Clinical trial NCT06114056: A Clinical Study Evaluating the Safety, Tolerability, and Initial Efficacy of Single Intravenous Infusion of JWK007 in Patients With Duchenne Muscular Dystrophy (DMD)
Official title: A Clinical Study Evaluating the Safety, Tolerability, and Initial Efficacy of Single Intravenous Infusion of JWK007 in Patients With Duchenne Muscular Dystrophy (DMD)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Duchenne Muscular Dystrophy
Keywords: Duchenne Muscular Dystrophy
Gene Therapy
Adeno-associated virus
Lead sponsor: West China Hospital
Sponsor class: OTHER
First posted: 2023-11-02
Enrollment: 3
Sex: MALE
Minimum age (years): 5
Maximum age (years): 10
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This study is a single-center, single-arm, non-randomized, open-label, non-controlled, dose-escalation, prospective clinical trial designed to assess the safety, tolerability, and preliminary efficacy of JWK007 injection in pediatric patients with Duchenne Muscular Dystrophy (DMD).

Detailed description: DMD is a rare genetic disorder that primarily affects males. This disease is closely associated with mutations in the DMD gene located on the X chromosome. The DMD gene encodes a protein known as dystrophin, which plays a crucial role in providing essential structural and protective support within the muscles. Gene therapy drugs using Adeno-Associated Virus (AAV) as a vector hold the promise of offering a convenient, effective, and safe treatment option for DMD patients. Therefore, we have independently developed and designed the JWK007 injection. The study will include two dosing groups and employ a '3+3' dose escalation design, incrementally increasing dosages in a sequential, ascending manner.

Eligibility criteria: Inclusion Criteria:

Participants meeting all of the following criteria may be considered for inclusion:

1. Male, aged 5 to 10 years (inclusive).
2. Diagnosis of Duchenne Muscular Dystrophy (DMD) confirmed through medical history and genetic testing, characterized by a frameshift mutation (deletion or duplication) or a premature stop codon mutation in the DMD gene between exons 18 to 58.
3. Below-average performance on motor assessment testing.
4. Ability to cooperate with motor assessment testing.
5. Tolerance for muscle biopsy under anesthesia with no contraindications for biopsy.
6. Participants must have been taking a stable dose of oral corticosteroids for at least 12 weeks prior to screening, and the expected dose should remain constant throughout the study, except for adjustments related to changes in body weight.

Exclusion Criteria:

Participants meeting any one of the following criteria are not eligible for inclusion:

1. Active viral infection based on clinical observations.
2. Signs of cardiomyopathy, including echocardiogram with ejection fraction below 40%.
3. Serological evidence of HIV infection, or Hepatitis B or C infection.
4. Diagnosis of (or ongoing treatment for) an autoimmune disease.
5. Abnormal laboratory values considered clinically significant (GGT \> 3XULN, bilirubin ≥ 3.0 mg/dL, creatinine ≥ 1.8 mg/dL, Hgb \< 80 or \> 180 g/L; WBC \> 18.5\*10\^9/L).
6. Concomitant illness or requirement for chronic drug treatment that in the opinion of the PI creates unnecessary risks for gene transfer.
7. Subjects with AAVrh74 neutralizing antibody titers \> 1:400 as determined by ELISA immunoassay.
8. Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's wellbeing, safety, or clinical interpretability.
9. Severe infection (eg. pneumonia, pyelonephritis, or meningitis) within 4 weeks before gene transfer visit (enrollment may be postponed).
10. Has received any investigational medication (other than corticosteroids) or exon skipping medications (including ExonDys 51), experimental or otherwise, in the last 6 months prior to screening for this study.
11. Has had any type of gene therapy, cell based therapy (eg. stem cell transplantation), or CRISPR/Cas9.
12. Family does not want to disclose patient's study participation with primary care physician and other medical providers

Primary outcomes:
measure: adverse events
timeFrame: 5 years
Secondary outcomes:
measure: North Star Ambulatory Assessment
timeFrame: 5 years
measure: Six-Minute Walk Test
timeFrame: 5 years
measure: 10-Meter Walk/Run Test
timeFrame: 5 years
measure: creatine kinase
timeFrame: 5 years
measure: the expression of micro-dystrophin gene
timeFrame: 6 months
Other outcomes:
Locations:
city: Chengdu
country: China
facility: West China Hospital, Sichuan University
state: Sichuan
Study officials:
affiliation: West China Hospital
name: Xingchen Xingchen, Ph.D
role: PRINCIPAL_INVESTIGATOR
References:
citation: Costa Verdera H, Kuranda K, Mingozzi F. AAV Vector Immunogenicity in Humans: A Long Journey to Successful Gene Transfer. Mol Ther. 2020 Mar 4;28(3):723-746. doi: 10.1016/j.ymthe.2019.12.010. Epub 2020 Jan 10.
citation: Mendell JR, Sahenk Z, Lehman K, Nease C, Lowes LP, Miller NF, Iammarino MA, Alfano LN, Nicholl A, Al-Zaidy S, Lewis S, Church K, Shell R, Cripe LH, Potter RA, Griffin DA, Pozsgai E, Dugar A, Hogan M, Rodino-Klapac LR. Assessment of Systemic Delivery of rAAVrh74.MHCK7.micro-dystrophin in Children With Duchenne Muscular Dystrophy: A Nonrandomized Controlled Trial. JAMA Neurol. 2020 Sep 1;77(9):1122-1131. doi: 10.1001/jamaneurol.2020.1484.
citation: Miesbach W, Meijer K, Coppens M, Kampmann P, Klamroth R, Schutgens R, Tangelder M, Castaman G, Schwable J, Bonig H, Seifried E, Cattaneo F, Meyer C, Leebeek FWG. Gene therapy with adeno-associated virus vector 5-human factor IX in adults with hemophilia B. Blood. 2018 Mar 1;131(9):1022-1031. doi: 10.1182/blood-2017-09-804419. Epub 2017 Dec 15.
citation: Duan D. Systemic AAV Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy. Mol Ther. 2018 Oct 3;26(10):2337-2356. doi: 10.1016/j.ymthe.2018.07.011. Epub 2018 Jul 17.
citation: Xue F, Li H, Wu X, Liu W, Zhang F, Tang D, Chen Y, Wang W, Chi Y, Zheng J, Du Z, Jiang W, Zhong C, Wei J, Zhu P, Fu R, Liu X, Chen L, Pei X, Sun J, Cheng T, Yang R, Xiao X, Zhang L. Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial. Lancet Haematol. 2022 Jul;9(7):e504-e513. doi: 10.1016/S2352-3026(22)00113-2. Epub 2022 May 19.
citation: Roberts TC, Wood MJA, Davies KE. Therapeutic approaches for Duchenne muscular dystrophy. Nat Rev Drug Discov. 2023 Nov;22(11):917-934. doi: 10.1038/s41573-023-00775-6. Epub 2023 Aug 31.