A Study of Fitusiran (ALN-AT3SC) in Severe Hemophilia A and B Patients With Inhibitors

The duration of treatment with fitusiran was 9 months. The estimated total time on study, inclusive of screening, for each participant was up to 11 months for all participants who enroll in the extension study and participants in the on-demand arm who did not enroll in the extension study. The estimated total time on study was up to 17 months in fitusiran treatment arm participants who did not enroll in the extension study due to the requirement for up to an additional 6 months of follow-up monitoring for antithrombin levels.

• fitusiran (Drug): solution for injection; by subcutaneous (SC) injection
• Bypassing agents (Drug): solution for injection; by intravenous (IV) injection

Primary outcomes

• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: ABR for a participant during efficacy period (EP) was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Treated Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when antithrombin (AT) lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This outcome measure (OM) represents estimated results (i.e., results received by applying negative binomial \[NB\] regression model on data collected during EP).
• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: ABR for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. ABR= number of bleeding episodes during EP divided by total number of days during EP*365.25. A bleeding episode was defined as any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on the data which was collected during EP).

Secondary outcomes

• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: ABR for a participant during treatment period (TP) was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of \[Day 246 or last day of bleeding follow up\])(maximum duration of TP: from Day 1 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during TP).
• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period [From Day 1 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: ABR for a participant during TP was defined as annualized number of bleeding episodes during TP annualized to a 1-year interval of time. ABR= number of bleeding episodes during TP divided by total number of days during TP*365.25. Bleeding episode: any occurrence of hemorrhage that required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. TP was sum of onset period (first 28 days after the first dose of fitusiran) and EP (starting on Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of \[Day 246 or the last day of bleeding follow up\]) (maximum duration of TP: from Day 1 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during TP).
• Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: Annualized spontaneous bleeding rate for a participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, particularly into joints, muscles, and soft tissues. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP was defined as time duration starting from Day 29 when AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents estimated results (i.e., results received by applying NB regression model on data collected during EP).
• Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: ABR for participant during EP was defined as annualized number of spontaneous bleeding episodes during EP annualized to a 1-year interval of time. ABR=number of treated spontaneous bleeding episodes during EP divided by total number of days during EP*365.25. Spontaneous bleeding episode was bleeding event that occurred for no apparent or known reason, into joints, muscles, and soft tissues. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM represents observed results (i.e., descriptive statistics values based on data collected during EP).
• Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: Annualized joint bleeding rate for a participant during EP was defined as annualized number of bleeding episodes during EP annualized to a 1-year interval of time. Joint bleeding episode was characterized by an unusual sensation in the joint ("aura") in combination with 1) increasing swelling or warmth over the skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using the limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after last treatment for the bleed. EP was defined as time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or the last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents estimated results (i.e., results received by applying NB regression model on data collected during EP).
• Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period [From Day 29 up to Day 246 or up to the last day of bleeding follow up (any day up to Day 246), whichever was the earliest]: Annualized joint bleeding rate for participant during EP was defined as annualized number of joint bleeding episodes during EP annualized to 1-year interval of time. ABR= number of treated joint bleeding episodes during EP divided by total number of days during EP*365.25. A joint bleeding episode was characterized by an unusual sensation in joint ("aura") in combination with 1) increasing swelling or warmth over skin, joint, 2) increased pain, or 3) progressive loss of range of motion or difficulty in using limb as compared with Baseline. It started from first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed. EP: time duration starting from Day 29 when the AT lowering capacity of fitusiran had achieved therapeutic target range to the earliest of (Day 246 or last day of bleeding follow up) (maximum duration of EP: from Day 29 to Day 246). This OM presents observed results (i.e., descriptive statistics values based on data collected during EP).
• Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 [Baseline (Day 1), Month 9]: Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Change from baseline in physical Health domain score was reported in this outcome measure. Raw score for physical health domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better physical health.
• Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 [Baseline (Day 1), Month 9]: Haem-A-QoL: participant-reported questionnaire designed for adult participants (>=17 years of age) with hemophilia; and consisted of 46 items comprising 10 domains (physical health, feelings, view of yourself, sports and leisure, work and school, dealing with hemophilia, treatment, future, family planning, partnership and sexuality). Items were rated along five response options: never, rarely, sometimes, often, or all the time. Raw score for each domain were transformed to a scale ranged from 0 to 100, where lower scores denoted better health. Haem-A-QoL Total Score was average of all domain scores and ranged from 0 to 100, where lower scores denoted better quality of life.
• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period [From Day 1 up to Day 28 or up to the last day of bleeding follow up (any day up to Day 28), whichever was the earliest]: ABR was annualized number of bleeding episodes during onset period per participant annualized to a 1-year interval of time. A treated bleeding episode was defined as any occurrence of hemorrhage that may required administration of BPA or factor. It started from the first sign of a bleed and ended no more than 72 hours after the last treatment for the bleed, within which any symptoms of bleeding at the same location or injections less than or equal to 72 hours apart were considered the same bleeding episode. The onset period was defined as time interval from Day 1 to the earlier of Day 28 or the last day of bleeding follow up. This OM represents estimated results (i.e., results received by applying NB regression model on data collected during onset period).
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) [From Baseline (Day 1) up to 15 months (i.e. 9 months treatment period + 6-months follow-up)]: An adverse Event (AE) was defined as any untoward medical occurrence in a participant who received study drug which did not necessarily have a causal relationship with the treatment. Treatment emergent AEs were defined as any AE with onset date after first dose of fitusiran in the fitusiran prophylaxis arm or after Day 1 visit in the BPA on-demand arm. A Serious AE (SAE) was defined as any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability or incapacity, was a congenital anomaly or birth defect, or was a medically important event.

Sex: Male, ages: 12 Years to any

Inclusion Criteria:

* Males, greater than or equal to (>=) 12 years of age.
* Severe hemophilia A or B with inhibitors.

  * (Severity confirmed by a central laboratory where coagulation factor VIII (FVIII) level was less than (<)1% or factor IX (FIX) level was less than or equal to \[<=\]2% at Screening; Inhibitors defined as inhibitor titer of >=0.6 Bethesda units per milliliter \[BU/mL\] or as evidenced by medical records).
* A minimum of 6 bleeding episodes requiring BPA treatment within the last 6 months prior to screening.
* Willing and able to comply with the study requirements and to provide written informed consent and assent.

Exclusion Criteria:

* Known co-existing bleeding disorders other than hemophilia A or B.
* Antithrombin (AT) activity <60% at Screening.
* Co-existing thrombophilic disorder.
* Clinically significant liver disease.
* Active hepatitis C virus infection.
* HIV positive with a cluster of differentiation-4 count of <200 cells/microliter.
* History of arterial or venous thromboembolism.
* Inadequate renal function.
* History of multiple drug allergies or history of allergic reaction to an oligonucleotide or N-Acetylgalactosamine.
* History of intolerance to SC injection(s).
* Any other conditions or comorbidities that would make the participant unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgement.

Participant flow

Outcome results

• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period (Primary), Number, episodes per participant per year: Bypassing Agents (BPA) On-demand 18.071 (10.598 to 30.812); Fitusiran 80 mg Prophylaxis 1.666 (1.014 to 2.736) (p <0.0001)
• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Efficacy Period (Primary), Mean, episodes per participant per year: Bypassing Agents (BPA) On-demand 18.1 +/- 14.9; Fitusiran 80 mg Prophylaxis 1.7 +/- 3.8
• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period (Secondary), Number, episodes per participant per year: Bypassing Agents (BPA) On-demand 18.819 (11.541 to 30.687); Fitusiran 80 mg Prophylaxis 2.024 (1.306 to 3.138) (p <0.0001)
• Observed Annualized Bleeding Rate (ABR) for Treated Bleeds During the Treatment Period (Secondary), Mean, episodes per participant per year: Bypassing Agents (BPA) On-demand 18.8 +/- 15.4; Fitusiran 80 mg Prophylaxis 2.0 +/- 3.7
• Estimated Annualized Spontaneous Bleeding Rate for Treated Bleeds During Efficacy Period (Secondary), Number, episodes per participant per year: Bypassing Agents (BPA) On-demand 15.675 (9.281 to 26.471); Fitusiran 80 mg Prophylaxis 0.872 (0.491 to 1.551) (p <0.0001)
• Observed Annualized Spontaneous Bleeding Rate for Treated Bleeds During the Efficacy Period (Secondary), Mean, episodes per participant per year: Bypassing Agents (BPA) On-demand 15.6 +/- 14.9; Fitusiran 80 mg Prophylaxis 0.9 +/- 2.0
• Estimated Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period (Secondary), Number, episodes per participant per year: Bypassing Agents (BPA) On-demand 13.759 (7.950 to 23.811); Fitusiran 80 mg Prophylaxis 1.349 (0.798 to 2.280) (p <0.0001)
• Observed Annualized Joint Bleeding Rate for Treated Bleeds During the Efficacy Period (Secondary), Mean, episodes per participant per year: Bypassing Agents (BPA) On-demand 13.8 +/- 12.2; Fitusiran 80 mg Prophylaxis 1.4 +/- 3.4
• Health-related Quality of Life (HRQOL): Change From Baseline in Haemophilia Quality of Life Questionnaire for Adults (Haem-A-QOL) Physical Health Domain Score at Month 9 (Secondary), Least squares mean, score on a scale: Bypassing Agents (BPA) On-demand -1.94 (-10.32 to 6.43); Fitusiran 80 mg Prophylaxis -30.67 (-36.90 to -24.43) (p <0.0001)
• Health-related Quality of Life (HRQOL): Change From Baseline in Haem-A-QOL Total Score at Month 9 (Secondary), Least squares mean, score on a scale: Bypassing Agents (BPA) On-demand -0.42 (-5.65 to 4.80); Fitusiran 80 mg Prophylaxis -15.27 (-19.30 to -11.24) (p <0.0001)
• Estimated Annualized Bleeding Rate (ABR) for Treated Bleeds During the Onset Period (Secondary), Number, episodes per participant per year: Bypassing Agents (BPA) On-demand 25.149 (15.819 to 39.981); Fitusiran 80 mg Prophylaxis 4.426 (2.439 to 8.030)
• Number of Participants With Treatment Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) (Secondary), Count of participants, Participants: Bypassing Agents (BPA) On-demand 11; Fitusiran 80 mg Prophylaxis 38

Adverse events

Time frame: AE data were collected from Baseline (Day 1) up to 15 months (i.e., 9 months treatment period + 6-months follow-up).

Serious adverse events by term

Other adverse events by term

• Results publication: Young G, Srivastava A, Kavakli K, Ross C, Sathar J, You CW, Tran H, Sun J, Wu R, Poloskey S, Qiu Z, Kichou S, Andersson S, Mei B, Rangarajan S. Efficacy and safety of fitusiran prophylaxis in people with haemophilia A or haemophilia B with inhibitors (ATLAS-INH): a multicentre, open-label, randomised phase 3 trial. Lancet. 2023 Apr 29;401(10386):1427-1437. doi: 10.1016/S0140-6736(23)00284-2. Epub 2023 Mar 29. PMID 37003287
• Results publication: The Lancet Haematology. The role of conferences in tackling inequalities. Lancet Haematol. 2022 Feb;9(2):e81. doi: 10.1016/S2352-3026(22)00008-4. No abstract available. PMID 35114155
• Results publication: Del Pozo Martin Y. 2021 ASH annual meeting. Lancet Haematol. 2022 Feb;9(2):e92-e93. doi: 10.1016/S2352-3026(21)00384-7. Epub 2021 Dec 16. No abstract available. PMID 34922648

• Study Protocol (PDF, 2018-06-27)
• Statistical Analysis Plan (PDF, 2020-07-16)

• Clinical Sciences & Operations, MD, Study director, Sanofi

NIH grants: 2016