Gene therapy study using a frozen formulation of OTL-200 in patients with Metachromatic Leukodystrophy (MLD)

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

Phenomena and Processes [G] - Genetic Phenomena [G05]

Trial duration

13 Dec 2017 → 11 Mar 2026

Decision date (initial)

2024-05-20

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-511970-66-00

EudraCT number

2017-001730-26

ClinicalTrials.gov

NCT03392987

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Others, Pharmacodynamic

To evaluate the clinical efficacy of the cryopreserved formulation of OTL200

Secondary objectives 1

1. 1. To evaluate the clinical efficacy of the cryopreserved formulation of OTL-200 (Other endpoints) 2. To evaluate engraftment of the cryopreserved formulation of OTL-200 3. To evaluate the pharmacodynamic effect of the cryopreserved formulation of OTL-200 4. To evaluate the safety and tolerability of the cryopreserved formulation of OTL-200

Conditions and MedDRA coding

Metachromatic Leukodystrophy (MLD)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 2

1. Documented biochemical and molecular diagnosis of MLD, based on ARSA activity below the normal range and identification of two disease-causing ARSA alleles, either known or novel mutations. Novel mutations will be analyzed with in silico prediction tools and excluded from being known common polymorphisms. In the case of a novel mutation(s), a 24-hour urine collection must show elevated sulfatide levels.
2. Eligible participants must have EITHER: a) an older sibling affected by MLD (index case), whose age of symptom onset was ≤6 years of age (i.e. had not celebrated 7th birthday). Participants will be classified as Late Infantile, Early Juvenile or Intermediate LI/EJ based on age of symptom onset in the index case and their ARSA genotype: i. LI: symptom onset in index case ≤30 months of age; genotype typically 0/0 ii. EJ: symptom onset in index case >30 months and ≤6 years of age; genotype typically 0/R iii. Intermediate LI/EJ: symptom onset in index case ≤6 years of age but unable to unambiguously characterize index case as LI or EJ OR b) If MLD is diagnosed in a pre-symptomatic child without an older affected sibling, (e.g. incidentally or via newborn screening) and the totality of the data available to the investigator strongly suggest that the patient has an early onset variant of MLD likely to benefit from gene therapy, and the patient is ≤6 years of age (i.e. has not celebrated 7th birthday), the patient may be considered eligible after discussion and approval by the Orchard Therapeutics (Europe) Ltd. Medical Monitor (Orchard-MM)

Exclusion criteria 2

1. If LI MLD variant, clinical manifestations of the disease defined as EITHER of the following: i. Delay in expected achievement of independent standing or independent walking, together with abnormal signs at neurological evaluation OR ii. Documented neurological signs and symptoms of MLD associated with cognitive, motor, or behavioral functional impairment or regression (substantiated by neurological examination and/or neuropsychological tests appropriate for age)
2. If EJ MLD variant, symptoms of MLD resulting in the loss of capacity of walking independently as defined by a GMFC level ≥2 or symptoms consistent with cognitive impairment as defined by an IQ<85 using age-appropriate neurocognitive instruments

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Gross motor function measure (GMFM) score at 24 months post gene therapy

Secondary endpoints 5

1. GMFM score post gene therapy at multiple visits over time; • Clinical efficacy at 24 months post gene therapy and multiple visits over time, as measured by: a) Gross Motor Function Classification (GMFC)- MLD score b) Neurological Examinations c) Assessment of Nerve Conduction Velocity (NCV) d) Evaluation of Brain Magnetic Resonance (MR) imaging assessments / parameters (e.g. Modified Loes Score) e) Neurocognitive assessments
2. • %LV positive clonogenic progenitors in bone marrow (BM) at Day 30 post-gene therapy and at multiple visits over time • Vector copy number (VCN) (in BM mononuclear cells) at Day 30 post-gene therapy and at multiple visits over time • VCN (in peripheral blood [PB] mononuclear cells) at Day 60 post-gene therapy and at multiple visits over time
3. • The following at Day 60 post-gene therapy and at multiple visits over time: i) Arylsulfatase A (ARSA) activity in Total Peripheral blood mononuclear cells (PBMCs) ii) ARSA activity in PB CD15+ cells iii) ARSA activity in PB CD14+ cells • ARSA activity in cerebral spinal fluid (CSF) at Day 90 post-gene therapy and at multiple visits over time
4. • Safety and tolerability as measured by adverse events (AEs) reporting; • Conditioning regimen related toxicity and AEs • Non-conditioning related AEs
5. • Hematological recovery, defined as reconstitution of absolute neutrophil count (ANC) > 500 neutrophils/ µL, associated with evidence of BM recovery (i.e. no hypocellular marrow) by day +60 • Incidence and titers of antibodies against ARSA • Absence of malignancy or abnormal clonal proliferation due to insertional oncogenesis • Absence of Replication Competent Lentivirus (RCL)

Investigational products

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

Test 1

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 14

Locations

1 EU/EEA country · 1 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 12 files

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

Application history

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