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    Summary
    EudraCT Number:2019-003213-34
    Sponsor's Protocol Code Number:270-205
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2022-05-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedGermany - PEI
    A.2EudraCT number2019-003213-34
    A.3Full title of the trial
    A Phase 1/2 Safety, Tolerability, and Efficacy Study of BMN 270, an Adeno-Associated Virus Vector-Mediated Gene Transfer of Human Factor VIII in Hemophilia A Patients with Active or Prior Inhibitors
    Phase-I/II-Studie zur Sicherheit, Verträglichkeit und Wirksamkeit von BMN 270, einem auf dem adenoassoziierten Virus basierenden Vektor für den Transfer des Gens für humanen Faktor VIII, bei Patienten mit Hämophilie A und aktiven Hemmkörpern bzw. früherem Vorliegen von Hemmkörpern
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.3.2Name or abbreviated title of the trial where available
    BMN 270 Gene Therapy in Severe Haemophilia A Patients with Inhibitors
    A.4.1Sponsor's protocol code number270-205
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorBioMarin Pharmaceutical Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBioMarin Pharmaceutical Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBioMarin Pharmaceutical Inc.
    B.5.2Functional name of contact pointClinical Trials Information
    B.5.3 Address:
    B.5.3.1Street Address105 Digital Drive
    B.5.3.2Town/ cityNovato
    B.5.3.3Post code94949
    B.5.3.4CountryUnited States
    B.5.6E-mailmedinfo@bmrn.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ROCTAVIAN
    D.2.1.1.2Name of the Marketing Authorisation holderBioMarin International Ltd
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/16/1622
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNValoctocogene roxaparvovec
    D.3.9.1CAS number 1819334-78-5
    D.3.9.2Current sponsor codeBMN 270
    D.3.9.3Other descriptive nameAAV5-hFVIII-SQ
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit vector genomes (vg)/mL
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2E13
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms Yes
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Hemophilia A
    E.1.1.1Medical condition in easily understood language
    Bleeding Disorder
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10060612
    E.1.2Term Hemophilia A
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    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)
    E.2.2Secondary objectives of the trial
    • 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 hemophilia therapy
    • 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.
    E.4Principal 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 would prevent the patient from fully complying with the requirements of the study (including ability to tolerate 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 result.
    19. Prior treatment with any vector or gene transfer agent.
    20. Major surgery planned in the 26-week period following the infusion with BMN 270.
    21. Use of systemic immunosuppressive agents, not including corticosteroids, or live vaccines within 30 days before the BMN 270 infusion.
    22. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study that does not interfere with the requirements of the current protocol or have the potential to impact the evaluation of safety and efficacy of BMN 270 and with prior consultation with the Medical Monitor.
    E.5 End points
    E.5.1Primary 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)
    •Liver tests (LTs, including ALT, AST, GGT, LDH, total bilirubin, and alkaline phosphatase)
    •Immune responses to AAV5 capsid proteins
    •Immunological assessments, including hFVIII TAb, IFNγ ELISpot, PBMC for exploratory immunogenicity assessments, a complement panel (C3, C3a, C4, Bb, and sC5b-9), and an exploratory biomarker panel.
    E.5.1.1Timepoint(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 weeks 2-52 then q24w and at End of Year visits
    E.5.2Secondary end point(s)
    •hFVIII activity
    •Change in anti-FVIII inhibitory titer post infusion (Part A)
    •Absence of anti-FVIII inhibitors (Part B)
    •Change in the annualized utilization of hemophilia therapy post-BMN 270 infusion from the baseline utilization of hemophilia therapy (Part A)
    •Change in the annualized utilization (IU/kg) of exogenous hemophilia therapy post-BMN 270 infusion from the baseline utilization of hemophilia 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 in the Haemo-QoL-A Total Score, Physical Functioning, Role Functioning, and Worry about Consequences of Bleeding.
    E.5.2.1Timepoint(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 hemophilia therapy (Part A); Day 8, Weeks 2-26, then per the protocol schedule q2w or q4w or q6w
    • Change in utilization of exogenous hemophilia 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
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA3
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Taiwan
    Brazil
    Israel
    Korea, Republic of
    South Africa
    Turkey
    United Kingdom
    United States
    Germany
    Italy
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 17
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    F.2 Gender
    F.2.1Female No
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state2
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 7
    F.4.2.2In the whole clinical trial 20
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2022-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-12-20
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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