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

NCT02576795 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: BMN 270-2012014-003880-38
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 5

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.

Conditions

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

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Treatment Emergent Adverse Events

  Adverse events (AEs) with onset or worsening after the investigational product were included. Participants with more than one AE of the same category were counted only once for that category. Serious adverse event (SAE)

  Approximately up to 7 years after dosing

• Number of Participant With Median FVIII Activity Levels >= 5 IU/dL Using Chromogenic Substrate Assay (CSA)

  Responder/Non responder status, where a responder was defined as a participant with median FVIII activity of \>= 5 IU/dL during Week 13-16 post-BMN 270 infusion

  Week 13-16 post-BMN 270 infusion

• Median FVIII Activity as Measured by Chromogenic Substrate Assay During Week 13-16 Post-BMN 270 Infusion

  Values for FVIII activity were excluded from analysis if obtained within 72 hours since the last infusion of exogenous FVIII replacement therapy FVIII activity levels below the Lower limit of quantitation (LLOQ) will be imputed with 0 IU/dL Q1: 25% Percentile; Q3: 75% Percentile

  Week 13-16 post-BMN 270 infusion

Secondary Outcomes (3)

• Annualized Bleeding Rate Requiring Exogenous Factor VIII Replacement Treatment During Week 5 and Beyond

  Week 5 and Beyond (Approximately 7 years post Infusion)

• Annualized Factor VIII Utilization During Week 5 and Beyond

  Week 5 and Beyond (Approximately 7 years post Infusion)

• Annualized Factor VIII Infusion Rate During Week 5 and Beyond

  Week 5 and Beyond (Approximately 7 years post Infusion)

Study Arms (1)

valoctocogene roxaparvovec

EXPERIMENTAL

Single administration of valoctocogene roxaparvovec at escalating doses.

Biological: valoctocogene roxaparvovec

Interventions

valoctocogene roxaparvovec BIOLOGICAL

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

Also known as: BMN 270

valoctocogene roxaparvovec

Eligibility Criteria

• Age: 18 Years+
• Gender Eligibility Details: Biological males only
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• Detectable pre-existing immunity to the AAV5 capsid as measured by adeno-associated virus 5 (AAV5) transduction inhibition (TI) 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
• \. 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.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (5)

Queen Elizabeth Hospital Birmingham

Birmingham, United Kingdom

Location

Addenbrooke's Hospital

Cambridge, United Kingdom

Location

St. Thomas' Hospital

London, United Kingdom

Location

The Royal London Hospital

London, United Kingdom

Location

University Hospital Southampton NHS Foundation Trust

Southampton, United Kingdom

Location

Related Publications (8)

• Santos S, Robinson TM, Trueman D. Estimated Long-Term Durability of Valoctocogene Roxaparvovec Treatment in Male patients with Severe Hemophilia A: An Extrapolation of Clinical Data. Adv Ther. 2025 Nov;42(11):5781-5793. doi: 10.1007/s12325-025-03368-4. Epub 2025 Sep 23.

  PMID: 40986187 DERIVED

• Symington E, Rangarajan S, Lester W, Madan B, Pierce GF, Raheja P, Millar C, Osmond D, Li M, Robinson TM. Valoctocogene roxaparvovec gene therapy provides durable haemostatic control for up to 7 years for haemophilia A. Haemophilia. 2024 Sep;30(5):1138-1147. doi: 10.1111/hae.15071. Epub 2024 Jul 8.

  PMID: 38975624 DERIVED

• 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.

  PMID: 35879931 DERIVED

• 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.

  PMID: 35411075 DERIVED

• 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.

  PMID: 34378280 DERIVED

• 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.

  PMID: 32915950 DERIVED

• 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.

  PMID: 31893514 DERIVED

• 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.

  PMID: 29224506 DERIVED

MeSH Terms

Conditions

Hemophilia A; Hemostatic Disorders; Hematologic Diseases; Blood Coagulation Disorders, Inherited; Blood Coagulation Disorders; Coagulation Protein Disorders; Hemorrhagic Disorders; Genetic Diseases, Inborn

Interventions

Valoctocogene Roxaparvovec

Condition Hierarchy (Ancestors)

Hemic and Lymphatic Diseases; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Vascular Diseases; Cardiovascular Diseases

Results Point of Contact

• Title: Konstantia-Maria Chavele, PhD, Director, Clinical Sciences
• Organization: BioMarin (UK) Ltd

KonstantiaMaria.Chavele@bmrn.com

+44 207-4203351

Study Officials

• Medical Director, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 5, 2015
• First Posted: October 15, 2015
• Study Start: September 28, 2015
• Primary Completion: February 14, 2024
• Study Completion: February 14, 2024
• Last Updated: April 10, 2025
• Results First Posted: April 10, 2025

Record last verified: 2025-03

Locations

GB (5)