RGX-111 Gene Therapy in Patients With MPS I

A Phase I/II Multicenter, Open-Label Study to Evaluate the Safety, Tolerability, and Pharmacodynamics of Intracisternal RGX-111 Gene Therapy in Participants With Mucopolysaccharidosis Type I

RGX-111 is a gene therapy which is intended to deliver a functional copy of the α-L-iduronidase (IDUA) gene to the central nervous system. This is a safety and dose ranging study to determine whether RGX-111 is safe and tolerated by patients with MPS I.

Study Overview

• Status: Suspended
• Conditions: Hurler Syndrome; Hurler-Scheie Syndrome; Mucopolysaccharidosis Type I (MPS I)
• Intervention / Treatment: Genetic: RGX-111

Detailed Description

Mucopolysaccharidosis type I (MPS I) is a rare recessive genetic disease caused by a deficiency of α-L-iduronidase (IDUA) leading to an accumulation of glycosaminoglycans (GAGs) in tissues of patients with MPS I. While currently available therapies, enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT), provide clinical benefit over untreated disease progression, they still possess significant limitations. ERT does not cross the blood-brain barrier and, therefore, does not treat the central nervous system (CNS) effects of the disease, and HSCT has clinically relevant morbidity and mortality and is not able to completely treat the CNS effects. RGX-111 is designed to deliver a functioning gene enabling the production of IDUA in the brain. This is a Phase I/II , first-in-human, multicenter, open-label, single-arm dose escalation study of RGX 111. Up to 21 subjects with MPS I will be treated in 2 dose cohorts and will receive a single dose of RGX-111 administered using an investigational device by IC or IVR injection. Safety will be the primary focus for the initial 24 weeks after treatment (primary study period). Following completion of the primary study period, subjects will continue to be assessed (safety and efficacy) for up to a total of 104 weeks following treatment with RGX-111. At the end of the study, all subjects will be invited to participate in a long-term observational follow-up study.

• Study Type: Interventional
• Enrollment (Estimated): 21
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Brazil
  • Rio Grande do Sul
    • Porto Alegre, Rio Grande do Sul, Brazil, 90035-903
      • Hospital De Clinicas De Porto Alegre
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 4 months and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. A male or female ≥ 4 months of age.
2. 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 participant is unable to provide informed consent, then informed assent will be obtained, and informed consent must be provided by the participant's legal guardian.
3. Having previously documented diagnosis of MPS I confirmed by molecular genetic testing, or IDUA deficiency in leucocytes or fibroblasts.

4. Has documented evidence of CNS involvement due to MPS I based on one of the following criteria, if not explainable by any other neurologic or psychiatric factors:

   1. A score of ≥ 1 standard deviation below mean on neurodevelopmental testing or in 1 domain of neuropsychological function.
   2. A decline of > 1 standard deviation on sequential neurodevelopmental testing or in 1 domain of neuropsychological function administered between 3 to 36 months apart.
   3. Has a documented diagnosis of severe MPS I confirmed by biallelic mutations predictive of the severe phenotype or has a relative clinically diagnosed with severe MPS I and the same IDUA mutations. This participant is not required to have documented evidence of neurocognitive deficit.
5. Participants who have had HSCT may be enrolled in the study if the investigator, Medical Monitor, and Sponsor agree that he/she can safely and successfully participate in the study.
6. Has sufficient auditory and visual capacity, with or without aids, to complete the required protocol testing and willing to be compliant with wearing the aid, if applicable, on testing days.
7. Females of childbearing potential must have negative serum pregnancy test at the screening visit, have negative results on Day 1, and be willing to have additional pregnancy tests during the study.
8. Sexually active male participants must be willing to use a medically accepted method of barrier contraception (eg, condom or female diaphragm) from the screening visit until 24 weeks after vector administration. Cessation of birth control after this point should be discussed with the participant's physician.
9. Sexually active females must be willing to use an effective method of birth control from the screening visit until 12 weeks after the last dose of sirolimus or tacrolimus, whichever is later. Cessation of birth control after this point should be discussed with the participant's physician. Effective methods of birth control include a double barrier method (eg, male condom plus a diaphragm), an intrauterine device, or hormonal contraception. Sustained abstinence is an acceptable practice; however, periodic abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception.

Exclusion Criteria:

1. Has any contradiction to MRI, contrast or to general anesthesia

   1. Has any contradiction to gadolinium
   2. Has renal insufficiency as determined by an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2, based on creatinine. If the laboratory determines that the creatinine level is less than the lower limit of assay validation or detection, then the lowest limit cutoff value will be used for the eGFR.

2. Has a contradiction for an IC and IVR infusion, including any of the following:

   1. Review of baseline MRI testing by the team of neuroradiologists/neurosurgeons participating in the study (1 per site) shows a contraindication for an IC and an IVR infusion.
   2. History of prior head/neck surgery, which resulted in a contraindication to IC and IVR infusion, based on review of available information by the team of neuroradiologists/neurosurgeons participating in the study.
   3. Has previously experienced a clinically significant intracranial bleed that, in the opinion of the investigator and team of neuroradiologists/neurosurgeons, is a contraindication to IC and IVR infusion.
3. Has any neurocognitive deficit not attributable to MPS I or has a diagnosis of a neuropsychiatric condition that may, in the opinion of the investigator, confound interpretation of study results.
4. Has any contradiction to lumbar puncture.
5. Has received IT laronidase at any time and experienced a significant AE considered related to IT administration that, in the opinion of the investigator, would put the participant at undue risk.
6. Has received IV laronidase at any time and experienced a significant AE considered related to IV administration that, in the opinion of the investigator, would put the participant at undue risk.
7. Has imminent plans to receive HSCT within the next year.
8. Has any history of lymphoma or history of another cancer other than squamous cell or basal cell carcinoma of the skin that has not been in full remission for at least 3 months before screening.
9. Has uncontrolled hypertension (systolic BP > 180 mmHg, diastolic BP > 100 mmHg) despite maximal medical treatment.
10. Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 × ULN or total bilirubin > 1.5 × ULN at screening, unless the participant has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin < 35% of total bilirubin.
11. Has a history of human immunodeficiency virus (HIV) or hepatitis B or hepatitis C virus infection, or positive screening tests for hepatitis B surface antigen or hepatitis B core antibody, or hepatitis C or HIV antibodies.
12. Received any IP within 30 days or 5 half-lives before signing of the Informed consent form (ICF), whichever is longer.
13. Is a first-degree family member of a clinical site employee or any other individual involved in the conduct of the study, or is a clinical site employee or any other individual involved in the conduct of the study.
14. Is pregnant, < 6 weeks postpartum, breastfeeding at screening, or planning to become pregnant (self or partner) at any time from signing of informed consent through Week 52. Plans to become pregnant after Week 52 should be discussed with the participant's physician.
15. Has history of alcohol or substance abuse within 1 year before screening.
16. Has a clinically significant ECG or transthoracic echocardiogram abnormality that, in the opinion of the investigator, would compromise the participant's safety.

17. Has a serious or unstable medical or psychological condition that, in the opinion of the investigator, would compromise the participant's safety or successful participation in the study or interpretation of study results.

    Exclusion criteria related to immunosuppressive therapy:

18. A history of a hypersensitivity reaction to tacrolimus, sirolimus, or prednisone.
19. A history of a severe immunodeficiency (eg, common variable immunodeficiency syndrome), splenectomy, or any underlying condition that predisposes the participant to infection.
20. Varicella zoster virus (VZV), herpes zoster (shingles), CMV, or EBV infection that has not completely resolved at least 12 weeks prior to screening.
21. Any infection requiring hospitalization or treatment with parenteral anti-infectives not resolved at least 8 weeks prior to Visit 2.
22. Any active infection requiring oral anti-infectives (including antivirals) within 10 days prior to Visit 2.
23. History of active tuberculosis (TB) or a positive QuantiFERON-TB Gold test during screening.
24. Any live vaccine within 4 weeks prior to Day -2.
25. Major surgery within 8 weeks before signing the ICF or major surgery planned during the study period.
26. Absolute neutrophil count < 1.3 × 103/µL.
27. Any condition or laboratory abnormality that the investigator believes would not be appropriate for immunosuppressive therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dose 1; 1x10^10 GC/g brain mass of RGX-111	Genetic: RGX-111; Recombinant adeno-associated virus serotype 9 capsid containing α-L-iduronidase expression cassette
Experimental: Dose 2; 5x10^10 GC/g brain mass of RGX-111	Genetic: RGX-111; Recombinant adeno-associated virus serotype 9 capsid containing α-L-iduronidase expression cassette

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability	Number of participants with treatment-related adverse events and serious adverse events. To evaluate safety and tolerability following a single IC or IVR dose administered to participants who have documented CNS involvement due to MPS I.	24 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Long-term Safety and Tolerability	Evaluate safety and tolerability through AE reporting using CTCAE Version 5.0.	104 Weeks
Evaluation of the impact of RGX-111 on neurodevelopmental parameters of cognitive, behavioral, and adaptive function (WASI-II)	Change from baseline in neurodevelopmental parameters as measured by the Wechsler Abbreviated Scale of Intelligence (WASI-II). The WASI-II assesses intelligence for individuals from ages 6 to 90 years old. The assessment yields composite scores that estimates verbal comprehension and perceptual reasoning abilities. The subtests have different scoring ranges, with higher subtest raw scores indicating completion of more complex items, but can be normalized for cross-subtest comparison.	104 Weeks
Evaluation of the impact of RGX-111 on neurodevelopmental parameters of cognitive, behavioral, and adaptive function (BSID-II)	Change from baseline in neurodevelopmental parameters as measured by the Bayley Scales of Infant and Toddler Development Third Edition (BSID-III). The BSID-III assesses children with developmental functioning ranging from 1-42 months. In this study, participants will be assessed for the Cognitive, Language, and Motor domains. The domains have different scoring ranges, with higher subtest raw scores indicating better function, but can be normalized for cross-domain comparison.	104 Weeks
Evaluation of the impact of RGX-111 on neurodevelopmental parameters of cognitive, behavioral, and adaptive function (WPPSI-IV)	Change from baseline in neurodevelopmental parameters as measured by the Wechsler Preschool and Primary Scale of Intelligence Fourth Edition (WPPSI-IV). The WPPSI-IV measures cognitive development in young children from ages 30-91 months of age. This study utilizes the General Ability Index (GAI) comprised of 4 core subtests depending on the child's age. The subtests have different scoring ranges, with higher subtest raw scores indicating completion of more complex items but can be normalized for cross-subtest comparison.	104 Weeks
Evaluation of the long-term impact of RGX-111 on neurodevelopmental parameters of cognitive, behavioral, and adaptive function (VABS-III)	Change in baseline adaptive behavior as measured by Vineland Adaptive Behavior Scales Third Edition (VABS-III). The VABS-III assesses adaptive behavior in individuals from infancy to age 90 years. In this study, 4 domains of Communication, Daily Living Skills, Socialization, and Motor Skills will be assessed. The domains have different scoring ranges, with higher subdomain raw scores indicating greater function, but can be normalized for cross-domain comparison	104 Weeks
Vector Concentrations	To evaluate vector concentrations in CSF and serum measured by qPCR for RGX-111	Baseline, Week 1, Week 6,Week 7,Week 9,Week 24,Week 32,Week 40, Week 52
Vector Shedding	To evaluate vector shedding in feces and urine by qPCR for RGX-111	Baseline, Week 1, Week 6,Week 7,Week 9,Week 24,Week 32,Week 40, Week 52
Pharmacodynamic Effect of RGX-111 on CSF Biomarkers (HS)	To assess the pharmacodynamic effect of RGX-111 on Hepran Sulfate (HS) levels measured by Lumbar Puncture at scheduled time points.	Baseline, Week 8, Week 16, Week 24, Week 56, Week 78, Week 104
Pharmacodynamic Effect of RGX-111 on CSF Biomarkers (IDUA)	To assess the pharmacodynamic effect of RGX-111 on α-L-iduronidase (IDUA) levels measured by Lumbar Puncture at scheduled time points.	Baseline, Week 8, Week 16, Week 24, Week 56, Week 78, Week 104
Pharmacodynamic Effect of RGX-111 on Plasma Biomarkers (HS)	To assess the pharmacodynamic effect of RGX-111 on Hepran Sulfate (HS) levels measured by plasma collection at scheduled time points.	Baseline, Week 2, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 52, Week 56, Week 78, Week 104
Pharmacodynamic Effect of RGX-111 on Plasma Biomarkers (IDUA)	To assess the pharmacodynamic effect of RGX-111 on α-L-iduronidase (IDUA) levels measured by plasma collections at scheduled time points.	Week 2, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 52, Week 56, Week 78, Week 104
Pharmacodynamic Effect of RGX-111 on Urine Biomarkers	To assess the pharmacodynamic effect of RGX-111 on glycosaminoglycans (GAGs) levels measured by urine analysis at scheduled time points.	Baseline, Week 1, Week 2, Week 4, Week 8, Week 16, Week 24, Week 32, Week 40, Week 48, Week 52, Week 56, Week 78, Week 104

Collaborators and Investigators

• Sponsor: REGENXBIO Inc.

Publications and helpful links

General Publications

• De BP, Rosenberg JB, Selvan N, Wilson I, Yusufzai N, Greco A, Kaminsky SM, Heier LA, Ricart Arbona RJ, Miranda IC, Monette S, Nair A, Khanna R, Crystal RG, Sondhi D. Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease. Hum Gene Ther. 2023 Sep;34(17-18):905-916. doi: 10.1089/hum.2023.067.

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2019
• Primary Completion (Estimated): July 7, 2027
• Study Completion (Estimated): March 6, 2029

Study Registration Dates

• First Submitted: June 18, 2018
• First Submitted That Met QC Criteria: July 5, 2018
• First Posted (Actual): July 9, 2018

Study Record Updates

• Last Update Posted (Actual): March 12, 2026
• Last Update Submitted That Met QC Criteria: March 9, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: MPS I , gene therapy, Hurler, Hurler- Scheie
• Additional Relevant MeSH Terms: Metabolism, Inborn Errors; Genetic Diseases, Inborn; Metabolic Diseases; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mucopolysaccharidoses; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Nutritional and Metabolic Diseases; Skin and Connective Tissue Diseases; Mucopolysaccharidosis I
• Other Study ID Numbers: RGX-111-002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No