Phase I/II/III Gene Transfer Clinical Trial of scAAV9.U1a.hSGSH for Mucopolysaccharidosis (MPS) IIIA

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ultragenyx Pharmaceutical Inc.

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

18 Apr 2017 → ongoing

Decision date (initial)

2024-02-07

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ultragenyx Pharmaceutical Inc

External identifiers

EU CT number

2023-510032-37-00

EudraCT number

2015-003904-21

ClinicalTrials.gov

NCT02716246

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Pharmacodynamic, Safety, Therapy, Efficacy, Pharmacokinetic, Dose response

To evaluate the efficacy and safety of UX111 (also known as ABO-102) for the treatment of mucopolysaccharidosis (MPS) IIIA

Secondary objectives 1

1. Not defined in the protocol

Conditions and MedDRA coding

Mucopolysaccharidosis type IIIA

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, The Spanish Agency Of Medicines And Medical Devices, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-002206-PIP02-19

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. 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)
2. 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.
3. 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 24

1. Inability to participate in the clinical evaluation as determined by PI
2. 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.
3. Bleeding disorder or any other medical condition or circumstance in which a LP (for collection of CSF) is contraindicated according to local institutional policy
4. Visual, hearing, or other impairment sufficient to preclude cooperation with neurodevelopmental testing in the judgment of the PI
5. Uncontrolled seizure disorder
6. 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
7. Any other situation that precludes the subject from undergoing procedures required in this study
8. Subjects with cardiomyopathy or significant congenital heart abnormalities
9. 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
10. 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
11. Female of childbearing potential who is pregnant or demonstrates a positive urine or β-human chorionic gonadotropin (hCG) result at screening assessment (if applicable)
12. 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)
13. 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)
14. Previous treatment by Hematopoietic Stem Cell transplantation
15. Previous participation in a gene/cell therapy or enzyme replacement therapy clinical trial.
16. 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)
17. Has evidence of an attenuated phenotype of MPS IIIA, in the judgment of the PI
18. Presence of a concomitant medical condition that precludes lumbar puncture or use of anesthetics
19. Active viral infection based on clinical observations (see also exclusion criterion #10)
20. 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
21. 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
22. Cohorts 1 to 3 only: Subjects with a positive response for the enzyme-linked immunospot assay (ELISpot) for T-cell responses to AAV9
23. 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.
24. 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety: Incidence of treatment-emergent adverse events (TEAEs) and treatment-emergent serious adverse events (SAEs)
2. Efficacy: Cerebrospinal fluid (CSF) heparan sulfate (HS) (disaccharide) exposure

Secondary endpoints 7

1. Bayley Scales of Infant and Toddler Development–Third edition (BSITD- III) Cognitive raw score
2. CSF ganglioside type 2 (GM2) exposure
3. CSF ganglioside type 3 (GM3) exposure
4. CSF HS percentage change from baseline
5. BSITD-III Receptive Communication raw score
6. BSITD-III Expressive Communication raw score
7. Total cortical volume (cm 3) percentage change from baseline

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ultragenyx Pharmaceutical Inc.

Sponsor organisation

Ultragenyx Pharmaceutical Inc.

Address

60 Leveroni Court Suite 200

City

Novato

Postcode

94949-5746

Country

United States

Scientific contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Medical Information

Public contact point

Organisation

Ultragenyx Pharmaceutical Inc.

Contact name

Medical Information

Third parties 18

Locations

1 EU/EEA country · 3 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications