Single-Arm Study To Evaluate The Efficacy and Safety of Valoctocogene Roxaparvovec in Hemophilia A Patients (BMN 270-301) (BMN 270-301)

A Phase 3 Open-Label, Single-Arm Study To Evaluate The Efficacy and Safety of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients With Residual FVIII Levels ≤ 1 IU/dL Receiving Prophylactic FVIII Infusions

This Phase III clinical study will assess the impact of BMN 270 (compared to FVIII prophylaxis) on the number of bleeding episodes irrespective of exogenous FVIII replacement treatment in the efficacy evaluation period (EEP) (from Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit"). The study will also assess the impact of BMN 270 (compared to FVIII prophylaxis) on: the number of bleeding episodes requiring exogenous FVIII treatment in "Post FVIII Prophylaxis to Last Visit", FVIII activity as measured by chromogenic sustrate assay at Week 104 following intravenous infusion of BMN 270, usage of exogenous FVIII replacement therapy in "Post FVIII Prophylaxis to Last Visit", health-related quality of life patient-reported outcomes at week 104 following intravenous infusion of BMN 270. The study will also evaluate the safety of the BMN 270.

Study Overview

• Status: Active, not recruiting
• Conditions: Hemophilia A
• Intervention / Treatment: Biological: valoctocogene roxaparvovec

• Study Type: Interventional
• Enrollment (Actual): 144
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • Adelaide, Australia
    • The Royal Adelaide Hospital (RAH)
  • Brisbane, Australia
    • Royal Brisbane and Women's Hospital
  • Melbourne, Australia
    • Alfred Hospital
  • Perth, Australia
    • Fiona Stanley Hospital
  • Sydney, Australia
    • Royal Prince Alfred Hospital
• Belgium
  • Leuven, Belgium
    • University Hospital Leuven
• Brazil
  • Campinas, Brazil
    • Campinas Estadual University (UNICAMP) / Campinas Hemocentro / Hematologia E Hemoterapia Center
  • Curitiba, Brazil
    • Parana's Hematology And Hemotherapy Center (HEMEPAR)
  • Rio De Janeiro, Brazil
    • Arthur De Siqueira Cavalcanti Hematology State Institute
  • São Paulo, Brazil
    • Sao Paulo University Clinical Hospital
  • Vitória, Brazil
    • Holy Spirit Hematology and Hemotherapy Center
• France
  • Lille, France
    • Regional University Hospital of Lille (CHRU de Lille)
  • Marseille, France
    • Hopital de la Timone Marseille - Assistance Publique des Hopitaux de Marseille
• Germany
  • Berlin, Germany
    • Vivantes Clinic im Friedrichshain- Landsberger Allee
  • Bonn, Germany
    • University Clinic Bonn
• Israel
  • Ramat Gan, Israel
    • Chaim Sheba Medical Center
• Italy
  • Milan, Italy
    • Maggiore Polyclinic Hospital, IRCCS Ca' Granda, Center for Hemophilia and Thrombosis Angelo Bianchi Bonomi
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Department of Pediatrics, Kyung Hee University Hospital at Gangdong
• South Africa
  • Johannesburg, South Africa
    • Charlotte Maxeke Johannesburg Academic Hospital, Hemophilia Comprehensive Care Center
• Spain
  • A Coruna, Spain
    • Hospital Teresa Herrera
  • Seville, Spain
    • University Hospital Virgen del Rocio (HUVR)
• Taiwan
  • Changhua, Taiwan
    • Changhua Christian Hospital
  • Kaohsiung, Taiwan
    • Kaohsiung Medical University Chung-Ho Memorial Hospital
  • Taichung, Taiwan
    • Taichung Veterans General Hospital
  • Taipei, Taiwan
    • Tri-Service General Hospital
  • Taipei, Taiwan
    • National Taiwan University Hospital
• United Kingdom
  • Birmingham, United Kingdom
    • Queen Elizabeth Hospital
  • Cambridge, United Kingdom
    • Addenbrookes Hospital
  • Glasgow, United Kingdom
    • Glasgow Royal Infirmary, Department of Hematology
  • London, United Kingdom
    • St Thomas' Hospital
  • London, United Kingdom
    • Barts and The London School of Medicine and Dentistry, Haemophilia Centre
  • London, United Kingdom
    • Hammersmith
  • Oxford, United Kingdom
    • Churchill Hospital, Oxford Hemophilia and Thrombosis Center
  • Southampton, United Kingdom
    • University Hospital Southampton NHS Foundation Trust
• United States
  • California
    • Los Angeles, California, United States, 90007-2664
      • Los Angeles Orthopedic Hospital, Orthopedic Hemophilia Treatment Center
    • Sacramento, California, United States, 95817
      • UC Davis Hemophilia Treatment Center
    • San Diego, California, United States, 92122
      • University of California San Diego, Hematology and Oncology, Hemophilia &Thrombosis Treatment Center
    • San Francisco, California, United States, 94143-0106
      • UCSF Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • Florida
    • Tampa, Florida, United States, 33607
      • St. Joseph's Children's Hospital, Center for Bleeding and Clotting Disorders
  • Illinois
    • Chicago, Illinois, United States, 60611-2605
      • Ann & Robert H. Lurie Children's Hospital of Chicago, Department of Hematology
  • Kentucky
    • Louisville, Kentucky, United States, 40202
      • James Graham Brown Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109-5718
      • University of Michigan, Pediatric Hematology and Oncology
    • Detroit, Michigan, United States, 48201
      • Wayne State University, Detroit Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • Missouri
    • Saint Louis, Missouri, United States, 63110-1093
      • Washington University School of Medicine, Department of Pediatrics, Division of Hematology/Oncology
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27517
      • UNC Hemophilia and Thrombosis Center
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Males ≥ 18 years of age with hemophilia A and residual FVIII levels ≤ 1 IU/dL as evidenced by medical history, at the time of signing the informed consent.
2. Must have been on prophylactic FVIII replacement therapy for at least 12 months prior to study entry.
3. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs).
4. No previous documented history of a detectable FVIII inhibitor, and results from a Bethesda assay or Bethesda assay with Nijmegen modification of less than 0.6 Bethesda Units (BU) on 2 consecutive occasions at least one week apart within the past 12 months.

Exclusion Criteria:

1. Detectable pre-existing antibodies to the adeno-associated virus 5 (AAV5) capsid.
2. Any evidence of active infection or any immunosuppressive disorder, except for HIV infection
3. Any evidence of active infection or any immunosuppressive disorder, including HIV infection (effective as of Protocol Amendment 3)
4. Significant liver dysfunction.
5. Prior liver biopsy showing significant fibrosis.
6. Evidence of any bleeding disorder not related to hemophilia A.
7. Platelet count of < 100 x 10^9/L.
8. Creatinine ≥ 1.5 mg/dL.
9. Liver cirrhosis of any etiology as assessed by liver ultrasound.
10. Chronic or active hepatitis B.
11. Active Hepatitis C.
12. Active malignancy, except non-melanoma skin cancer.
13. History of hepatic malignancy.
14. History of arterial or venous thromboembolic events.
15. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: valoctocogene roxaparvovec Open Label; Single administration of valoctocogene roxaparvovec at a dose of 6E13 vg/kg	Biological: valoctocogene roxaparvovec; Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A; Other Names: BMN 270

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Annualized Number of Bleeding Episodes Irrespective of Exogenous FVIII Replacement Treatment [Annualized Bleeding Rate (ABR) for All Bleeds] in EEP.	All bleeds comprises both treated and non-treated bleeds. In this definition, all bleeds are included, irrespective of treatment with coagulation factors, with the following exception: bleeds due to surgery/procedure are excluded. All bleeds are any reported bleeding events regardless of the use of FVIII or other treatments. ABR for all bleeds= Number of bleeding episodes for all bleeds during the calculation period / total number of days during the calculation period * 365.25. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").	Baseline to efficacy evaluation period (EEP)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in the Annualized Number of Bleeding Episodes Requiring Exogenous FVIII Replacement Therapy (ABR for Treated Bleeds) in the EEP.	ABR for treated bleeds=Number of bleeding episodes for treated bleeds during the calculation period/total number of days during the calculation period * 365.25 Bleeds that were treated with FVIII replacement therapy (recorded as "treatment for bleed") within 72 hours and were not associated with surgery or a procedure were included. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").	Baseline to EEP
Change From Baseline in FVIII Activity at Week 104	The change from baseline (assuming no treatment for severe hemophilia A) in FVIII activity, as measured by chromogenic substrate assay, at Weeks 104 post-BMN 270 infusion. Each subject's FVIII activity level at Week 104 is defined as the median of the values obtained at Week 104 with the analysis window defined. The baseline value is imputed as 1 IU/dL for each subject. Note: One of the subject's wk104 duplicate data issue was corrected in the 3 year analysis per which the mean (standard deviation) values are reported in outcome measure table. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis.	Baseline to Week 104
Change From Baseline in Annualized FVIII Utilization in EEP.	The change from baseline in the annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy in the Post FVIII Prophylaxis to Last Visit in the EEP. The annualized utilization (IU/kg/year) of exogenous FVIII replacement therapy is defined as Sum of FVIII use (IU/kg) during calculation period/Total number of days during the calculation period ×365.25. Baseline: prior to BMN 270 infusion while receiving FVIII prophylaxis. EEP: From Week 5 post-BMN 270 infusion (Study Day 33) or the end of FVIII prophylaxis plus the washout period (3 days for products of standard half-life or plasma-derived and 5 days for products of extended half-life), whichever is later, to last visit by the data cut-off for the 2-year analysis, hereafter referred to as "Post FVIII Prophylaxis to Last Visit").	Baseline to EEP
Change From Baseline in Haemo-QoL-A Quality of Life: Total Score at Week 104	The change from baseline(assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at wk104 post-BMN 270 infusion.The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life(HRQoL)questionnaire for adults consisting of 41 items covering 6 domains(Physical Functioning,Role Functioning,Worry,Consequences of Bleeding,Emotional Impact &Treatment Concerns). The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0(none of the time)to 5 (all of the time).The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-QoL-A domain(physical functioning, role functioning, worry, consequences of bleeding, emotional impact, treatment concern) scores range from 0 to 5 and the total score is derived by summing each domain score (range, 0 to 30). Domain and total scores are transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia related quality of life.	Baseline to Week 104
Change From Baseline in Haemo-QoL-A Quality of Life: Physical Functioning Domain Score, at Week 104	The change from baseline (assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life (HRQoL) questionnaire for adults consisting of 41 items covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns).The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0 (none of the time) to 5 (all of the time).The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-Qol-A physical functioning domain score is an average of each item value within a domain.The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The physical functioning domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related physical functioning	Baseline to Week 104
Change From Baseline in Haemo-QoL-A Quality of Life: Consequences of Bleeding Domain Score, at Week 104	The change from baseline(assuming no treatment for severe hemophilia A)in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life(HRQoL)questionnaire for adults consisting of 41 items covering 6 domains(Physical Functioning,Role Functioning,Worry,Consequences of Bleeding,Emotional Impact and Treatment Concerns). The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0(none of the time) to 5(all of the time). The recall period for the Haemo-Qol-A is one month (4-wks). The Haemo-Qol-A consequences of bleeding domain score is an average of each item value within a domain. The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The consequences of bleeding domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related consequences of bleeding	Baseline to Week 104
Change From Baseline in Haemo-QoL-A Quality of Life: Role Functioning Domain Score, at Week 104	The change from baseline (assuming no treatment for severe hemophilia A) in Haemo-Qol-A score, at week 104 post-BMN 270 infusion. The Haemo-Qol-A questionnaire is a fit for purpose hemophilia-specific health related quality of life (HRQoL) questionnaire for adults consisting of 41 items covering six domains (Physical Functioning, Role Functioning, Worry, Consequences of Bleeding, Emotional Impact and Treatment Concerns).The Haemo-Qol-A items are answered on a 6-point Likert scale ranging from 0 (none of the time) to 5 (all of the time). The recall period for the Haemo-Qol-A is one month (4-weeks). The Haemo-Qol-A role functioning domain score is an average of each item value within a domain. The range of domain scores is 0 to 5; higher scores mean better HRQoL or less impairment for the domain. The role functioning domain score is transformed to a 0 (minimum) to 100 (maximum) scale with higher scores indicating a better or less impaired haemophilia-related role functioning.	Baseline to Week 104

Other Outcome Measures

Outcome Measure	Time Frame
Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 in the first 52 weeks following valoctocogene roxaparvovec infusion	52 weeks
Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors in the first 52 weeks following valoctocogene roxaparvovec infusion	52 weeks
Percentage of participants with treatment-related adverse events, as assessed by CTCAE v4.03 during years 2-5 following valoctocogene roxaparvovec infusion	5 years
Percentage of participants with treatment-related adverse events, as assessed by de novo development of FVIII inhibitors during years 2-5 following valoctocogene roxaparvovec infusion	5 years

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Medical Monitor, MD, BioMarin Pharmaceutical

Publications and helpful links

General Publications

• Quinn J, Delaney KA, Wong WY, Miesbach W, Bullinger M. Psychometric Validation of the Haemo-QOL-A in Participants with Hemophilia A Treated with Gene Therapy. Patient Relat Outcome Meas. 2022 Jul 18;13:169-180. doi: 10.2147/PROM.S357555. eCollection 2022.
• Ozelo MC, Mahlangu J, Pasi KJ, Giermasz A, Leavitt AD, Laffan M, Symington E, Quon DV, Wang JD, Peerlinck K, Pipe SW, Madan B, Key NS, Pierce GF, O'Mahony B, Kaczmarek R, Henshaw J, Lawal A, Jayaram K, Huang M, Yang X, Wong WY, Kim B; GENEr8-1 Trial Group. Valoctocogene Roxaparvovec Gene Therapy for Hemophilia A. N Engl J Med. 2022 Mar 17;386(11):1013-1025. doi: 10.1056/NEJMoa2113708.
• Rosen S, Tiefenbacher S, Robinson M, Huang M, Srimani J, Mackenzie D, Christianson T, Pasi KJ, Rangarajan S, Symington E, Giermasz A, Pierce GF, Kim B, Zoog SJ, Vettermann C. Activity of transgene-produced B-domain-deleted factor VIII in human plasma following AAV5 gene therapy. Blood. 2020 Nov 26;136(22):2524-2534. doi: 10.1182/blood.2020005683.

Study record dates

Study Major Dates

• Study Start (Actual): December 19, 2017
• Primary Completion (Actual): November 16, 2020
• Study Completion (Estimated): November 1, 2024

Study Registration Dates

• First Submitted: November 27, 2017
• First Submitted That Met QC Criteria: December 7, 2017
• First Posted (Actual): December 13, 2017

Study Record Updates

• Last Update Posted (Actual): December 20, 2023
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Gene Therapy; Hematologic Diseases; Blood Coagulation Disorders; Factor VIII; Genetic Diseases; Hemorrhagic Disorders; Coagulants; Inborn; Clotting Disorders; Blood Disorder; Coagulation Protein Disorders; Inherited Blood Coagulation disorders
• Additional Relevant MeSH Terms: Hematologic Diseases; Blood Coagulation Disorders, Inherited; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn; Blood Coagulation Disorders; Hemophilia A
• Other Study ID Numbers: 270-301; 2017-003215-19 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No