Clinical trial NCT05208281: A Multi-cohort Study of Safety, Efficacy, PK and PD of GNR-055 in Patients With Mucopolysaccharidosis Type II
Official title: Multicenter, Open-Label, Multi-cohort Study to Evaluate Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of Drug Product GNR 055 (JSC "GENERIUM", Russia) in Patients With Mucopolysaccharidosis Type II
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
PHASE3
Conditions: Mucopolysaccharidosis Type II
Metabolic Diseases
Keywords: Mucopolysaccharidosis type II
Cognitive Dysfunction
Metabolic Diseases
Lysosomal Storage Diseases
Neurocognitive Disorders
Metabolism, Inborn
Genetic Diseases, Inborn
Neurobehavioral Manifestations
Neurologic Manifestations
Genetic Diseases, X-Linked
Hunter syndrome
Iduronate-2-sulfatase
Modified I2S protein
Connective Tissue Diseases
Mental Disorders
Intellectual Disability
Nervous System Diseases
Heredodegenerative Disorders, Nervous System
Cognition Disorders
Mental Retardation, X-Linked
Lead sponsor: AO GENERIUM
Sponsor class: INDUSTRY
First posted: 2022-01-26
Enrollment: 32
Sex: MALE
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential Assignment
Primary purpose: TREATMENT

Brief summary: This is phase 2/3 study to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational product GNR-055 in MPS II (Hunter syndrome) patients of different age groups.

Detailed description: GNR-055 is intended for ERT in patient with Mucopolysaccharidosis type II (MPS II), or Hunter syndrome. MPS II is a recessive X-linked inheritance lysosomal storage disease, which is characterized by a deficiency of the lysosomal enzyme iduronate-2-sulfatase (ID2S), caused by a mutation in the ID2S gene. Enzyme deficiency leads to the accumulation of Glycosaminoglycans (GAG) (mainly of heparan and dermatan sulfates) in lysosomes of almost all types of cells of various tissues and organs. The disease is manifested by growth retardation, damage of many organs and systems, severe deformations of bones and joints, gross facial features, pathology of the respiratory and cardiovascular systems, damage to parenchymal organs (hepatosplenomegaly), and hearing impairment. A severe form of the disease occurs with the involvement of the nervous system in the pathological process, including mental retardation, behavior anomalies, and impaired motor function.

GNR-055 is a recombinant modified ID2S capable to penetrate the blood-brain barrier and thus expected to prevent neurodegenerative consequences and the cognitive deficit and to attain a significant improvement in the life quality and expectancy of patients with MPS II.

Study IDB-MPS-II-III is a multicenter, open-label, multi-cohort study to assess safety, PK and PD, and efficacy of GNR-055 in patients of different age groups with MPS II (Hunter syndrome).

Eligibility criteria: Inclusion Criteria:

* Signed inform consent;
* Verified diagnosis of MPS II (Hunter syndrome);
* Naïve patients or patients who have received standard ERT whit idursulfase products;
* No contraindications for lumbar puncture as judged by the Investigator;
* Willingness and ability to follow study procedures.

Exclusion Criteria:

* Clinically pronounced hypersensitivity to ID2S or any other component of the drug product;
* History of hematopoietic stem cell transplantation (HSCT) or bone marrow transplantation;
* Implanted or external non-removable metal devices, a cardiac pacemaker, or other objects sensitive to the magnetic field that may pose a danger to both the wearer and the correct operation of magnetic resonance imaging (MRI) equipment;
* Concomitant diseases and conditions that, in the Investigator's opinion, can put at risk the patient's safety during his/her participation in the study, or which will influence the safety data analysis in case of the disease/condition exacerbation during the study.

Primary outcomes:
measure: Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Baseline to Week 56
measure: Urine GAG excretion
timeFrame: Baseline to Week 4, 8, 10, 26, and 52
Secondary outcomes:
measure: Serum concentration of the GNR-055
timeFrame: Week 52
measure: GAG level in CerebroSpinal Fluid (CSF)
timeFrame: Baseline to Week 6, 10, 26, and 52
measure: Serum GAG level
timeFrame: Baseline to Week 4, 8, 10, 26, and 52
measure: Large joint range of motion
timeFrame: Week 8, 10, 26, and 52
measure: Liver and spleen volumes (MRI)
timeFrame: Baseline to Week 8, 10, 26, and 52
measure: 6-minute walk test
timeFrame: Baseline to Week 8, 10, 26, and 52
measure: Left ventricular mass by EchoCG
timeFrame: Baseline to Week 8, 10, 26, and 52
measure: Lung Forced Vital Capacity (FVC)
timeFrame: Baseline to Week 8, Week 26, and Week 52
measure: Neurocognitive functions assessment
timeFrame: Baseline to Week 12, 26, and 52
measure: Brain white/gray matter structures (MRI)
timeFrame: Baseline to Week 26, and 52
measure: Serum neuromarkers
timeFrame: Baseline to Week 24, and 52
measure: CSF neuromarkers
timeFrame: Baseline to Week 24, and 52
Other outcomes:
Locations:
city: Ekaterinburg
country: Russian Federation
facility: State Autonomous Healthcare Institution of the Sverdlovsk Region Regional Children's Clinical Hospital
city: Moscow
country: Russian Federation
facility: Federal State-Funded Healthcare Institution Central Clinical Hospital of the Russian Academy of Sciences (Research Institute of Pediatrics and Child Health Protection of the Central Clinical Hospital of the Russian Academy of Sciences)
city: Simferopol
country: Russian Federation
facility: V.I. Vernadsky Crimean Federal University
city: St. Petersburg
country: Russian Federation
facility: Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University" of the Ministry of Health of the Russian Federation
city: Ufa
country: Russian Federation
facility: State Budgetary Healthcare Institution Republican Medical Genetic Center
Study officials:
affiliation: AO GENERIUM
name: Oksana A. Markova, MD, MSc
role: STUDY_DIRECTOR
References: