A Study to Evaluate the Tolerability, Safety and Efficacy of GNR-097 Gene Therapy in Pediatric Patients With Duchenne Muscular Dystrophy

Multicenter, Single-blind, Randomized, Placebo-controlled Study of a Single Intravenous Infusion of a Gene Therapy Product GNR-097 in Pediatric Patients With Duchenne Muscular Dystrophy

The study will evaluate the tolerability, safety and efficacy of gene therapy product in boys with Duchenne muscular dystrophy (DMD). In Phase I the participants will be included in two sequential dose cohorts with increasing doses of the investigational product. Based on the results of Phase I, the dose of the investigational product for use in Phase II will be determined. Phase II is a randomized, single-blind, placebo-controlled study. The participants who are randomized to the placebo arm will have an opportunity for treatment with gene therapy at the beginning of the second year.

Inclusion Criteria:

1. Written informed consent for participation in the trial.

2. Ambulatory boys aged 4-9 years with a documented diagnosis of DMD and clinical manifestations of the disease.

3. A frameshift mutation or nonsense mutation in the DMD gene.

4. Сreatine phosphokinase level >5000 U/L.

5. Binding antibody titer to AAV9 ≤1:50 [method: ELISA].

6. The patient is able to interact with the study physician and perform tests to assess functional activity.

7. Results of functional activity assessment tests at screening (at least in one of the two attempts performed on different days):

   • NSAA ≥22;
   • time to rise from a supine position without using surrounding objects or furniture <5 sec;
   • 6MWT distance ≥350 m.

8. The patient received oral glucocorticosteroids at a stable dose for ≥12 weeks prior to signing the Informed Consent Form, and it is planned that glucocorticosteroids will be continued during the screening stage and after the patient's inclusion in the study.

9. For patients receiving deflazacort at study entry: switching the patient from deflazacort to prednisolone, in the opinion of the investigator, will not result in a significant deterioration in the patient's health.

10. The patient has been immunized with a vaccine against meningococcal serotypes A, C, Y, W135 (and B, if available) no later than 4 weeks prior to administration of GNR-097/placebo, and the immunization period expires no more than three months after the expected date of administration of GNR-097/placebo.

Exclusion Criteria:

1. Hypersensitivity to any component of GNR-097 or placebo.

2. Patient with cognitive impairment or a sedentary lifestyle that, in the opinion of the investigator, may interfere with the development or manifestation of motor activity.

3. Mutations in exons 8 and/or 9 of the DMD gene; for patients planned for inclusion in Cohort A, additionally: mutations in exons 1-17 and/or 59-71 of the DMD gene.

4. Clinical signs of cardiomyopathy, including left ventricular ejection fraction (Simpson) <40% based on echocardiography performed during screening.

5. Contraindications to magnetic resonance imaging.

6. History of any autoimmune disease, with the exception of drug-compensated autoimmune thyroiditis.

7. History of tuberculosis; positive or indeterminate result of Diaskintest® TigraTest® or T-SPOT.TB screening.

8. Positive results of tests for hepatitis B, hepatitis C, or HIV screening.

9. Acute infectious diseases that resolved less than 4 weeks before administration of GNR-097/placebo.

10. Immunization with a live attenuated vaccine less than 3 months before administration of GNR-097/placebo OR immunization with any inactivated vaccine less than 4 weeks before administration of GNR-097/placebo.

11. Abnormal laboratory parameters:

    • GGT level is more than three upper limits of normal;
    • total bilirubin >50.0 μmol/L (except for patients with a confirmed diagnosis of Gilbert's syndrome);
    • creatinine >160.0 μmol/L;
    • hemoglobin <80 or >180 g/L;
    • white blood cell count >18,500/μL;
    • platelet count below the lower limit of normal.

12. History of taking antisense oligonucleotides, ataluren, gene therapy using vector constructs, or cell therapy.

13. Use of immunosuppressive drugs other than glucocorticosteroids less than 12 weeks prior to signing the Informed Consent Form.

14. Participation in clinical trials less than 6 months prior to signing the Informed Consent Form.

15. Unwillingness or inability of the patient and/or their parent/legal guardian to comply with the protocol requirements and/or the trial procedures.

16. Other diseases or conditions not listed above that, in the opinion of the physician investigator and/or the Sponsor, prevent the patient from participating in the trial, including for safety reasons.