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A Phase 3 Open-Label, Multicenter Study of the Safety, Efficacy, and Pharmacokinetics of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein (rFVIIIFc-VWF-XTEN; BIVV001) in Previously Treated Patients >=12 Years of Age With Severe Hemophilia A

A Phase 3 Open-label Interventional Study of Intravenous Recombinant Coagulation Factor VIII Fc-von Willebrand Factor-XTEN Fusion Protein, Efanesoctocog Alfa (BIVV001), in Patients With Severe Hemophilia A (XTEND-1)

159

A total of 159 participants were enrolled in this study, of which 92 participants were rolled over from study OBS16221. All 159 participants received at least 1 dose of BIVV001. One female participant was enrolled; all other participants were male. The mean (standard deviation, SD) age of the participants was 35.4 (15.1) years with: - 12 to 17 years: 25 (15.7%) participants, all in prophylaxis arm - 18 to 64 years: 129 (81.1%) participants - 65 years or older: 5 (3.1%) participants The main geographic regions in the study were represented: Europe (81 [50.9%] participants), Asia/Pacific (33 [20.8%] participants), and North America (26 [16.4%] participants). Baseline disease characteristics were representative of an adult and adolescent population with severe hemophilia A.

- Enrolled: 159 (Prophylaxis arm: 133, On-demand then prophylaxis arm: 26) - Completed: 149 (Prophylaxis arm: 124, On-demand then prophylaxis arm: 25) - Not Completed: 10 (Prophylaxis arm: 9, On-demand then prophylaxis arm: 1)

Of the 159 participants, 123 participants (77.4%) had at least one treatment-emergent adverse event (TEAE), with a total of 394 TEAEs reported. The most frequently reported TEAEs were: headache (32 [20.1%] participants), arthralgia (26 [16.4%] participants), fall (10 [6.3%] participants), back pain (9 [5.7%] participants), COVID-19 and fatigue (7 [4.4%] participants, each), contusion, haemophilic arthropathy, and nasopharyngitis (6 [3.8%] participants, each), and joint injury, pain in extremity, and toothache (5 [3.1%] participants, each). The majority of TEAEs were assessed by the Investigator as mild in severity and not related to BIVV001. Fifteen (9.4%) participants experienced a total of 18 serious adverse events (TESAEs). Haemophilic arthropathy was reported in 2 (1.3%) participants and all other serious adverse events (TESAEs) were reported in 1 (0.6%) participant each. Inhibitor development to factor VIII (FVIII) was not detected and there were no reports of serious allergic reaction, anaphylaxis, or vascular thrombotic events.

Prevention of bleeding: - The study met the primary endpoint, annualized bleeding rate (ARB) in prophylaxis arm. The estimated mean ABR was 0.71 (95% confidence interval [CI]: 0.52 to 0.97). The median (first quatile [Q1]; third quatile [Q3]) ABR was 0.00 (0.00; 1.04). The upper limit of the 1-sided 97.5% CI was less than the prespecified value of 6.

- The study met the key secondary endpoint. Intra-participant comparison demonstrated the non-inferiority of BIVV001 prophylaxis as compared with prestudy prophylaxis on estimated mean ABR with an estimated mean difference in ABR (BIVV001 prophylaxis versus prestudy FVIII prophylaxis) of -2.30 (95% CI: -3.49 to -1.11). Superiority of BIVV001 prophylaxis as compared with standard of care prestudy prophylaxis was also demonstrated with a rate ratio of 0.23 (95% CI: 0.13; 0.42, p<0.0001), showing a reduction of 77% in estimated mean ABR. - The ABRs were consistently low with BIVV001 weekly prophylaxis: across type and location of bleeding, when including untreated and treated bleeding episodes, as well as in all subgroups studied including in participants aged 12 through 17 years. - In on-demand then prophylaxis arm, intra-participant comparison of ABR showed a clinically important reduction of 97% (95% CI: 93% to 98%) in ABR with prophylaxis treatment as compared to on demand treatment with BIVV001. - While a single dose of 50 IU/kg BIVV001 maintained mean FVIII activity levels in the normal to near-normal range for 3 to 4 days, 99.0% of participants maintained FVIII activity levels at 7 days postdose >5% throughout the study duration. In 83.5% and 40.8% of participants, FVIII activity levels of >10%, and >15%, respectively, were maintained. Treatment of bleeds: - A total of 362 bleeding episodes were treated with BIVV001. Most of the bleeding episodes (96.7%) were controlled by a single injection of BIVV001. The mean dose per injection to treat a bleeding episode was 49.56 IU/kg and the mean number of injections for resolution of a bleeding episodes was 1.0. - The hemostatic response was rated by the participants as excellent or good in 94.9% for all evaluable injections for treatment of a bleed. Joint health: - BIVV001 prophylaxis demonstrated a statistically significant improvement in joint health with reduction in Hemophilia Joint Health Score (HJHS) (least square [LS] mean decrease between baseline and Week 52 of -1.54 [95% CI: -2.70 to -0.37]; p-value=0.0101 [hierarchical testing procedure]). - The Annualized Joint Bleeding Rate (AJBR) was low with BIVV001 prophylaxis and, in participants who switched from on demand to prophylaxis treatment with BIVV001, there was a clinically important reduction in AJBR (rate ratio: 0.04 [95% CI: 0.01 to 0.08]) resulting in an AJBR close to the one observed with weekly prophylaxis in prophylaxis arm. Physical functioning and pain: - Prophylaxis with BIVV001 demonstrated a statistically significant decrease in the hemophilia-specific health-related quality of life questionnaire for adults (Haem-A-QoL) physical health score between baseline and Week 52 in adults of -6.74 (95% CI: -10.13 to -3.36; p-value=0.0001 [hierarchical testing procedure]). - In participants receiving BIVV001 prophylaxis, the adjusted mean change from baseline to Week 52 in Patient-Reported Outcomes Measurement Information System (PROMIS) Pain Intensity first item score (past 7 days intensity of pain at its worst score) was -0.21 (95% CI: -0.41 to -0.02, p-value=0.0276 [hierarchical testing procedure]) demonstrating a statistically significant improvement in pain. Perioperative management: Efficacy during perioperative management was assessed in 12 major surgical procedures in 11 participants. Hemostatic responses were rated as excellent by the Investigators/Surgeons in all 12 surgeries, indicating that intraoperative and postoperative blood loss was estimated by the Investigators/Surgeons as comparable to what would have been expected for a patient who does not have hemophilia. Pharmacokinetics: A single BIVV001 dose of 50 IU/kg resulted in mean FVIII activities in the normal to near-normal range (>40 IU/dL) for 3 to 4 days and mean FVIII activity of 11.92 IU/dL at the end of the 7-day dosing interval. After a 50 IU/kg of BIVV001, the majority of participants showed peak FVIII activities (mean maximum activity [Cmax] 131 IU/dL) below the upper physiological limit of 150 IU/dL. The mean (SD) half-life of BIVV001 was 47.6 (8.86) hours and the mean (SD) incremental recovery (IR) was 2.60 (0.648). Once weekly 50 IU/kg regimen showed minimal accumulation (mean accumulation index: 1.17).

A total of 159 participants were enrolled and all of them received BIVV001. For the primary endpoint of ARB in prophylaxis arm, the estimated mean ABR was 0.71. Superiority to prior prophylactic FVIII replacement therapy was demonstrated, with a statistically significant reduction in ABR based on intra-patient comparison. BIVV001 was well tolerated and reported TEAEs were generally consistent with what is anticipated in an adult and adolescent population with severe hemophilia.

Jan. 26, 2023

https://www.nejm.org/doi/10.1056/NEJMoa2209226

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/95/NCT04161495/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

May. 13, 2020

Interventional

Non-randomized, Open Label, Parallel

treatment purpose

3

1. Participant, male or female, must be equal to or greater than 12 years of age inclusive, at the time of signing the informed consent.
2. Severe hemophilia A, defined as <1 IU/dL (<1%) endogenous FVIII activity as documented either by central laboratory testing at Screening or in historical medical records from a clinical laboratory demonstrating <1% FVIII coagulant activity (FVIII:C) or a documented genotype known to produce severe hemophilia A
3. Previous treatment for hemophilia A (prophylaxis or on demand) with any recombinant and/or plasma-derived FVIII, or cryoprecipitate for at least 150 exposure days.
4. Current regimen includes one of the following:
- Prophylactic treatment regimen with a FVIII product or prophylactic emicizumab therapy for at least 6 months during the previous 12 months. Appropriate washout time needs to be taken into account.
- On-demand regimen with a FVIII product with a history of at least 12 bleeding episodes in the previous 12 months or at least 6 bleeding episodes in the previous 6 months prior to
study enrollment.
- - On-demand participant is accepting to move to a prophylaxis treatment regimen after 26-week on-demand period.
5. Willingness and ability of the participant or surrogate (a caregiver or a family member >=18 years of age) to complete training in the use of the study electronic Patient Diary (ePD) and to use the ePD throughout the study.
6. Ability of the participant or his or her legally authorized representative (eg., parent or legal guardian) to understand the purpose and risks of the study, willing and able to comply with study requirements and provide signed and dated informed consent or assent (as applicable) and authorization to use protected health information in accordance with national and local participant privacy regulations.

Participants are excluded from the study if any of the following criteria apply:
- Clinically significant liver disease.
- Serious active bacterial or viral infection (other than chronic hepatitis or HIV) present within 30 days of Screening.
- Other known coagulation disorder(s) in addition to hemophilia A.
- History of hypersensitivity or anaphylaxis associated with any FVIII product
- Positive inhibitor results, defined as >=0.6 BU/mL at Screening. History of a positive inhibitor test defined as >=0.6 BU/mL. Family history of inhibitors will not exclude the participant.
- Use of Emicizumab within the 20 weeks prior to Screening
- Major surgery within 8 weeks prior to Screening.

Both

Factor VIII deficiency

Investigational drug: efanesoctocog alfa (BIVV001)
Control drug: NA
Dosage and Administration:
- Prophylaxis arm: prophylaxis treatment regimen with once weekly injection of BIVV001 for 52 weeks
- On-demand then prophylaxis arm: on-demand regimen with BIVV001 for 26 weeks followed by prophylaxis treatment regimen with once weekly injection of BIVV001 for 26 weeks

1. Annualized bleeding rate (ABR) in prophylaxis treatment arm [Time frame: baseline to 52 weeks]
ABR will be estimated for the weekly (QW) prophylaxis treatment arm.

1. Intra-patient comparison of ABR of participants of this study to the ABR of same participants previously participated in an observational study [Time frame: baseline to week 52]
Intra patient comparison of ABR during the BIVV001 weekly prophylaxis treatment period versus the historical prophylaxis ABR for participants in prophylaxis treatment who participated in Study 242HA201/OBS16221, an observational study
2. ABR by type of bleed [Time frame: baseline to week 52]
ABR by type of bleed such as spontaneous or traumatic per study arm
3. ABR by location of bleed [Time frame: baseline to week 52]
ABR by location of bleed such as joint, muscle, internal, or skin/mucosa per study arm
4. ABR for all bleeding episodes including untreated bleeding episodes [Time frame: baseline to week 52]
ABR for all bleeding episodes (including untreated bleeding episodes) for prophylaxis treatment per study arm
5. Intra-patient comparison of ABR during the weekly once (QW) prophylaxis treatment period versus ABR during the on-demand treatment period [Time frame: baseline to week 52]
Intra-patient comparison of ABR during the QW prophylaxis treatment period versus the ABR during the on-demand treatment period in the On-demand then prophylaxis arm
6. Percentage of participants who maintain FVIII activity levels [Time frame: 52 weeks]
Percentage of participants who maintain FVIII activity levels in prophylaxis treatment arm
7. Number of injection and dose of BIVV001 to treat a bleeding episode [Time frame: 52 weeks]
Number of injections and dose of BIVV001 to treat a bleeding episode per study arm and treatment regimen
8. Percentage of bleeding episodes treated with a single injection of BIVV001 [Time frame: 52 weeks]
Percentage of bleeding episodes treated with a single injection of BIVV001 per study arm and treatment regimen
9. Assessment of response to BIVV001 treatment of individual bleeding episodes [Time frame: baseline to week 52]
Assessment of response to BIVV001 treatment of individual bleeding episodes based on the International Society on Thrombosis and Haemostasis (ISTH) 4-point response scale per study arm and treatment regimen
10. Physician's global assessment of the participant's response based on BIVV001 treatment [Time frame: baseline to week 52]
Physician's global assessment (PGA) of participant's response to BIVV001 treatment based on a 4-point response scale per study arm and treatment regimen
11. Total annualized BIVV001 consumption [Time frame: baseline to week 52]
Total annualized BIVV001 consumption per participant per study arm and treatment regimen
12. Change in Hemophilia Joint Health Score
(HJHS) total score and domain scores [Time frame: baseline to week 52]
Change from baseline to week 52 in total score and domain scores (e.g., swelling and strength) assessed by the HJHS in prophylaxis treatment arm.
13. Annualized Joint Bleeding Rate (AJBR) [Time frame: baseline to week 52]
AJBR per study arm and treatment regimen
14. Target joint resolution [Time frame: baseline to week 52]
Target joint resolution at week 52, based on ISTH criteria, for the prophylaxis treatment arm
15. Changes in Haem-A-QoL total score and physical health score [Time frame for evaluation: baseline to week 52]
Changes in Haem-A-QoL (>=17 years old) total score and physical health score measures from baseline to Week 52 in prophylaxis treatment arm
16. Change in Patient-Reported Outcomes Measurement Information System (PROMIS) Pain intensity [Time frame: baseline to week 52]
Changes in PROMIS Pain Intensity from Baseline to Week 52 in prophylaxis treatment arm
17. Change in Patient-Reported Outcomes
Measurement Information System-Short Form (PROMIS-SF) Physical Function [Time frame: baseline to week 52]
Changes in PROMIS-SF Physical Function (>=18 years old) measures from baseline to week 52 in prophylaxis treatment arm
18. Investigators' or Surgeons' assessment of
participant's hemostatic response to BIVV001 treatment [Time frame: baseline to week 52]
Investigators' or Surgeons' assessment of participant's hemostatic response to BIVV001 treatment on the ISTH 4 point response for surgical procedures scale
19. Number of injections and dose to maintain hemostasis during perioperative period for major surgery [Time frame: baseline to week 52]
20. Total BIVV001 consumption during perioperative period for major surgery [Time frame: baseline to week 52]
21. Number of blood component transfusions used during perioperative period for major surgery [Time frame: baseline to week 52]
22. Type of blood component transfusions used during perioperative period for major surgery [Time frame: baseline to week 52]
23. Estimated blood loss during perioperative
period for major surgery [Time frame: baseline to week 52]
24. Number of participants with occurrences of adverse events (AEs) and serious adverse events (SAEs) [Time frame: baseline to week 52]
Participants with occurrences of AEs and SAEs
25. Number of participants with inhibitor development [Time frame: baseline to week 52]
Development of inhibitors (neutralizing antibodies directed against VIII [FVIII]) as determined via the Nijmegen modified Bethesda assay
26. Number of participants with occurrence of embolic and thrombotic events [Time frame: baseline to week 52]
27. PK parameter: Maximum activity (Cmax) [Time frame: baseline to week 52]
28. PK parameter: Elimination half-life (t1/2) [Time frame: baseline to week 26]
29. PK parameter: Total clearance (CL) [Time frame: baseline to week 26]
30. PK parameter: Total clearance at steady state (CLss) [Time frame: baseline to week 26]
31. PK parameter: Accumulation index (AI) [Time frame: baseline to week 26]
32. PK parameter: Area under the activity time curve (AUC) [Time frame: baseline to week 26]
33. PK parameter: Volume of distribution at steady state (Vss) [Time frame: baseline to week 26]
34. PK parameter: Mean residence time (MRT) [Time frame: baseline to week 26]
35. PK parameter: Incremental recovery (IR) [Time frame: baseline to week 26]
36. PK parameter: Trough activity (Ctrough) [Time frame: baseline to week 52]
37. PK parameter: Time above FVIII activity levels [Time frame: baseline to week 52]

Feb. 10, 2020