A multi-center, randomized, active controlled clinical trial to evaluate the efficacy and safety of OTL-203 in subjects with mucopolysaccharidosis type I, Hurler syndrome (MPS-IH) compared to standard of care with allogeneic hematopoietic stem cell transplantation (allo-HSCT)
- Trial ID
- 2022-500306-17-00
- Protocol
- OTL-203-02
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this clinical trial is to evaluate the **event-free survival** of subjects with **Mucopolysaccharidosis type I, Hurler Syndrome** (MPS-IH) when treated with OTL-203, compared to the standard of care (SoC) involving allogeneic hematopoietic stem cell transplantation (allo-HSCT). This objective is clinically relevant as it aims to determine the potential of OTL-203 to improve survival outcomes without adverse events, which is crucial for enhancing the quality of life and long-term prognosis in patients with MPS-IH.
Secondary objectives include:
- Assessing the pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT).
- Evaluating the effects of OTL-203 on relevant MPS-IH symptomatic manifestations, referred to as "disease burden," in comparison to SoC (allo-HSCT).
- Investigating the effects of OTL-203 and SoC on health-related quality of life and health resource utilization.
- Assessing the engraftment and pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT).
- Evaluating the safety and tolerability of gene therapy with OTL-203 in comparison to the SoC (allo-HSCT procedure).
Participants
The clinical trial involves a total of **29 participants** diagnosed with **Mucopolysaccharidosis type I, Hurler Syndrome**. The study population includes both male and female subjects, with an age range from 28 days to 30 months. Participants above 30 months may also be considered for enrolment in the EU/UK under specific conditions. The trial population was selected based on a confirmed laboratory diagnosis of MPS-IH, with biallelic mutations in the gene coding for the IDUA enzyme, and a norm-referenced cognitive standard score of 70 or above. The participants are part of a vulnerable population, and written informed consent was obtained from a parent or legal guardian. The study does not specify any particular lifestyle considerations such as diet or physical activity. The trial aims to assess event-free survival with OTL-203 compared to the Standard of Care (SoC; allo-HSCT).
Plans and Procedures
The clinical trial is designed to evaluate the efficacy and safety of **OTL-203** in subjects with **Mucopolysaccharidosis type I, Hurler Syndrome** (MPS-IH) compared to the standard of care with allogeneic hematopoietic stem cell transplantation (allo-HSCT). This is a multi-center, randomized, active-controlled trial. The study is conducted in a double-blind manner to ensure unbiased results. The trial is expected to commence recruitment on May 30, 2024, and is estimated to conclude by November 30, 2030. The primary objective is to assess event-free survival with OTL-203 in comparison to the standard of care. The primary endpoint is event-free survival at Year 2, defined by specific events such as death post-treatment, rescue allo-HSCT, treatment failure, immunological complications, severe cognitive impairment, and short stature.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, cognitive standard score, and confirmed laboratory diagnosis of MPS-IH. Follow-up visits will be scheduled to monitor various endpoints, including changes in IDUA activity, urinary heparan sulfate levels, cognitive function, joint range motion, and other health parameters. The end-of-study visit will mark the completion of the participant's involvement in the trial. The expected length of participant involvement is up to 6 years, with conditions for early termination including severe adverse events or non-compliance with study protocols.
Participants will receive OTL-203, a gene therapy investigational medicinal product, administered as a single dose via intravenous infusion. The trial will also involve the use of auxiliary products such as **Plerixafor**, **Busulfan**, **Laronidase**, **Fludarabine**, and **Rituximab**, each with specific dosing regimens and administration routes. The trial will adhere to rigorous safety monitoring, with assessments of adverse events, immune response, and potential complications. The study aims to provide comprehensive data on the long-term efficacy and safety of OTL-203, contributing to the understanding and treatment of MPS-IH.
Treatment
**Plerixafor** is administered as a **solution for injection** with a subcutaneous route. The dosage is calculated based on body weight, with a maximum daily dose of 0.40 mg/kg and a total maximum dose of 1.20 mg/kg over a treatment period of up to 3 days. This chemical compound is utilized as an auxiliary treatment in the trial.
**Busulfan** is provided as a **concentrate for solution for infusion** and is administered intravenously. The dosage is determined by body surface area, with a maximum daily dose of 80 mg/m² and a total maximum dose of 85 mg/m² over a treatment period of up to 4 days. It serves as an auxiliary chemical treatment in the study.
**Laronidase** is also a **concentrate for solution for infusion** administered intravenously. The dosage is based on body weight, with a maximum daily dose of 100 IU/kg and a total maximum dose of 26,000 IU/kg over a treatment period of up to 60 days. This biological product is used as an auxiliary treatment in the trial.
**Fludarabine** is administered as a **concentrate for solution for infusion** via the intravenous route. The dosage is calculated based on body surface area, with a maximum daily dose of 40 mg/m² and a total maximum dose of 160 mg/m² over a treatment period of up to 4 days. It is used as an auxiliary chemical treatment in the study.
**OTL-203** is a **dispersion for infusion** administered as a single intravenous infusion. It is a gene therapy investigational medicinal product consisting of autologous CD34+ hematopoietic stem and progenitor cells genetically modified with a lentiviral vector encoding the human IDUA gene. The maximum dose is 35 dosage forms, administered once. This product is the primary investigational treatment in the trial.
The trial also includes an **immunostimulant** with a maximum daily dose of 10 µg/kg and a total maximum dose of 30 µg/kg over a treatment period of up to 3 days, administered subcutaneously. The specific product name and pharmaceutical form are not provided.
**Rituximab** is provided as a **concentrate for solution for infusion** and is administered intravenously. The dosage is based on body surface area, with a maximum daily dose of 375 mg/m² and a total maximum dose of 750 mg/m² over a treatment period of up to 40 days. This biologic is used as an auxiliary treatment in the study.
Efficacy
The efficacy of the investigational medicinal product OTL-203 in subjects with **mucopolysaccharidosis type I, Hurler syndrome (MPS-IH)** will be assessed through a multi-center, randomized, active-controlled clinical trial. The primary endpoint for evaluating efficacy is the event-free survival (EFS) at Year 2, which is a composite endpoint defined by the occurrence of specific events such as death post-treatment, rescue allo-HSCT, treatment failure, immunological complications, severe cognitive impairment, and short stature.
Secondary endpoints include changes from baseline to Year 2 in IDUA activity in leukocytes and urinary heparan sulfate levels, defined as a ratio to the upper limit of normal (ULN). Additional assessments will be conducted at each scheduled visit, evaluating cognitive function, joint range of motion, dysostosis multiplex, auditory and visual function, imaging, presence of cardiac abnormalities associated with MPS-I, motor function, functional capacity, auxological measurements, quality of life (QoL), and activities of daily living (ADLs). Healthcare resource utilization and surgical burden will also be monitored.
Engraftment and pharmacodynamic effects will be assessed, alongside the safety of OTL-203 compared to the allo-HSCT procedure. Safety will be measured by the overall incidence of adverse events (AEs), including NIMP/AxMP-related AEs, study procedure-related AEs, disease-related AEs, treatment-related AEs, and serious adverse events (SAEs). The immune response against the IDUA enzyme will be evaluated via immunoassay, and the emergence of replication-competent lentivirus (RCL) will be monitored.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Written informed consent by parent/legal guardian.
- Male or female subject with age at enrolment: ≥ 28 days to ≤30 months. Note: In addition, subjects aged above 30 months shall be considered for enrolment and treatment with OTL-203 in EU/UK only, if they meet all the eligibility criteria and upon agreement with the Medical Monitor (MM), to comply with the EU/UK PIP. Any subject aged > 30 months enrolled and treated with OTL-203 will be followed as per the SoA of the study but will not be included in the primary statistical analysis.
- Norm-referenced cognitive standard score of ≥70 evaluated within the Screening period of the study and measured by age-appropriate cognitive domains of Bayley Scale of Infant Development (BSID)-III or Wechsler Preschool and Primary Scale of Intelligence (WPPSI)-IV (“visual spatial index” for WPPSI-IV).
- Confirmed laboratory diagnosis of MPS-IH as demonstrated by biallelic mutation(s) in the gene coding for IDUA enzyme (at a CLIA-accredited laboratory): a. homozygosity or compound heterozygosity for two known severe alleles, both of which must be associated with a severe (Hurler) phenotype according to the literature, or b. If mutation(s) are unknown/novel, either of the following: i. sibling known to have MPS-IH with severe phenotype, or ii. presence of somatic features (confirmed by an MPS-I specialist) presenting in the first two years of life, which are consistent with MPS-IH severe phenotype [including but not limited to frequent ear infections, frequent upper respiratory infections, umbilical/inguinal hernia, kyphosis/gibbus, corneal clouding, hepatosplenomegaly, dysostosis multiplex, cognitive impairment, cardiac valve abnormalities, joint contractures]
- Final confirmation of MPS-IH diagnosis by Diagnostic Review Committee (DRC), following the review of: a. gene mutation analysis b. documented biochemical evidence of a deficiency in IDUA enzyme activity c. documented evidence of altered GAG metabolism d. somatic manifestations of the disease.
Exclusion Criteria
- Previous allo-HSCT or gene therapy.
- Current enrollment or past treatment in any other study/trial using a novel investigational agent for which the washout cannot be confirmed by the time of anticipated treatment.
- Evidence of: a. Positivity to serological testing for: i. Human immunodeficiency virus (HIV-1 or HIV-2), ii. Human T lymphotropic virus (HTLV-1 or HTLV-2), iii. Hepatitis B virus (HBV) core. Subjects positive for Hepatitis B core antibodies due to prior resolved disease may be enrolled, if a confirmatory negative Hepatitis B surface antigen and negative HBV deoxyribonucleic acid test are obtained iv. Hepatitis C virus (HCV). Subjects who have previously tested positive for antibodies against HCV may be enrolled, provided ongoing infection is excluded using nucleic acid testing v. Mycoplasma, unless ongoing infection can be excluded (e.g., on the basis of a negative result on a repeat serological testing or molecular testing (polymerase chain reaction) and the investigator’s assessment); b. Active tuberculosis (TB) c. Not meeting the microbiology biological screening requirements for drug product (DP) manufacturing.
- Malignant neoplasia (except local skin cancer). Subjects with a prior successfully treated malignancy and a sufficient follow-up to exclude recurrence (based on oncologist opinion) can be included after discussion and approval by the Sponsor’s MM.
- Myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML).
- History of uncontrolled seizures.
- Subjects with an active infection not responsive to treatment, end-organ damage, or any other disease that contraindicates performance of any of the procedures detailed in the protocol (for example, but not limited to, general anesthesia, mobilization of CD34+ cells from the bone marrow into the peripheral circulation using G-CSF ± plerixafor, leukapheresis and myeloablative conditioning with busulfan and fludarabine).
- Subjects, who in the opinion of the Investigator, may not be able to comply with protocol requirements or cooperate fully with the study procedures and necessary long-term follow up.
- Subjects with any of the following: • Alanine transaminase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN), • Total bilirubin >1.5 × ULN at screening unless the subject has a previously known history of Gilbert's syndrome and a fractionated bilirubin that shows conjugated bilirubin <35% of total bilirubin, • Renal creatinine clearance <30 mL/min, • Left ventricular ejection fraction (LVEF) < 45% by echo or diagnosis of severe pulmonary hypertension, • Medical conditions or extenuating circumstances that, in the opinion of the Investigator, might compromise the subject’s well-being or safety, or the interpretability of the subject’s clinical data.
- Subjects who have contraindications for MRI scans (for example, but not limited to, cardiac pacemaker, metal implants).
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Not Recruiting | 30 May 2024 | 7 |
 The Netherlands | Not Recruiting | 30 May 2024 | — |
| Netherlands | — | — | 4 |
Sites & 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 |
|---|---|---|---|---|---|---|
PLERIXAFOR | Other | — | SUBCUTANEOUS | 0.40 | 3 | SUB28849 |
- | Other | PHF00007MIG | SUBCUTANEOUS | 10 | 3 | L03A |
FLUDARABINE | Other | — | INTRAVENOUS | 40 | 4 | SUB07678MIG |
OTL-203 | Test | DISPERSION FOR INFUSION | INTRAVENIOUS INFUSION | 35 | 1 | PRD9558907 |
RITUXIMAB | Other | — | INTRAVENOUS | 375 | 40 | SUB12570MIG |
LARONIDASE | Other | — | INTRAVENOUS | 100 | 60 | SUB20048 |
BUSULFAN | Other | — | INTRAVENOUS | 80 | 4 | SUB05993MIG |