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Gene Therapy Study in Severe Haemophilia A Patients (270-201)

Primary Purpose

Severe Haemophilia A

Status

Active

Phase

Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

valoctocogene roxaparvovec

About this trial

This is an interventional treatment trial for Severe Haemophilia A focused on measuring Haemophilia A, Gene Therapy, Clotting Disorders, Blood Disorder, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII, Coagulants, AAV5 vector

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

Males 18 years or older with established severe Haemophilia A (endogenous FVIII level ≤1 IU/dL) as evidenced by their medical history.
Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs)
Greater than or equal to 12 bleeding episodes for patients on on-demand FVIII replacement therapy over the previous 12 months. Does not apply to patients on prophylaxis
No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within the past 12 months
Sexually active patients must be willing to use an acceptable method of contraception.

Exclusion Criteria:

Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition or AAV5 total antibodies
Any evidence of immunosuppressive disorder or active chronic infection including hepatis B, hepatitis C, HIV
Significant liver dysfunction as defined by abnormal elevation ofliver function tests, or for patients who have undergone liver imaging or biopsy and found to have evidence of grade 3 or higher fibrosis
Evidence of any bleeding disorder not related to haemophilia A
12. Treatment with any investigational product within 30 days prior to the end of the screening period, or any previous exposure to any gene transfer therapy
Any disease or condition that per the physician's discretion would prevent the patient from fully complying with the requirements of the study including possible corticosteroid treatment outlined in the protocol. The physician may exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion.

Sites / Locations

Queen Elizabeth Hospital Birmingham
Addenbrooke's Hospital
St. Thomas' Hospital
The Royal London Hospital
University Hospital Southampton NHS Foundation Trust

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

valoctocogene roxaparvovec

Arm Description

Single administration of valoctocogene roxaparvovec at escalating doses.

Outcomes

Primary Outcome Measures

Number of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for 7 years following valoctocogene roxaparvovec infusion.

To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.

The kinetics, duration and magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose.

Secondary Outcome Measures

To describe the immune response to the FVIII transgene product and AAV capsid proteins following systemic administration of AAV5-hFVIII-SQ

Frequency of FVIII replacement therapy during the study

Number of bleeding episodes requiring treatment during the study

Full Information

NCT ID

NCT02576795

First Posted

October 5, 2015

Last Updated

October 13, 2022

Sponsor

BioMarin Pharmaceutical

1. Study Identification

Unique Protocol Identification Number

NCT02576795

Brief Title

Gene Therapy Study in Severe Haemophilia A Patients (270-201)

Official Title

A Phase 1/2, Dose-Escalation, Safety, Tolerability and Efficacy Study of Valoctocogene Roxaparvovec, an Adenovirus-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Patients With Severe Haemophilia A

Study Type

Interventional

2. Study Status

Record Verification Date

October 2022

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 2015 (undefined)

Primary Completion Date

March 2024 (Anticipated)

Study Completion Date

March 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

BioMarin Pharmaceutical

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Product Manufactured in and Exported from the U.S.

Yes

5. Study Description

Brief Summary

This study is being conducted by BioMarin Pharmaceutical Inc. as an open label, dose escalation study in order to determine the safety and efficacy of valoctocogene roxaparvovec (an Adenovirus-Associated Virus based gene therapy vector in participants with severe haemophilia A.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Severe Haemophilia A

Keywords

Haemophilia A, Gene Therapy, Clotting Disorders, Blood Disorder, Blood Coagulation Disorders, Inherited, Blood Coagulation Disorders, Hematologic Diseases, Coagulation Protein Disorders, Hemorrhagic Disorders, Genetic Diseases, Inborn, Factor VIII, Coagulants, AAV5 vector

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

15 (Actual)

8. Arms, Groups, and Interventions

Arm Title

valoctocogene roxaparvovec

Arm Type

Experimental

Arm Description

Single administration of valoctocogene roxaparvovec at escalating doses.

Intervention Type

Biological

Intervention Name(s)

valoctocogene roxaparvovec

Other Intervention Name(s)

BMN 270

Intervention Description

Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Severe Hemophilia A

Primary Outcome Measure Information:

Title

Number of participants with treatment-related adverse events, as assessed by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for 7 years following valoctocogene roxaparvovec infusion.

Time Frame

85 Months

Title

To determine the dose of AAV5-hFVIII-SQ required to achieve expression of FVIII at or above 5% of normal activity (>5 IU/dL) at 16 weeks after infusion.

Description

The kinetics, duration and magnitude of AAV-mediated FVIII activity in individuals with haemophilia A will be determined and correlated to an appropriate BMN 270 dose.

Time Frame

85 Months

Secondary Outcome Measure Information:

Title

To describe the immune response to the FVIII transgene product and AAV capsid proteins following systemic administration of AAV5-hFVIII-SQ

Time Frame

85 Months

Title

Frequency of FVIII replacement therapy during the study

Time Frame

85 Months

Title

Number of bleeding episodes requiring treatment during the study

Time Frame

85 Months

10. Eligibility

Sex

Male

Gender Based

Yes

Gender Eligibility Description

Biological males only

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Males 18 years or older with established severe Haemophilia A (endogenous FVIII level ≤1 IU/dL) as evidenced by their medical history. Treated/exposed to FVIII concentrates or cryoprecipitate for a minimum of 150 exposure days (EDs) Greater than or equal to 12 bleeding episodes for patients on on-demand FVIII replacement therapy over the previous 12 months. Does not apply to patients on prophylaxis No history of inhibitor, and results from a modified Nijmegen Bethesda assay of less than 0.6 Bethesda Units (BU) 2 consecutive occasions at least one week apart within the past 12 months Sexually active patients must be willing to use an acceptable method of contraception. Exclusion Criteria: Detectable pre-existing immunity to the AAV5 capsid as measured by AAV5 transduction inhibition or AAV5 total antibodies Any evidence of immunosuppressive disorder or active chronic infection including hepatis B, hepatitis C, HIV Significant liver dysfunction as defined by abnormal elevation ofliver function tests, or for patients who have undergone liver imaging or biopsy and found to have evidence of grade 3 or higher fibrosis Evidence of any bleeding disorder not related to haemophilia A 12. Treatment with any investigational product within 30 days prior to the end of the screening period, or any previous exposure to any gene transfer therapy Any disease or condition that per the physician's discretion would prevent the patient from fully complying with the requirements of the study including possible corticosteroid treatment outlined in the protocol. The physician may exclude patients unwilling or unable to agree on not using alcohol for the 16-week period following the viral infusion.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Medical Director, MD

Organizational Affiliation

BioMarin Pharmaceutical

Official's Role

Study Director

Facility Information:

Facility Name

Queen Elizabeth Hospital Birmingham

City

Birmingham

Country

United Kingdom

Facility Name

Addenbrooke's Hospital

City

Cambridge

Country

United Kingdom

Facility Name

St. Thomas' Hospital

City

London

Country

United Kingdom

Facility Name

The Royal London Hospital

City

London

Country

United Kingdom

Facility Name

University Hospital Southampton NHS Foundation Trust

City

Southampton

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

35879931

Citation

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.

Results Reference

derived

PubMed Identifier

35411075

Citation

Fong S, Yates B, Sihn CR, Mattis AN, Mitchell N, Liu S, Russell CB, Kim B, Lawal A, Rangarajan S, Lester W, Bunting S, Pierce GF, Pasi KJ, Wong WY. Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A. Nat Med. 2022 Apr;28(4):789-797. doi: 10.1038/s41591-022-01751-0. Epub 2022 Apr 11.

Results Reference

derived

PubMed Identifier

34378280

Citation

Pasi KJ, Laffan M, Rangarajan S, Robinson TM, Mitchell N, Lester W, Symington E, Madan B, Yang X, Kim B, Pierce GF, Wong WY. Persistence of haemostatic response following gene therapy with valoctocogene roxaparvovec in severe haemophilia A. Haemophilia. 2021 Nov;27(6):947-956. doi: 10.1111/hae.14391. Epub 2021 Aug 11.

Results Reference

derived

PubMed Identifier

32915950

Citation

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.

Results Reference

derived

PubMed Identifier

31893514

Citation

Pasi KJ, Rangarajan S, Mitchell N, Lester W, Symington E, Madan B, Laffan M, Russell CB, Li M, Pierce GF, Wong WY. Multiyear Follow-up of AAV5-hFVIII-SQ Gene Therapy for Hemophilia A. N Engl J Med. 2020 Jan 2;382(1):29-40. doi: 10.1056/NEJMoa1908490.

Results Reference

derived

PubMed Identifier

29224506

Citation

Rangarajan S, Walsh L, Lester W, Perry D, Madan B, Laffan M, Yu H, Vettermann C, Pierce GF, Wong WY, Pasi KJ. AAV5-Factor VIII Gene Transfer in Severe Hemophilia A. N Engl J Med. 2017 Dec 28;377(26):2519-2530. doi: 10.1056/NEJMoa1708483. Epub 2017 Dec 9.

Results Reference

derived

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Gene Therapy Study in Severe Haemophilia A Patients (270-201)

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