REBISUFLIGENE ETISPARVOVEC for Mucopolysaccharidosis type IIIA

Inclusion criteria

• {"criterion_text":"- Diagnosis of MPS IIIA confirmed by the following methods:a. No detectable or significantly reduced SGSH enzyme activity by leukocyte assay, and b) Genomic DNA analysis demonstrating homozygous or compound heterozygous mutations in the SGSH gene (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)\n- Age: For Cohorts 1 to 3: From birth (participating sites in USA and Australia) OR 6 months (participating sites in Spain) to 2 years of age with no BSITD-III Cognitive development Quotient (DQ) requirement, or older than 2 years with a BSITD-III Cognitive DQ of 60 or above (participating sites globally). For Cohort 4 (participating sites in Spain): 3 months to ≤ 2 years of age with no BSITD-III Cognitive DQ requirement, or > 2 years of age with a BSITD-III Cognitive DQ of 60 or above at Screening Visit 1 (n = up to 6). Up to 2 additional subjects > 2 years and ≤ 5 years of age with a BSITD-III Cognitive DQ < 60 may also be enrolled. • Subjects must be ≥ 3 months of age before any screening assessments or procedures are performed. • For children ≤ 24 months chronological age who were born prematurely, defined as born at < 36 weeks gestational age, the corrected gestational age must be used for determining inclusion. • The BSITD-III Cognitive DQ is assessed during the onsite Screening visit. • The age of the child on the date of the Screening BSITD-III assessment is used to determine the requirement for the BSITD-III Cognitive DQ score.\n- Cohort 4 only: Vaccination status based on age according to country-specific guidelines that is up to date 30 days prior to Enrollment as verified by documentation from the subject’s primary care physician, and willing to defer vaccines through 6 months after completion of the subject’s IM medication, or longer per Principal Investigator (PI) judgment. Emergency use authorization of coronavirus disease (COVID) vaccines is included unless there is an accepted medical exemption."}

Exclusion criteria

• {"criterion_text":"- Inability to participate in the clinical evaluation as determined by PI\n- Cohorts 1 to 3: Abnormal laboratory values Grade 2 or higher as defined in Common Terminology Criteria for Adverse Events (CTCAE) v4.03 for gamma-glutamyl transferase (GGT), total bilirubin, creatinine, hemoglobin, white blood cell (WBC) count, platelet count, prothrombin time (PT) and activated partial thromboplastin time (aPTT) Cohort 4: Any of the following abnormal laboratory values from screening assessment: 1.\tAspartate aminotransferase (AST), alanine aminotransaminase (ALT), and/or GGT and/or alkaline phosphatase ≥ 2 × upper limit of normal (ULN) and/or total bilirubin > 1.5 × ULN 2.\tAnemia (hemoglobin < 10 g/dL) 3.\tLeukopenia or leukocytosis (total WBC count < 3,000/mm3 and > 15,000/mm3 respectively) 4.\tAbnormal absolute neutrophil count (ANC) of < 1000/mm3 5.\tPlatelet count < 100,000/mm3 6.\tCoagulopathy (international normalized ratio [INR] > 1.5) or aPTT > 40 seconds 7.\tRenal impairment, defined as estimated glomerular filtration rate (eGFR) below the lower limit of normal (age and sex appropriate) based on Bedside Schwartz equation\n- Female of childbearing potential who is pregnant or demonstrates a positive urine or β-human chorionic gonadotropin (hCG) result at screening assessment (if applicable)\n- Cohorts 1 to 3 only: Identification of two nonsense or null variants on genetic testing of the SGSH gene (based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)\n- Cohorts 1 to 3 only: Any vaccination with viral attenuated vaccines less than 30 days prior to the scheduled date of treatment (and use of prednisolone)\n- Previous treatment by Hematopoietic Stem Cell transplantation\n- Previous participation in a gene/cell therapy or enzyme replacement therapy clinical trial.\n- At least one S298P mutation in the SGSH gene based upon review of documented results from a qualified laboratory, and with confirmation with Medical Monitor)\n- Has evidence of an attenuated phenotype of MPS IIIA, in the judgment of the PI\n- Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics\n- Active viral infection based on clinical observations (see also exclusion criterion #10)\n- Cohorts 1 to 3: Serology consistent with exposure to human immunodeficiency virus (HIV), or serology consistent with active hepatitis B or C infection Cohort 4: Current clinically significant infections (including any requiring systemic treatment including, but not limited to, HIV; hepatitis A, B, or C; varicella zosters virus; human T cell lymphotropic virus type 1 [HTLV 1]; tuberculosis; or COVID-19) that would interfere with participation in the study.\n- Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer, or precludes the child from participating in the protocol assessments and follow-up\n- Cohorts 1 to 3 only: Subjects with total anti-AAV9 antibody titers ≥ 1:100 equivalent to a positive screen as determined by enzyme-linked immunosorbent assay (ELISA) binding assay in serum\n- Cohorts 1 to 3 only: Subjects with a positive response for the enzyme-linked immunospot assay (ELISpot) for T-cell responses to AAV9\n- Known hypersensitivity to UX111 or its excipients, rituximab, sirolimus, prednisone or prednisolone, bortezomib (as applicable), eculizumab, proton pump inhibitors, H2 antagonists, or peanut or soya that, in the judgment of the PI, places the subject at increased risk for adverse effects.\n- Unwilling to avoid consumption of grapefruit juice and the use of strong inhibitors of CYP3A4 and/or P-gp (eg, ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin, or clarithromycin), strong inducers of CYP3A4 and/or P-gp (eg, rifampin, rifabutin, phenobarbital, carbamazepine, or phenytoin), and St. John’s Wort from 30 days prior to Screening through completion of the sirolimus and bortezomib (as applicable) regimens, due to potential interaction with sirolimus or bortezomib (as applicable).\n- Bleeding disorder or any other medical condition or circumstance in which a LP (for collection of CSF) is contraindicated according to local institutional policy\n- Visual, hearing, or other impairment sufficient to preclude cooperation with neurodevelopmental testing in the judgment of the PI\n- Uncontrolled seizure disorder\n- Any item (braces, etc.) or circumstance which would exclude the subject from being able to undergo magnetic resonance imaging (MRI) according to local institutional policy\n- Any other situation that precludes the subject from undergoing procedures required in this study\n- Subjects with cardiomyopathy or significant congenital heart abnormalities\n- Thepresence of significant non-MPS IIIA related central nervous system (CNS) impairment or behavioral disturbances that would confound the scientific rigor or interpretation of results of the study"}

Primary endpoints

• {"endpoint_text":"- Safety: Incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs)","definition_or_measurement_approach":"Incidence (counts and proportion) of TEAEs and SAEs reported during the study (safety monitoring)."}
• {"endpoint_text":"- Efficacy: Cerebrospinal fluid (CSF) heparan sulfate (HS) (disaccharide) exposure","definition_or_measurement_approach":"Measurement of CSF heparan sulfate (HS) (disaccharide) exposure/concentration in cerebrospinal fluid."}

Secondary endpoints

• {"endpoint_text":"- Bayley Scales of Infant and Toddler Development–Third edition (BSITD- III) Cognitive raw score","definition_or_measurement_approach":"Raw cognitive score from the BSITD-III administered onsite."}
• {"endpoint_text":"- CSF ganglioside type 2 (GM2) exposure","definition_or_measurement_approach":"Measurement of GM2 concentration/exposure in CSF."}
• {"endpoint_text":"- CSF ganglioside type 3 (GM3) exposure","definition_or_measurement_approach":"Measurement of GM3 concentration/exposure in CSF."}
• {"endpoint_text":"- CSF HS percentage change from baseline","definition_or_measurement_approach":"Percent change in CSF heparan sulfate (HS) from baseline over specified timepoints."}
• {"endpoint_text":"- BSITD-III Receptive Communication raw score","definition_or_measurement_approach":"Raw receptive communication score from the BSITD-III assessment."}
• {"endpoint_text":"- BSITD-III Expressive Communication raw score","definition_or_measurement_approach":"Raw expressive communication score from the BSITD-III assessment."}
• {"endpoint_text":"- Total cortical volume (cm 3) percentage change from baseline","definition_or_measurement_approach":"Percent change from baseline in total cortical volume (cm3), measured by MRI."}

Spain

Earliest CTIS Part Ii Submission Date

30-01-2024

Latest Decision Or Authorization Date

12-12-2025

Processing Time Days

682

Number Of Sites

3

Number Of Participants

21

Primary sponsor

Full Name

Ultragenyx Pharmaceutical Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Primevigilance Limited

Responsibilities

Pharmacovigilance Services

Name

MARKEN Germany GmbH

Responsibilities

Collection/shipping of Lab Kit

Name

Marken LLP

Responsibilities

Lab samples courier

Name

DF/Net Research

Name

Fortrea Inc.

Responsibilities

Home Nursing

Name

BioAgilytix Europe GmbH

Responsibilities

AV9 testing

Third parties

• {"country":"Germany","full_name":"BioAgilytix Europe GmbH","duties_or_roles":"AV9 testing","organisation_type":"Pharmaceutical company"}
• {"country":"Australia","full_name":"Sa Pathology","duties_or_roles":"Laboratory analysis","organisation_type":"Hospital/Clinic/Other health care facility"}
• {"country":"United States","full_name":"EPL Archives, LLC","duties_or_roles":"Sample Storage","organisation_type":"Health care"}
• {"country":"United States","full_name":"Life Courier (fka Optimize Courier)","duties_or_roles":"Lab sample courier","organisation_type":"Industry"}
• {"country":"Canada","full_name":"Intelerad (Ambra)","duties_or_roles":"Central MRI portal","organisation_type":"Industry"}
• {"country":"United States","full_name":"Lumanity Patient Centered Outcomes LLC","duties_or_roles":"Qualitative Interviews","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Trulab","duties_or_roles":"Lab samples management","organisation_type":"Industry"}
• {"country":"United States","full_name":"Fortrea Inc.","duties_or_roles":"Home Nursing","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Patient Primary","duties_or_roles":"Patient reimbursement, Patient Travel Coordination","organisation_type":"Industry"}
• {"country":"United States","full_name":"DF/Net Research","duties_or_roles":"","organisation_type":"Industry"}
• {"country":"United Kingdom (Northern Ireland)","full_name":"Almac Diagnostic Services Limited","duties_or_roles":"Clinical supply","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"MARKEN Germany GmbH","duties_or_roles":"Collection/shipping of Lab Kit","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Bioagilytix Labs LLC","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Marken LLP","duties_or_roles":"Lab samples courier","organisation_type":"Pharmaceutical company"}
• {"country":"United Kingdom","full_name":"Primevigilance Limited","duties_or_roles":"Pharmacovigilance Services","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Quantims, LLC (Igor Nestrasil)","duties_or_roles":"Central MRI reader","organisation_type":"Industry"}
• {"country":"United States","full_name":"Pharmapace Inc.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Quanterix Corp.","duties_or_roles":"","organisation_type":"Pharmaceutical company"}