Hematopoietic stem cell gene therapy study

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

8 Apr 2010 → 20 Sep 2025

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

External identifiers

EU CT number

2024-515253-25-00

EudraCT number

2009-017349-77

ClinicalTrials.gov

NCT01560182

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

Evaluation of the safety of gene therapy in MLD subjects, considering both the conditioning regimen safety and the safety of LV-transduced cell infusion, short and long-term after the treatment (for details see safety primary endpoint);"Evaluation of the efficacy of gene therapy, assessed as reduction in the progression of the clinical motor impairment in treated subjects as compared to the progression measured in untreated MLD patients in our disease natural history study, accompanied by a significant increase of residual ARSA activity as compared to pre-treatment subjects’ values. Motor functions will be measured by the clinically relevant GMFM scoring system (for details see efficacy primary endpoint). Indeed, there is a clear causal relationship between the potential beneficial outcome measured with the GMFM and the treatment, being motor impairment consequent to the involvement of both central and peripheral nervous system, and less influenced by other variables. Residual ARSA activity will be measured on hematopoietic cells (PBMC and BM cells)

Secondary objectives 5

1. Evaluation of the efficacy of the procedure in reducing the progression of demyelination (and atrophy) in the central and peripheral nervous system in comparison with that documented in our historical controls, as assessed by validated instrumental parameters, total brain MRI score and NCV Index at ENG recordings (see secondary efficacy end-points).
2. Evaluation of the efficacy of the procedure in reducing the progression of clinical motor impairment as assessed by GMFC-MLD, in treated subjects as compared to historical controls.
3. Evaluation of the efficacy of the procedure in reducing the progression of the cognitive impairment, as assessed by the administration of neuropsychological tests.
4. Evaluation of the biological efficacy of the procedure in treated subjects, which consists of the sustained engraftment of the transduced cells, essential prerequisite for achieving clinical benefit. Long-term transduced cell engraftment will prove that i) ARSA LV transduced HSPC with long-term repopulation potential and ii) the conditioning regimen was adequate for allowing transduced cell engraftment.
5. Evaluation of correlations occurring between transduced cell engraftment levels and busulfan exposure

Conditions and MedDRA coding

Metachromatic Leukodystrophy (MLD)

Study design 1 period

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

EMA paediatric investigation plan (PIP)

EMEA-001765-PIP02-15

Plan to share IPD

No

IPD plan description

N/A

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 3

1. Pre-symptomatic late infantile patients;
2. Pre- or early-symptomatic early juvenile patients;
3. Parental/guardian/patientsigned informed consent.

Exclusion criteria 2

1. • HIVRNA and/or HCVRNA and/or HBVDNA-positive patients; • Patients affected by neoplastic diseases; • Patients with cytogenetic alterations typical of MDS/AML; • Patients with end-organ functions or any other severe disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study; • Patients enrolled in other trials;
2. • Patients who underwent allogeneic hematopoietic stem cell transplantation in the previous 6 months; • Patients who underwent allogeneic hematopoietic stem cell transplantation with evidence of residual cells of donor origin.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 3

1. Safety endpoint- 1. Conditioning regimen-related safety, consisting of the absence of engraftment failure or delayed hematological reconstitution (prolonged aplasia) and surveillance of non-hematological regimen related toxicity (AEs with NCI Common Toxicity Criteria grade ≥ 2; and laboratory parameters with NCI Common Toxicity Criteria grade ≥ 3).
2. 2. Safety of LV-transduced cell infusion, defined as: a) short-term safety and tolerability of lentiviraltransduced cell infusion; b) long-term safety of lentiviral-transduced cell infusion (absence of Replication Competent Lentivirus (RCL) and abnormal clonal proliferation).
3. Efficacy endpoints- 1. An improvement of ≥ 10% of the total score at gross motor function measure (GMFM) at comparison with the GMFM scores obtained by aged matched untreated MLD patients, evaluated 24 months after treatment. 2. A significant increase of Arylsulfatase A (ARSA) activity as compared to pre-treatment values, measured in total peripheral blood mononuclear cells 24 months after treatment

Secondary endpoints 3

1. Safety endpoint- 1. Absence of immune responses against the transgene
2. Efficacy Endpoints- o The Nerve Conduction Velocity Index at 24 months after treatment compared to scores observed in the historical control MLD population. Nerve conduction velocity in individual sensory and motor nerves will also be evaluated. o The total brain MRI scores at 24 months after treatment compared to scores observed in the historical control MLD population. o GMFC-MLD levels at different ages in treated subjects compared to the historical control MLD population
3. o The measurement of Intelligence Quotient (IQ) values above 55 at 24, 30 and 36 months after treatment. o An engraftment of the transduced cells above 4% in bone marrowderived clonogenic progenitor cells at 12 months after the transplant. o Vector copy number (VCN) per cell in total PBMC, total BM, and peripheral blood (PB) and BM cell subpopulations will also be evaluated. o Evaluation of correlations occurring between transduced cell engraftment levels and busulfan exposure.

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 12

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

Summary of results Art. 37(4) CTR

Layperson summary Annex V

Documents 21 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