Evaluation of scAAV9.U1a.hSGSH Gene Transfer Therapy with Rebisufligene Etisparvovec in Mucopolysaccharidosis Type IIIA Patients
- Trial ID
- 2023-510032-37-00
- Protocol
- ABT-001
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **efficacy** and **safety** of UX111 (also known as ABO-102) for the treatment of **Mucopolysaccharidosis type IIIA**. This is clinically relevant as Mucopolysaccharidosis type IIIA is a severe lysosomal storage disorder characterized by progressive neurodegeneration, and there is a critical need for effective therapeutic interventions. The trial aims to assess whether the gene therapy product, which involves the use of the recombinant gene therapy vector scAAV9.U1a.hSGSH, can successfully transduce patient cells to produce the N-sulfoglucosamine sulfohydrolase protein, thereby restoring the damaged metabolic pathway. The secondary objectives are not defined in the protocol.
Participants
The clinical trial involves a total of **15 participants** diagnosed with **Mucopolysaccharidosis type IIIA**. The study population includes both male and female subjects, with an age range from birth to 5 years. Participants were selected based on a confirmed diagnosis of MPS IIIA, characterized by no detectable or significantly reduced SGSH enzyme activity and specific genetic mutations. The trial includes vulnerable populations, as it involves young children. Participants' vaccination status is considered, with requirements for up-to-date vaccinations according to country-specific guidelines. The trial does not specify particular lifestyle considerations such as diet or physical activity. The selection criteria ensure that the study population is representative of the disease's clinical presentation, focusing on evaluating the efficacy and safety of the investigational treatment UX111 (ABO-102).
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **UX111** (also known as **ABO-102**) for the treatment of **Mucopolysaccharidosis type IIIA**. This is a Phase I/II/III integrated clinical trial, employing a randomized, double-blind, and controlled methodology. The trial is expected to run from September 2017 to July 2027, with participant involvement varying based on cohort assignment and individual response to treatment.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility. Eligibility criteria include a confirmed diagnosis of MPS IIIA through specific enzyme activity assays and genomic DNA analysis. The trial will include multiple cohorts, with age and cognitive development quotient (DQ) requirements varying by cohort. Following the screening, participants will receive the investigational product, **rebisufligene etisparvovec**, administered as a **suspension for injection** via **intravenous use**.
Subsequent follow-up visits will be scheduled to monitor safety and efficacy outcomes, including the incidence of treatment-emergent adverse events (TEAEs) and changes in cerebrospinal fluid (CSF) biomarkers. Secondary endpoints will assess cognitive development and communication skills using the Bayley Scales of Infant and Toddler Development–Third edition (BSITD-III). The end-of-study visit will conclude the participant's involvement, unless early termination is warranted due to adverse events or withdrawal of consent.
Participant involvement is expected to last until the end of the trial or until early termination criteria are met. Conditions for early termination include the occurrence of serious adverse events or significant protocol deviations. The trial aims to provide comprehensive data on the therapeutic potential of **UX111** in restoring the metabolic pathway affected by MPS IIIA, thereby contributing to the advancement of treatment options for this rare disease.
Treatment
The clinical trial involves the administration of **ABO-102**, a gene therapy product developed by Ultragenyx Pharmaceutical Inc. The active substance in ABO-102 is **rebisufligene etisparvovec**, a structurally diverse substance classified as a recombinant gene therapy vector. This vector is designed to transduce cells in patients with Mucopolysaccharidosis IIIA, enabling the production of the N-sulfoglucosamine sulfohydrolase protein, which is intended to restore the damaged metabolic pathway. ABO-102 is provided as a **suspension for injection** and is administered via **intravenous use**. The dosing schedule and frequency of administration are determined based on the trial protocol, with careful monitoring of participant compliance to ensure adherence to the treatment regimen.
In this trial, ABO-102 is the primary investigational product, and no additional non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The trial aims to evaluate the efficacy and safety of ABO-102 in treating Mucopolysaccharidosis IIIA. The administration of ABO-102 is conducted under controlled conditions, with participants being closely monitored for any adverse effects or reactions to the treatment. The trial does not include a pediatric formulation, and the product is designated as an orphan drug, highlighting its use in treating a rare condition.
Efficacy
The efficacy of the gene transfer clinical trial for **Mucopolysaccharidosis IIIA** will be assessed using both primary and secondary endpoints. The primary efficacy endpoint involves measuring cerebrospinal fluid (CSF) heparan sulfate (HS) (disaccharide) exposure. Secondary efficacy endpoints include the Bayley Scales of Infant and Toddler Development–Third edition (BSITD-III) Cognitive raw score, CSF ganglioside type 2 (GM2) exposure, CSF ganglioside type 3 (GM3) exposure, CSF HS percentage change from baseline, BSITD-III Receptive Communication raw score, BSITD-III Expressive Communication raw score, and total cortical volume (cm³) percentage change from baseline.
The efficacy parameters will be collected and analyzed at specified timepoints throughout the trial. The BSITD-III scales will be utilized to assess cognitive and communication development, providing a comprehensive evaluation of the treatment's impact on neurodevelopmental outcomes. The changes in CSF biomarkers and cortical volume will be measured to evaluate the biochemical and structural effects of the treatment. These assessments will be conducted using validated scales and laboratory tests to ensure the reliability and accuracy of the data collected.
Inclusion and Exclusion Criteria
Inclusion Criteria
- 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)
- 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.
- 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
- Inability to participate in the clinical evaluation as determined by PI
- 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.
- Bleeding disorder or any other medical condition or circumstance in which a LP (for collection of CSF) is contraindicated according to local institutional policy
- Visual, hearing, or other impairment sufficient to preclude cooperation with neurodevelopmental testing in the judgment of the PI
- Uncontrolled seizure disorder
- 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
- Any other situation that precludes the subject from undergoing procedures required in this study
- Subjects with cardiomyopathy or significant congenital heart abnormalities
- 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
- 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. Aspartate 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. Anemia (hemoglobin < 10 g/dL) 3. Leukopenia or leukocytosis (total WBC count < 3,000/mm3 and > 15,000/mm3 respectively) 4. Abnormal absolute neutrophil count (ANC) of < 1000/mm3 5. Platelet count < 100,000/mm3 6. Coagulopathy (international normalized ratio [INR] > 1.5) or aPTT > 40 seconds 7. Renal impairment, defined as estimated glomerular filtration rate (eGFR) below the lower limit of normal (age and sex appropriate) based on Bedside Schwartz equation
- Female of childbearing potential who is pregnant or demonstrates a positive urine or β-human chorionic gonadotropin (hCG) result at screening assessment (if applicable)
- 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)
- 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)
- Previous treatment by Hematopoietic Stem Cell transplantation
- Previous participation in a gene/cell therapy or enzyme replacement therapy clinical trial.
- 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)
- Has evidence of an attenuated phenotype of MPS IIIA, in the judgment of the PI
- Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
- Active viral infection based on clinical observations (see also exclusion criterion #10)
- 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
- 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
- Cohorts 1 to 3 only: Subjects with a positive response for the enzyme-linked immunospot assay (ELISpot) for T-cell responses to AAV9
- 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.
- 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).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Spain | Recruiting | 01 Sept 2017 | 21 |
Sites & Investigators
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
ABO-102 | Test | SUSPENSION FOR INJECTION | INTRAVENOUS USE | — | — | PRD10602522 |
ABO-102 | Test | SUSPENSION FOR INJECTION | INTRAVENOUS USE | — | — | PRD10602523 |
ABO-102 | Test | SUSPENSION FOR INJECTION | INTRAVENOUS USE | — | — | PRD10602521 |