Hemophilia A MedDRA version: 20.0 Level: LLT Classification code 10060612 Term: Hemophilia A System Organ Class: 100000004850
Conditions
Sponsors
BioMarin Pharmaceutical Inc.
Eligibility
Sex/Gender
Male
Inclusion criteria
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 =65 years) yes F.1.3.1 Number of subjects for this age range 3
Exclusion criteria
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 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the safety of a single IV administration of BMN 270 in HA subjects with active inhibitors (Part A), or prior inhibitors (Part B);Secondary Objective: - To assess the efficacy of BMN 270 as measured by FVIII activity together with the level of inhibitor titer (Part A) and the recurrence of inhibitors (Part B) - To assess the impact of BMN 270 on the use of emicizumab (Part A) and FVIII prophylaxis (Part B) - To assess the impact of BMN 270 on the number of bleeding episodes requiring pharmacologic intervention - To assess the impact of BMN 270 on quality of life as measured by the Haemo-QoL-A questionnaire;Primary end point(s): •FVIII inhibitors •Incident of AEs and SAEs •Change in clinical laboratory tests (serum chemistry and hematology) •Change in vital signs •Change in physical examination •Vector shedding (blood, urine, semen, stool, saliva) •Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase) •Immune responses to AAV5 capsid proteins •Immunological assessments, including hFVIII TAb, IFN? ELISpot, PBMC for exploratory immunogenicity assessments, a complement panel (C3, C3a, C4, Bb, and sC5b-9), and an exploratory biomarker panel. ;Timepoint(s) of evaluation of this end point: •cNBA for FVIII inhibitor level; Throughout the weeks 1-52 and then q4w on Year 2 and q6w on Year 3-5 •Adverse events; Day 8, then throughout the weeks 2-52 and then q4w on Year 2 and q6w on Year 3-5 •Vital Signs; Day 8 and then throughout the weeks 2-52 and then q12w •Physical examination; Throughout the weeks 4-52 and then q12w •Clinical laboratory tests; Throughout the weeks 2-52 and then q12w •Vector shedding; Day 8 and then throughout the weeks 4-52 and then q12w •Liver tests; Day 2, 4 and 8, and then throughout the weeks 2-52 and then q4w on Year 2 and q6w on Year 3-5 •Immune response to AAV5 capsid proteins; Throughout the weeks 4-52 and then annually until the study end •Immunological assessments; Throughout the week | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): •hFVIII activity •Decrease in anti-FVIII inhibitory titer post infusion (Part A) •Absence of anti-FVIII inhibitors (Part B) •Change in the annualized utilization of emicizumab post-BMN 270 infusion from the baseline utilization of emicizumab (Part A) •Change in the annualized utilization (IU/kg) of exogenous FVIII replacement therapy post-BMN 270 infusion from the baseline utilization of exogenous FVIII replacement therapy (Part B) •Change in the annualized number of bleeding episodes requiring treatment (annualized bleeding rate, ABR) post-BMN 270 infusion from the baseline ABR •Change from baseline on quality of life as measured by Haemo-QoL-A questionnaire;Timepoint(s) of evaluation of this end point: • Measured FVIII concentration/activity will be used for plasma profiles to determine PD parameters. • cNBA for hFVIII inhibitor level; Part A: Day 4 and 8, weeks 2-26 then per the protocol schedule q2w or q4w or q6w and Part B: Weeks 1-26 then per the protocol schedule q2w or q4w, or q6w • Change in utilization of emicizumab (Part A); Day 8, Weeks 2-26, then per the protocol schedule q2w or q4w or q6w • Change in utilization of exogenous FVIII replacement therapy (Part B); Day 8, Weeks 2-26, then per the protocol schedule q2w or q4w or q6w • Change in bleeding episodes; Throughout the study every week • Impact of BMN 270 on quality of life as measured by the Haemo-QoL-A questionnaire; throughout the weeks 4-52 and then q12w | — |
Countries
France, Germany, Italy, United Kingdom, United States
Contacts
Public ContactClinical Trials Information
BioMarin Pharmaceutical Inc.
Outcome results
None listed