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: 10010331 - Congenital, familial and genetic disorders
Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

Registration Number: EUCTR2019-003213-34-DE

Lead Sponsor: BioMarin Pharmaceutical Inc.

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

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 (where laboratory results are not influenced by the presence of an inhibitor).
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: Subjects must have documented evidence of no immunological tolerance to exogenous FVIII (ie documented failure of immune tolerance induction or an increase in inhibitor titer following a dose of exogenous FVIII, or current inhibitor titer =0.6 BU from the cNBA).
• For Part B: Subjects must have demonstrated immunological tolerance to exogenous FVIII (ie documented successful ITI or continuous use of FVIII replacement therapy) and a negative FVIII inhibitor test per central lab at Screening, defined as inhibitor titer < 0.6 BU from the cNBA.
3. Subjects must be on prophylactic or on-demand hemophilia therapy in the last 12 months prior to Screening and have high quality, well-documented historical data concerning bleeding episodes, inhibitor history, and hemophilia therapy over the previous 12 months.
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. If the subject is unable to provide consent, a legally authorized representative may provide written informed consent.
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 and any female partner must agree to contraception use for 26 weeks post-infusion.
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: 0
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, except for HIV infection. HIV-positive patients who meet all other eligibility criteria may be included if they have a CD4 count > 200/mm3 and an undetectable viral load (unquantifiable viral load as defined as less than the limit of quantification by the testing laboratory’s assay is permitted) while receiving an antiretroviral therapy (ART) regimen that does not contain efavirenz or another potentially hepatotoxic ART.
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:
o ALT (alanine aminotransferase) > 1.25x ULN;
o AST (aspartate aminotransferase) > 1.25x ULN;
o GGT (gamma-glutamyltransferase) > 1.25x ULN;
o Total bilirubin > 1.25x ULN;
o Alkaline phosphatase > 1.25x ULN; or
o 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:
o serum creatinine >1.5 mg/dL
o estimated glomerular filtration rate (eGFR) <90 mL/min/1.73m2 by the Modification of Diet in Renal Disease (MDRD) equation
o hematuria or proteinuria as indicated by urinalysis at screening.
9. Liver cirrhosis or other clinically significant liver disease 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.
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
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 medical or psychiatric condition that, in the opinion of the Investigator or Sponsor