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ATLAS-PPX: an Open-label, Multinational, Switching Study to Describe the Efficacy and Safety of Fitusiran Prophylaxis in Patients With Hemophilia A and B Previously Receiving Factor or Bypassing Agent Prophylaxis.

A Study of Fitusiran in Severe Hemophilia A and B Patients Previously Receiving Factor or Bypassing Agent Prophylaxis (ATLAS-PPX)

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Eighty participants were enrolled in this study, including 30 participants with inhibitors (Cohort A) and 50 participants without inhibitors (Cohort B). Seventy-eight of the 80 participants enrolled entered the factor/BPA prophylaxis period. Sixty-seven participants completed the factor/BPA prophylaxis period, and 65 of them started with fitusiran 80 mg once monthly (QM), and 2 started with fitusiran 50 mg once every other month (Q2M). Two participants enrolled started directly with fitusiran 80 mg QM without entering the factor/BPA period. In Efficacy Analysis Set (EAS) 1 (ie, 65 participants who started with fitusiran 80 mg QM), all participants were male. The median age was 23.0 years, 19 (29.2%) participants were adolescents (12 to 17 years), and 1 participant was 65 years or older. A total of 20 (30.8%) participants were Asian, 42 (64.6%) white, and 2 (3.1%) other. Generally, the demographics and participant characteristics at baseline were comparable between Cohort A (inhibitor) and Cohort B (non-inhibitor).

Factor/BPA Prophylaxis Period (Day -168 to -1): - Started: 80 (Cohort A: 30, Cohort B: 50) - Started Directly With Fitusiran: 2 (Cohort A: 2, Cohort B: 0) - Started with Factor or BPA Prophylaxis: 78 (Cohort A: 28, Cohort B: 50) - Completed: 69 (Cohort A:23, Cohort B: 46) - Not Completed: 11 (Cohort A: 7, Cohort B: 4) Fitusiran Treatment Period (Day 1 to Day 190): - Started: 69 (Cohort A: 23, Cohort B: 46) - Received 80 mg QM (Safety Analysis Set 1 [SAS 1]): 67 (Cohort A: 21, Cohort B: 46) - Received 50 mg Q2M (Safety Analysis Set 2 [SAS 2]): 2 (Cohort A: 2, Cohort B: 0) - Efficacy Analysis Set 1 (EAS 1): 65 (Cohort A: 19, Cohort B: 46) - Efficacy Analysis Set 2 (EAS 2): 2 (Cohort A: 2, Cohort B: 0) - Completed: 54 (Cohort A: 17, Cohort B: 37) - Not Completed: 15 (Cohort A: 6, Cohort B: 9)

For participants in SAS 1 (participants received at least 1 dose of fitusiran 80 mg QM), 48 (71.6%) participants experienced at least one adverse event (AE) during the fitusiran prophylaxis period (from Day 1 to AT follow up) and 22 (33.8%) participants during the factor/BPA prophylaxis period, 16 (76.2%) versus 11 (57.9%) for Cohort A (inhibitor), and 32 (69.6%) versus 11 (23.9%) for Cohort B (non-inhibitor). During the fitusiran prophylaxis period, AEs were most commonly reported in the system organ class (SOC) of infections and infestations (25 [37.3%] participants) and the most common AE (preferred term [PT]) reported was alanine aminotransferase (ALT) increased (18 [26.9%] participants). During the factor/BPA prophylaxis period, AEs were most commonly reported in the SOC of infections and infestations (13 [20.0%] participants) and the most common AEs reported were upper respiratory tract infection and arthralgia, which were reported in 4 (6.2%) participants each. During the fitusiran prophylaxis period, AEs were assessed as related to study drug in 27 (40.3%) participants. The most common AE assessed as related to study drug was ALT increased (17 [25.4%] participants). Overall, a total of 13 serious adverse events (SAEs) were reported in 9 (13.4%) participants during the fitusiran prophylaxis period and a total of 5 SAEs were reported in 5 (7.7%) participants during the factor/BPA prophylaxis period. One SAE (cerebrovascular accident) in 1 (1.5%) participant resulted in study drug discontinuation. There were no AEs leading to death.

Primary endpoint - During the efficacy period, participants in the overall EAS 1 population (participants received factor or BPA prophylaxis and fitusiran 80 mg QM) achieved an estimated ABR of 2.908 (95% CI: 1.727, 4.898) while receiving fitusiran 80 mg QM regimen and the estimated ABR of 7.482 (95% CI: 5.520, 10.141) while receiving factor/BPA prophylaxis, corresponding to a statistically significant 61.1% bleeding rate reduction in favor of fitusiran during the efficacy period (rate ratio of 0.389 [95% CI: 0.224, 0.675], P=0.0008). - Consistently low ABRs with fitusiran were observed for participants in Cohort A (inhibitor) and Cohort B (non-inhibitor). - A total of 63.1% of participants had no (zero) bleeding episodes during the efficacy period while receiving fitusiran prophylaxis versus 16.9% of participants while receiving factor/BPA prophylaxis. - The ABRs estimated in the treatment period were 3.317 (95% CI: 2.111, 5.211) for the overall EAS 1 participants while receiving fitusiran and 7.502 (95% CI: 5.537, 10.165) while receiving the factor/BPA prophylaxis, corresponding to a 55.8% bleeding rate reduction in favor of fitusirann (rate ratio of 0.442 [95% CI: 0.271, 0.722], nominal P=0.0011).

Secondary endpoint - Substantially lower rates of other bleeding-related endpoints, including events of spontaneous bleeding, joint bleeding, were also observed during fitusiran prophylaxis compared to factor/BPA prophylaxis. - - Participants achieved a spontaneous estimated ABR of 2.222 (95% CI: 1.190, 4.152) while receiving fitusiran 80 mg QM and an estimated ABR of 5.002 (95% CI: 3.424, 7.305) while receiving factor/BPA prophylaxis, corresponding to a significant 55.6% reduction in the spontaneous bleeds in favor of fitusiran prophylaxis during the efficacy period. - - The estimated ABR in joints was 2.564 (95% CI: 1.440, 4.566) and 5.282 (95% CI: 3.647, 7.651) while receiving fitusiran prophylaxis and factor/BPA prophylaxis, respectively, corresponding to a significant 51.5% joint bleeds reduction in favor of fitusiran prophylaxis during the efficacy period. - - Consistently low ABRs with fitusiran were observed for the participants in Cohort A (inhibitor) and Cohort B (non-inhibitor). - The results of total score (transformed) of Haem-A-QOL showed a significant improvement for fitusiran treatment overall, with the LS mean differences of the change from Month -6 to Month 7 versus the change from Month -6 to Day 1 of -4.55 (nominal P=0.0039) overall. Likewise, a nominal improvement for fitusiran treatment was observed in the results of the physical health sub score (transformed) of Haem-A-QOL overall, with the LS mean differences (95% CI) of the change from Month -6 to Month 7 versus the change from Month -6 to Day 1 of -3.60 (-10.52, 3.33). Similar trends were observed for the participants in Cohort A (inhibitor) and Cohort B (non-inhibitor).

Fitusiran 80 mg QM prophylaxis demonstrated a statistically significant 61.1% bleeding rate reduction in participants with hemophilia A or B, with or without inhibitors switching from their previous factor or BPA prophylaxis. Reported AEs in the factor/BPA prophylaxis period and the fitusiran prophylaxis period were generally consistent with the known risks of fitusiran.

Yes

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

https://storage.googleapis.com/ctgov2-large-docs/71/NCT03549871/Prot_000.pdf

Tanaka Tomoyuki

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

clinical-trials-jp@sanofi.com

Clinical Study Unit

Sanofi K.K.

Tokyo Opera City Tower, 3-20-2, Nishi Shinjuku, Shinjuku-ku, Tokyo 163-1488, Japan

+81-3-6301-3670

clinical-trials-jp@sanofi.com

completed

Mar. 16, 2019

Interventional

Allocation: Not applicable (single arm) Masking: Open Label Design: Single arm

treatment purpose

3

- Males, >= 12 years of age
- Severe hemophilia A or B (as evidenced by a central laboratory measurement at screening or documented medical record evidence of FVIII <1% or FIX level <= 2%)
- A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening for patients with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode requiring factor treatment within the last 12 months prior to Screening for patients without inhibitory antibodies to factor VIII or factor IX (Cohort B).
- Must meet either the definition of inhibitor or non-inhibitor patient as below:"
< Inhibitor >
Use of BPAs for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay results criteria:
- Inhibitor titer of >= 0.6 BU/mL at Screening, or
- Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2 consecutive titers >= 0.6 BU/mL, or
- Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of anamnestic response
- The subgroup of patients in Cohort A patients must additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period:
- - Hemophilia B with inhibitory antibody to Factor IX as defined above
- - Not responding adequately to BPA treatment (historical ABR >= 20) prior to enrollment
- - In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.
< Non-inhibitor >
Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion:
- Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening and
- No use of bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening and
- No history of immune tolerance induction therapy within the past 3 years prior to Screening.
- Documented prophylactic treatment with factor concentrates or bypassing agents for the treatment of hemophilia A or B for at least 6 months prior to Screening
- Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening per Investigator assessment
- Willing and able to comply with the study requirements and to provide written informed consent and assent

- Known co-existing bleeding disorders other than hemophilia A or B
- AT activity <60% at Screening
- Co-existing thrombophilic disorder
- Clinically significant liver disease
- Active Hepatitis C virus infection
- Acute or chronic Hepatitis B virus infection
- HIV positive with a CD4 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 (GalNAc)
- History of intolerance to SC injection(s)
- Any other conditions or comorbidities that would make the patient unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgment

Male

Hemophilia

Drug: Fitusiran
Pharmaceutical form: solution for injection Route of administration: subcutaneous
Drug: BPA prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous
Drug: Factor (FVIII or FIX) prophylaxis
Pharmaceutical form: solution for injection Route of administration: Intravenous
Cohort A [inhibitor]: participants with severe hemophilia A/B and inhibitory antibodies to coagulation factor VIII (FVIII)/factor IX (FIX) previously received BPA prophylaxis. Cohort B [non-inhibitor]: participants with severe hemophilia A/B without inhibitory antibodies to FVIII/FIX previously received factor prophylaxis. Participants from both cohorts will be enrolled into 6-month factor/BPA prophylaxis period and continue their pre-study, regularly scheduled prophylaxis regimen with factor/BPAs. This period can be skipped by subgroup of Cohort A (hemophilia B with inhibitors to FIX and historical annualized bleeding rate [ABR] >=20) that started directly with fitusiran. Post completing factor/BPA prophylaxis period, participants will enter 7-month fitusiran treatment period (1-month onset +6-month efficacy) followed by AT follow-up/roll-over into LTE15174 (jRCT2080225111). Throughout study, participants can receive on-demand treatment for breakthrough BE with factor/BPAs, as appropriate.

1. Annualized bleeding rate (ABR)
Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the factor or BPA prophylaxis period

1. Annualized spontaneous bleeding rate
Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period
2. Annualized joint bleeding rate
Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period
3. Quality of Life (QOL) as measured by Haem-A-QOL Questionnaire score on a scale of 0-100 with higher scores representing greater impairment
Change in Haem-A-QOL physical health score and total score in the fitusiran treatment period
4. ABR in the onset period
ABR in the fitusiran onset period
5. ABR in the treatment period
ABR in the fitusiran treatment period
6. Annualized weight-adjusted consumption of factor/BPA
7. Number of patients reported with treatment emergent adverse events

Sept. 26, 2018