Cell-mediated skipping of exon 51 for the genetic correction of dystrophin, based upon a single injection of autologous mesoangioblasts (MABs) in individual skeletal muscles of five non-ambulant patients affected by Duchenne Muscular Dystrophy: a non randomized, open-label, phase I/IIa study

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ospedale San Raffaele S.r.l., University Of Manchester

Participant type

Pediatric, Patients

Age range

0-17 years

Gender

Male

Therapeutic area

Diseases [C] - Musculoskeletal Diseases [C05]

Trial duration

27 Jun 2024 → ongoing

Decision date (initial)

2024-10-01

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

External identifiers

EU CT number

2024-514860-14-00

EudraCT number

2023-000148-47

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy

We will test safety of treatment and efficacy in restoring synthesis of dystrophin in
the injected muscle.
Safety
1. To assess the incidence of adverse events in DMD patients treated with
intra-muscular foot injections of auto-MABS after genetic correction with a lentiviral
vector expressing a small nuclear RNA engineered to skip exon 51 of the dystrophin
gene.
Note: In vitro/in vivo pre-clinical safety assessments will be performed on ATIMP
prior to injection, as described in the IMPD.
Efficacy
2. To determine dystrophin expression (>= 10% of a healthy subject) after a
single intra- muscular injection into the foot medial Extensor Digitorum Brevis (EDB)
of genetically corrected auto-MABS.

Conditions and MedDRA coding

Duchenne Muscular Dystrophy

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Age between >= 12 and <18 years at time of study entry, provided that participants matching the eligibility criteria can be identified.
2. Non-ambulant at the time of recruitment.
3. Confirmed diagnosis of DMD with documented exon 51 skippable mutations in dystrophin gene.
4. Progression of muscle degeneration =< to 50% reduction of muscle mass as determined by quantitative MRI (grade 2: Kinali et al. 2011).
5. Written informed consent of caregivers of DMD patients and patient’s assent.

Exclusion criteria 11

1. Positive hepatitis B surface antigen, hepatitis C antibody test, or Human immunodeficiency virus (HIV) test, TPHA test.
2. Presence of immune deficiency, neoplastic or autoimmune disease (based on clinical history).
3. Bleeding disorder.
4. Any known allergies to products likely to be used in the study.
5. Prior or ongoing medical condition (e.g. concomitant illness, psychiatric condition, behavioural disorder, drug abuse), medical history, physical findings, or laboratory abnormality that, in the investigator’s opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow up would be completed, or could impair the assessment of study results.
6. Ongoing participation in any other therapeutic clinical trial or treatment with exon skipping oligonucleotides. Use of steroids is considered standard care and therefore permitted.
7. LVEF (Left Ventricle Ejection Fraction) < 45% of a healthy subject or ECG finding significant for underlying cardiac impairment.
8. Pulmonary function tests assessed by spirometry (if cooperative) of FEV1 and FVC <30% of the predicted values. If unable, pulse oximetry < 95 % in room air.
9. Change of medication related to DMD within last 3 months with the exception of adjustment based on weight gain of current medications.
10. Presence of severe scoliosis (curve >50°).
11. Presence of significant impairment of renal or hepatic function.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Safety 1. Incidence and severity of local (foot) and systemic adverse events (any grade) in DMD patients treated with intra- muscular injections of genetically corrected auto-MABS for one year from the injection.
2. Efficacy 2.Presence of dystrophin (≥ to 1:10 dilution of a control muscle for WB; ≥ 10% of gene expression of skipped dystrophin at ddPCR; ≥ 10% of dystrophin positive fibers for IF respect to a control muscle) on muscle biopsy of the EDB muscle transplanted with genetically corrected auto-MABS, in at least two out of the three assays (Quantitative IF , ddPCR, and Western Blot) at two months after injection.

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ospedale San Raffaele S.r.l.

Sponsor organisation

Ospedale San Raffaele S.r.l.

Address

Via Olgettina 60

City

Milan

Postcode

20132

Country

Italy

Scientific contact point

Organisation

Ospedale San Raffaele S.r.l.

Contact name

Stefano Previtali

Public contact point

Organisation

Ospedale San Raffaele S.r.l.

Contact name

Stefano Previtali

University Of Manchester

Sponsor organisation

University Of Manchester

Address

2nd Floor, Christie Building, Oxford Road Christie Building Oxford Road

City

Manchester

Postcode

M13 9PL

Country

United Kingdom

Public contact point

Organisation

University Of Manchester

Contact name

Mohammed Zubair

Sponsor responsibilities

Article 77 compliance

Ospedale San Raffaele S.r.l.

Contact point sponsor

Ospedale San Raffaele S.r.l.

Article 77 implementation

Ospedale San Raffaele S.r.l.

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

Application history

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