A study to investigate the efficacy and safety of OTL-203 in subjects with mucopolysaccharidosis type I, Hurler syndrome (MPS-IH) compared with standard of care with allogeneic hematopoietic stem cell transplantation (allo-HSCT)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Orchard Therapeutics (Europe) Limited

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male and Female

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18], Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Trial duration

20 Sep 2024 → ongoing

Decision date (initial)

2024-04-29

Transition trial

No

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Orchard Therapeutics (Europe) Ltd

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacodynamic, Safety, Therapy

Assessing the event-free survival with OTL-203 in comparison to Standard of Care (SoC; allo-HSCT)

Secondary objectives 5

1. Assessing the pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT) (Key secondary endpoint).
2. Assessing the effects of OTL-203 on relevant MPS-IH symptomatic manifestations (“disease burden”) in comparison to SoC (allo-HSCT).
3. Assessing the effects of OTL-203 and SoC on health-related quality of life and health resource utilization.
4. Assessing the engraftment and pharmacodynamic effects of OTL-203 in comparison to SoC (allo-HSCT).
5. Assessing the safety and tolerability of gene therapy with OTL-203 in comparison to SoC (allo-HSCT procedure).

Conditions and MedDRA coding

Mucopolysaccharidosis type I, Hurler Syndrome

Study design 4 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

EMA paediatric investigation plan (PIP)

EMEA-003001-PIP01-21

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Written informed consent by parent/legal guardian.
2. 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.
3. 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).
4. 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]
5. 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 10

1. Previous allo-HSCT or gene therapy.
2. 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.
3. 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.
4. 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.
5. Myelodysplastic syndrome (MDS)/ acute myeloid leukemia (AML).
6. History of uncontrolled seizures.
7. 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).
8. 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.
9. 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.
10. Subjects who have contraindications for MRI scans (for example, but not limited to, cardiac pacemaker, metal implants).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Event-free survival (EFS; composite endpoint) at Year 2 (the primary analysis timepoint) defined by the following events: 1. Death post-treatment 2. Rescue allo-HSCT 3. Treatment Failure 4. Immunological complications 5. Severe Cognitive Impairment 6. Short Stature.

Secondary endpoints 6

1. • Change from Baseline (CFB) to Year 2 in IDUA activity in leukocytes • CFB to Year 2 in urinary heparan sulfate levels, defined as ratio to the upper limit of normal (ULN).
2. Long Term EFS at the time of the final analysis.
3. The following endpoints will be assessed at each visit scheduled in the SoA: Cognitive Function, Joint Range Motion, Dysostosis Multiplex, Auditory function, Visual function and corneal clouding, 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).
4. Healthcare resource utilization (HRU) and Surgical Burden.
5. Assessments of Engraftment and Pharmacodynamic Effects.
6. Safety of OTL-203 compared to allo-HSCT procedure as measured by: overall incidence of adverse events (AEs), NIMP/AxMP-related AEs, Study Procedure-related AEs, Disease-related AEs, Treatment related AEs, Serious adverse events (SAEs). Immune response against IDUA enzyme (anti-IDUA antibodies), evaluated via immunoassay. Malignancy or Abnormal Clonal Proliferation (ACP). Emergence of Replication Competent Lentivirus (RCL).

Investigational products

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

Test 1

Auxiliary 6

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Orchard Therapeutics (Europe) Limited

Sponsor organisation

Orchard Therapeutics (Europe) Limited

Address

245 Hammersmith Road

City

London

Postcode

W6 8PW

Country

United Kingdom

Scientific contact point

Organisation

Orchard Therapeutics (Europe) Limited

Contact name

Clinical

Public contact point

Organisation

Orchard Therapeutics (Europe) Limited

Contact name

Clinical

Third parties 20

Locations

2 EU/EEA countries · 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 86 files

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

Application history

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