is an investigational, subcutaneously administered small interfering RNA therapy that targets antithrombin to enhance thrombin generation potential and rebalance hemostasis among people with hemophilia regardless of inhibitor status.
“Non-factor therapies [such] as fitusiran present a new therapeutic approach in hemophilia,” Srivastava said. “The novel siRNA technology enables fitusiran to harness natural mechanisms to rebalance thrombin generation via lowering of antithrombin.”
The open-label, multinational ATLAS-A/B trial included 120 males aged 12 years or older with severe hemophilia A or B without inhibitors.
Researchers assigned 80 patients to once-monthly fitusiran prophylaxis, administered in once-monthly 80-mg subcutaneous doses. The other 40 patients received on-demand factor concentrates for treatment of bleeding episodes. Treatment continued for 9 months.
Patient characteristics and baseline demographics appeared balanced in both treatment groups.
Three-quarters (77.5%) of study participants had hemophilia A (fitusiran, n = 62; on-demand treatment, n = 31) and about one-quarter (22.5%) had hemophilia B (fitusiran, n = 18; on-demand treatment, n = 9).
Annualized bleeding rate in the efficacy period — defined as day 29 after the first fitusiran dose up to day 246 — served as the primary endpoint.
Secondary endpoints included annualized spontaneous bleeding rate and annualized joint bleeding rate in the efficacy period, as well as health-related quality of life during the treatment period as assessed by the Haemophilia Quality of Life Questionnaire for Adults. Researchers also assessed tolerability and safety.
Seventy-nine patients (98.8%) assigned fitusiran and 37 patients (92.5%) assigned on-demand treatment completed the study.
The study met all primary and secondary efficacy endpoints.
Results showed fitusiran significantly reduced median observed annualized bleeding rate (0.0 vs. 21.8), equating to a reduction in estimated annualized bleeding rate of 89% (95% CI, 84.1-93.6). Forty patients (50.6%) assigned fitusiran experienced no bleeds that required on-demand treatment with factor concentrates.
Results also favored fitusiran with regard to median observed annualized spontaneous bleeding rate (0.0 vs. 16.1), equating to a reduction in estimated annualized spontaneous bleeding rate of 91.7% (95% CI, 85.9-95.1); median observed annualized joint bleeding rate (0.0 vs. 15.9), equating to a reduction in estimated annualized joint bleed rate of 90.3% (95% CI, 83.9-94.1); and improvements in transformed total health score (mean difference, –7.07; 95% CI, –11.23 to –2.9) and physical health score (mean difference, –19.75; 95% CI, –27 to –12.5).
“Some of the earlier studies with other products attempting to rebalance hemostasis did not achieve the desired results in clinical trials,” Srivastava said. “Compared with those outcomes, this fitusiran study met its primary and all secondary endpoints with once-monthly prophylactic 80-mg dosing, significantly reducing annualized bleeding rates for all treated bleeds, including joint bleeds, and achieving zero bleeds in about 50% of patients and less than three annual bleeds in nearly 85% of patients when compared with episodic or on-demand [treatment].”
A safety analysis included 79 patients who received at least one dose of fitusiran and 40 patients assigned on-demand treatment.
A higher percentage of patients assigned fitusiran experienced at least one treatment-emergent adverse event (78.5% vs. 45%).
Reported treatment-emergent serious adverse events in the fitusiran group generally appeared consistent with previously identified risks, according to investigators.
Researchers reported five treatment-emergent serious events in the fitusiran group and nine in the on-demand group. Treatment-emergent serious adverse events in the fitusiran group included two cases of cholelithiasis and one case each of cholecystitis, lower respiratory tract infection and asthma.
Two patients (2.5%) assigned fitusiran experienced treatment-emergent adverse events that led to discontinuation. One developed cholecystitis and another developed increased alanine aminotransferase.
Researchers reported no fatal treatment-emergent adverse events and no treatment-emergent thrombotic events.
“Up to now, the reported treatment-emergent adverse events were generally consistent with previously identified risks of fitusiran, or what would be anticipated in an adult and adolescent population with severe hemophilia A or B,” Srivastava said. “The sponsor has amended the protocol in ongoing studies, including a revised dose and dosing regimen and a target antithrombin range to mitigate the risk for thrombotic events. We need to wait for those results and further data to fully define the safety profile of fitusiran.”
Srivastava said he is optimistic that the range of dosages being evaluated will provide the research community “some very instructive data.”
“This is the first time in hemophilia therapy that we are not only seeing a novel approach through rebalancing of hemostasis, but also a unique attempt to correlate clinical efficacy with a specific biomarker, blood antithrombin level, which in turn reflects the dose of fitusiran,” Srivastava told Healio.
“The data presented at ASH are very encouraging and underscore the potential of fitusiran to address many of the persistent challenges in the management of hemophilia as an effective therapeutic option for patients, caregivers and physicians,” he added. “An important feature that could emerge from the range of doses being assessed already — again an unprecedented phenomenon in the history of hemophilia therapy — is that there could be unique possibilities for personalization of doses based [on individual] variations in responses, determined by a very specific biomarker.”
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Srivastava A, et al. Abstract LBA-3. Presented at: ASH Annual Meeting & Exposition; Dec. 11-14, 2021; Atlanta.
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