A Phase 1/2 study to evaluate the safety and efficacy of BMN 270 gene transfer in patients with severe hemophilia A and active or prior inhibitors

Phase 1

• Conditions: Hemophilia A; MedDRA version: 20.0Level: LLTClassification code 10060612Term: Hemophilia ASystem Organ Class: 100000004850; Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2019-003213-34-GB
• Lead Sponsor: BioMarin Pharmaceutical Inc.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2020-03-17
• Last Update Posted: 19 October 2020

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: Male
• Target Recruitment: 20

Inclusion Criteria

1. Males = 18 years of age with hemophilia A and documented prior residual FVIII activity = 1 IU/dL including, but not limited to, at the time of detected inhibitors, at the time of signing the informed consent.
2. Documented history of a prior positive inhibitor result (results from a Bethesda Assay or Nijmegen Bethesda Assay = 0.6 BU), with the first detection of the inhibitor at least 12 months prior to Screening.
For Part A: Positive FVIII inhibitor test per central lab at Screening, defined as inhibitor titer = 0.6 BU from the chromogenic Nijmegen-Bethesda Assay (cNBA). The first 3 subjects enrolled in Part A must have an inhibitor titer = 5 BU.
For Part B: Negative FVIII inhibitor test per central lab at Screening, defined as inhibitor titer < 0.6 BU from cNBA.
3. For Part A: Subject must be on emicizumab prophylaxis for at least 6 months prior to Screening. Subjects are required to be taking emicizumab at a maintenance dose of 1.5 mg/kg weekly, or be willing to switch to this regimen, prior to dosing with BMN 270. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available.
For Part B: Subject must be on FVIII replacement prophylaxis therapy for at least
12 months prior to Screening. High quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months must be available.
4. Willing and able to provide written, signed informed consent after the nature of the study has been explained and prior to any study-related procedures.
5. Sexually active participants must agree to use an acceptable method of effective contraception, either double-barrier contraception (ie, condom + diaphragm; or condom or diaphragm + spermicidal gel or foam) or their female partner either using hormonal contraceptives or having an intrauterine device. Participants must agree to contraception use for at least 12 weeks post-infusion; after 12 weeks, subjects may stop contraception use only if they have had 3 consecutive semen samples with viral vector DNA below the limit of detection.
6. Willing to abstain from consumption of alcohol for at least the first 52 weeks following BMN 270 infusion.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 17
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 3

Exclusion Criteria

1. Detectable pre-existing antibodies to the AAV5 capsid.
2. Any evidence of active infection, including COVID-19, or any immunosuppressive disorder, including HIV infection.
3. Currently undergoing, or plan to receive during the study, immune tolerance induction therapy or prophylaxis with FVIII (Part A only).
4. Significant liver dysfunction with any of the following abnormal laboratory results:
a. ALT (alanine aminotransferase) > 1.25x ULN;
b. AST (aspartate aminotransferase) > 1.25x ULN;
c. GGT (gamma-glutamyltransferase) > 1.25x ULN;
d. Total bilirubin > 1.25x ULN;
e. Alkaline phosphatase > 1.25x ULN; or
f. INR (international normalized ratio) = 1.4
Subjects whose liver laboratory assessments fall outside of these ranges may undergo repeat testing of the entire liver test panel within the same Screening window and, if eligibility criteria are met on retest, may be enrolled after confirmation by the Medical Monitor.
5. Most recent, prior FibroScan or prior liver biopsy showing significant fibrosis of 3 or
4 as rated on a scale of 0-4 on the Batts-Ludwig (Batts 1995) or METAVIR (Bedossa 1996) scoring systems, or an equivalent grade of fibrosis if an alternative scale is used.
6. Evidence of any bleeding disorder not related to hemophilia A.
7. Platelet count of < 100 x 109/L.
8. Significant renal dysfunction with any of the following abnormal laboratory results:
a. serum creatinine >1.5 mg/dL
b. estimated glomerular filtration rate (eGFR) <90 mL/min/1.73m2 by the Modification of Diet
in Renal Disease (MDRD) equation
c. hematuria or proteinuria as indicated by urine dipstick test at screening.
9. Liver cirrhosis of any etiology as assessed by liver ultrasound/FibroScan.
10. Chronic or active hepatitis B as evidenced by positive serology testing (hepatitis B surface antigen [HBsAg], hepatitis B surface antibody [HBsAb], and hepatitis B core antibody [HBcAb]) and confirmatory HBV DNA testing. Refer to the Centers for Disease Control (CDC) table for the interpretation of serological test results.
11. Active Hepatitis C as evidenced by detectable HCV RNA, or currently on antiviral therapy.
12. Active malignancy, except non-melanoma skin cancer.
13. History of hepatic malignancy.
14. History of arterial or venous thromboembolic events (eg, deep vein thrombosis, non-hemorrhagic stroke, pulmonary embolism, myocardial infarction, arterial embolus), except for catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing.
15. Known inherited or acquired thrombophilia, including conditions associated with increased thromboembolic risk, such as atrial fibrillation.
16. A history of known inflammatory, connective tissue, or autoimmune disorders (eg, vasculitis).
17. Treatment with any Investigational Product within 30 days or 5 half-lives of the investigational product (whichever is longer) prior to the screening period. For subjects who have received a prior investigational product, all ongoing adverse events (AEs) experienced while receiving that investigational product must have resolved prior to screening for this study.
18. Any condition that, in the opinion of the investigator or Sponsor would prevent the patient from fully complying with the requirements of the study (including corticosteroid treatment and/or use of alternative immunosuppressive agents outlined in the protocol) and/or would impact or interfere with evaluation and interpretation of subject safety or efficacy resul

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified