A Multi-cohort Study of Safety, Efficacy, PK and PD of GNR-055 in Patients With Mucopolysaccharidosis Type II

Metabolic Diseases Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05208281
• Other study ID #: IDB-MPS-II-III
• Status: Recruiting
• Phase: Phase 2/Phase 3
• Start date: November 30, 2021
• Est. completion date: March 2028

Study information

• Verified date: March 2024
• Source: AO GENERIUM
• Contact: Svetlana B. Korotkova, MD, PhD
• Phone: +7(495) 988 47 94
• Email: sbkorotkova[@]generium.ru
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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).

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 32
• Est. completion date: March 2028
• Est. primary completion date: February 2025
• Accepts healthy volunteers: No
• Gender: Male
• Age group: N/A and older

Eligibility

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.

Related Conditions & MeSH terms

• Metabolic Diseases
• Mucopolysaccharidoses
• Mucopolysaccharidosis II
• Mucopolysaccharidosis Type II

Intervention

Drug:
• GNR-055 1.0-2.0-3.0 mg/kg
Weekly IV infusion (lyophilized powder) 1.0-2.0-3.0 mg/kg
• GNR-055 2.0 mg/kg
Weekly IV infusion (lyophilized powder) 2.0 mg/kg
• GNR-055 3.0 mg/kg
Weekly IV infusion (lyophilized powder) 3.0 mg/kg

Locations

Country	Name	City	State
Russian Federation	State Autonomous Healthcare Institution of the Sverdlovsk Region Regional Children's Clinical Hospital	Ekaterinburg
Russian Federation	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)	Moscow
Russian Federation	V.I. Vernadsky Crimean Federal University	Simferopol
Russian Federation	Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University" of the Ministry of Health of the Russian Federation	St. Petersburg
Russian Federation	State Budgetary Healthcare Institution Republican Medical Genetic Center	Ufa

Sponsors (1)

Lead Sponsor	Collaborator
AO GENERIUM

Country where clinical trial is conducted

Russian Federation, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs)	Safety assessment will be performed based on the subjective complaints, physical examination, assessment of vital signs, laboratory tests, and 12-lead ECG; Incidence of allergic and infusion-related reactions; Incidence of Anti-Drug Antibodies (ADAs) against GNR-055 and their neutralizing activity.	Baseline to Week 56
Primary	Urine GAG excretion	Changes in levels of urine GAG excretion after multiple-dose administration of GNR-055	Baseline to Week 4, 8, 10, 26, and 52
Secondary	Serum concentration of the GNR-055	Assessment of the serum concentration of GNR-055 and calculation of Cmax, AUC, T1/2, Cl et other parameters after multiple-dose administration	Week 52
Secondary	GAG level in CerebroSpinal Fluid (CSF)	Changes in levels of CSF GAG after multiple-dose administration of GNR-055	Baseline to Week 6, 10, 26, and 52
Secondary	Serum GAG level	Changes in levels of serum GAG after multiple-dose administration of GNR-055	Baseline to Week 4, 8, 10, 26, and 52
Secondary	Large joint range of motion	Changes over time in the large joint range of motion after multiple-dose administration of GNR-055	Week 8, 10, 26, and 52
Secondary	Liver and spleen volumes (MRI)	Changes over time in liver and spleen volume according to ultrasound/MRI after multiple-dose administration of GNR-055	Baseline to Week 8, 10, 26, and 52
Secondary	6-minute walk test	Changes over time in the results of the 6-minute walk test after multiple-dose administration of GNR-055	Baseline to Week 8, 10, 26, and 52
Secondary	Left ventricular mass by EchoCG	Changes over time in the left ventricular mass according to Echocardiography (Echo-CG) after multiple-dose administration of GNR-055	Baseline to Week 8, 10, 26, and 52
Secondary	Lung Forced Vital Capacity (FVC)	Changes over time in FVC according to spirometry after multiple-dose administration of GNR-055	Baseline to Week 8, Week 26, and Week 52
Secondary	Neurocognitive functions assessment	Changes over time in neurocognitive functions after multiple-dose administration of GNR-055	Baseline to Week 12, 26, and 52
Secondary	Brain white/gray matter structures (MRI)	Changes over time in the quantitative MRI brain structure parameters after multiple-dose administration of GNR-055	Baseline to Week 26, and 52
Secondary	Serum neuromarkers	Changes in levels of serum neuromarkers after multiple-dose administration of GNR-055	Baseline to Week 24, and 52
Secondary	CSF neuromarkers	Changes in levels of CSF neuromarkers after multiple-dose administration of GNR-055	Baseline to Week 24, and 52