Fitusiran prophylaxis ‘great option’ for reducing bleeds in people with hemophilia A or B
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Key takeaways:
- The subcutaneously administered small interfering RNA therapy conferred a 90.8% reduction in the annualized bleeding rate among people with inhibitors.
- Half of those without inhibitors had no bleeding events.
Once-monthly prophylactic fitusiran resulted in significantly fewer bleeding episodes compared with on-demand treatment among men with hemophilia A or B with or without inhibitors, according to results of two randomized phase 3 studies.
Findings from the ATLAS-INH trial published in The Lancet revealed two-thirds of men with hemophilia A or B with inhibitors who received prophylactic fitusiran (Sanofi) — a subcutaneous small interfering RNA therapy — did not require treatment for a bleeding episode during the study period compared with one patient in a comparator group that received on-demand treatment only.
Meanwhile, results of the ATLAS-A/B trial published in The Lancet Hematology showed more than half of participants with hemophilia A or B without inhibitors treated prophylactically with the investigational therapy did not require treatment for a bleeding episode compared with 5% of patients who received on-demand treatment.
The clinical efficacy suggests a major role for prophylactic fitusiran in treatment of both hemophilia A and B with or without inhibitors, but further study is needed to determine proper dosing and fully understand the scope of treatment-related toxicities, investigators on both studies noted.
“Once-monthly subcutaneous fitusiran is a safe and effective option for managing patients with hemophilia A or B with inhibitors,” Guy Young, MD, ATLAS-INH study investigator, director of the hemostasis and thrombosis program at Children’s Hospital Los Angeles and professor of pediatrics at Keck School of Medicine of USC, told Healio. “Thus far, there are no effective options for [patients with] hemophilia B with inhibitors, and fitusiran may represent a great option for those patients.”
With inhibitors: ATLAS-INH
ATLAS-INH is an international, randomized, open-label study to determine the safety and effectiveness of fitusiran compared with standard on-demand treatments for individuals with hemophilia A or B with inhibitors.
In the study, Young and colleagues randomly assigned 57 men (median age, 27 years; interquartile range, 19.5-33.5) with severe hemophilia A or B with inhibitors in a 2:1 ratio to receive either subcutaneous fitusiran dosed at 80 mg once monthly as prophylaxis therapy (n = 38) or to continue receiving bypassing agents on demand (n = 19) for a 9-month study period.
Mean annualized bleeding rate among the intent-to-treat population during the study period served as the study’s primary endpoint. Investigators evaluated safety as a secondary endpoint.
Investigators reported a significantly lower annualized bleeding rate among patients in the fitusiran prophylaxis group compared with those who received on-demand therapy (1.7 [95% CI, 1-2.7] vs. 18.1 [95% CI, 10.6-30.8]).
The improvement seen with fitusiran prophylaxis represented a 90.8% (95% CI, 80.8-95.6) reduction in the annualized bleeding rate.
Twenty-five patients (66%) in the fitusiran prophylaxis group had no bleeding events requiring treatment during the study period compared with one patient (5%) in the on-demand treatment group.
No treatment-related deaths occurred during the study. However, suspected or confirmed thromboembolism occurred in two patients (5%) who received fitusiran prophylaxis.
Investigators reported increased alanine aminotransferase occurred in 32% of patients eligible for safety analysis in the fitusiran prophylaxis group. No similar cases occurred in the on-demand treatment group.
Without inhibitors: ATLAS-A/B
ATLAS-A/B is an international, multicenter, randomized, open-label study to investigate the safety and efficacy of fitusiran prophylaxis vs. episodic on-demand treatment with clotting factor concentrates among males with hemophilia A or B without inhibitors.
In the study, Alok Srivastava, MD, professor in the department of hematology at Christian Medical College in Vellore, India, and colleagues randomly assigned 120 participants in a 2:1 ratio to receive either prophylactic therapy with subcutaneous fitusiran 80 mg once monthly (n = 80; mean age, 33.9 ± 14.6 years; range, 12-68) or on-demand clotting factor concentrates (n = 40; mean age, 33.6 ± 13·6 years; range, 12–60) for a 9-month period. The investigators stratified randomization by the number of bleeding events in the 6 months prior to screening ( 10 bleeds and > 10 bleeds) and hemophilia type.
Mean annualized bleeding rate among the intent-to-treat population during the study period served as the study’s primary endpoint. Investigators evaluated safety as a secondary endpoint.
Investigators reported a median annualized bleeding rate of zero (interquartile range, 0–3.4) in the fitusiran group compared with 21.8 (interquartile range, 8.4-41) in the on-demand treatment group.
Fitusiran prophylaxis resulted in a significantly lower estimated mean annualized bleeding rate compared with on-demand treatment (3.1 [95% CI, 2.3-4.3] vs. 31 [95% CI, 21.1-45.5]).
Forty patients (51%) treated with fitusiran had no reported bleeds requiring treatment compared with two patients (5%) in the on-demand treatment group.
Eighteen patients (23%) eligible for safety analysis in the fitusiran group had reported increased alanine aminotransferase concentration during the study period. Hypertension occurred in four patients who received on-demand treatment, making it the most frequently reported treatment-related adverse event among patients in the group.
No treatment-related deaths or thrombosis occurred during the study.
Clinical implications
Further study to optimize the dosing regimen is still required to “minimize the risks and maximize the benefits” of prophylactic fitusiran, Young said. Additionally, more investigation is needed to understand the scope of the treatment’s potential adverse effect on liver function, he added.
Nevertheless, Young said fitusiran could become the “go-to medication” for patients with hemophilia B.
“There is no current subcutaneous medication option for [patients with] hemophilia B without inhibitors and, thus, fitusiran offers such a low treatment burden option for all [patients with] hemophilia B,” Young told Healio.
Emicizumab-kxwh (Hemlibra, Genentech) — a bispecific factor IXa- and factor X-directed antibody — is an effective option for individuals with hemophilia A, but some recipients still experience frequent bleeding events whereas, in rare cases, others are unable to tolerate the agent, he said.
“Fitusiran can offer a second option for [patients with] hemophilia A who are interested in a subcutaneous therapy,” Young said.
In an editorial that accompanied the ATLAS-A/B study, Victor Jiménez-Yuste, MD, PhD, and María Teresa Álvarez-Román, MD, both of the department of hematology at La Paz University Hospital and University of Madrid, noted the broader potential of fitusiran.
“Developments in hemophilia care have paved the way towards transformative therapies that address the limitations of current factor-replacement regimens,” they wrote. “Fitusiran is one of the first therapeutics to provide an effective and safe prophylactic alternative for both hemophilia A and hemophilia B without inhibitors, opening the door to its use in the treatment of other severe coagulation disorders.”
References:
- Jiménez-Yuste V, et al. Lancet Haematol. 2023;doi:10.1016/S2352-3026(23)00057-1.
- Srivastava A, et al. Lancet Haematol. 2023;doi:10.1016/S2352-3026(23)00037-1.
- Young G, et al. Lancet. 2023;doi:10.1016/S0140-6736(23)00284-2.
For more information:
Guy Young, MD, can be reached at Hemostasis and Thrombosis Center, Cancer and Blood Disease Institute, Children’s Hospital Los Angeles, University of Southern California, 4650 Sunset Blvd., Los Angeles, CA 90027; email: gyoung@chla.usc.edu.
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