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

• ClinicalTrials.gov Identifier: NCT05208281
• Recruitment Status: Recruiting
• First Posted: January 26, 2022
• Last Update Posted: February 23, 2023
• Sponsor: AO GENERIUM
• Information provided by (Responsible Party): AO GENERIUM

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Mucopolysaccharidosis Type II; Metabolic Diseases	Drug: GNR-055 1.0-2.0-3.0 mg/kg; Drug: GNR-055 2.0 mg/kg; Drug: GNR-055 3.0 mg/kg	Phase 2; Phase 3

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).

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 32 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment
• Intervention Model Description: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: November 30, 2021
• Estimated Primary Completion Date: February 2025
• Estimated Study Completion Date: March 2028

Arms and Interventions

Arm	Intervention/treatment
Experimental: Adult: GNR-055; GNR-055: 1.0-2.0-3.0 mg/kg	Drug: GNR-055 1.0-2.0-3.0 mg/kg; Weekly IV infusion (lyophilized powder) 1.0-2.0-3.0 mg/kg; Other Name: GNR-055
Experimental: Paediatric: GNR-055 2.0 mg/kg; GNR-055 2.0 mg/kg	Drug: GNR-055 2.0 mg/kg; Weekly IV infusion (lyophilized powder) 2.0 mg/kg; Other Name: GNR-055
Experimental: Paediatric: GNR-055 3.0 mg/kg; GNR-055 3.0 mg/kg	Drug: GNR-055 3.0 mg/kg; Weekly IV infusion (lyophilized powder) 3.0 mg/kg; Other Name: GNR-055

Outcome Measures

Primary Outcome Measures :

1. Incidence of Adverse events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline to Week 56 ]
   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.
2. Urine GAG excretion [ Time Frame: Baseline to Week 4, 8, 10, 26, and 52 ]
   Changes in levels of urine GAG excretion after multiple-dose administration of GNR-055

Secondary Outcome Measures :

1. Serum concentration of the GNR-055 [ Time Frame: Week 52 ]
   Assessment of the serum concentration of GNR-055 and calculation of Cmax, AUC, T1/2, Cl et other parameters after multiple-dose administration
2. GAG level in CerebroSpinal Fluid (CSF) [ Time Frame: Baseline to Week 6, 10, 26, and 52 ]
   Changes in levels of CSF GAG after multiple-dose administration of GNR-055
3. Serum GAG level [ Time Frame: Baseline to Week 4, 8, 10, 26, and 52 ]
   Changes in levels of serum GAG after multiple-dose administration of GNR-055
4. Large joint range of motion [ Time Frame: Week 8, 10, 26, and 52 ]
   Changes over time in the large joint range of motion after multiple-dose administration of GNR-055
5. Liver and spleen volumes (MRI) [ Time Frame: Baseline to Week 8, 10, 26, and 52 ]
   Changes over time in liver and spleen volume according to ultrasound/MRI after multiple-dose administration of GNR-055
6. 6-minute walk test [ Time Frame: Baseline to Week 8, 10, 26, and 52 ]
   Changes over time in the results of the 6-minute walk test after multiple-dose administration of GNR-055
7. Left ventricular mass by EchoCG [ Time Frame: Baseline to Week 8, 10, 26, and 52 ]
   Changes over time in the left ventricular mass according to Echocardiography (Echo-CG) after multiple-dose administration of GNR-055
8. Lung Forced Vital Capacity (FVC) [ Time Frame: Baseline to Week 8, Week 26, and Week 52 ]
   Changes over time in FVC according to spirometry after multiple-dose administration of GNR-055
9. Neurocognitive functions assessment [ Time Frame: Baseline to Week 12, 26, and 52 ]
   Changes over time in neurocognitive functions after multiple-dose administration of GNR-055
10. Brain white/gray matter structures (MRI) [ Time Frame: Baseline to Week 26, and 52 ]
    Changes over time in the quantitative MRI brain structure parameters after multiple-dose administration of GNR-055
11. Serum neuromarkers [ Time Frame: Baseline to Week 24, and 52 ]
    Changes in levels of serum neuromarkers after multiple-dose administration of GNR-055
12. CSF neuromarkers [ Time Frame: Baseline to Week 24, and 52 ]
    Changes in levels of CSF neuromarkers after multiple-dose administration of GNR-055

Eligibility Criteria

• Ages Eligible for Study: Child, Adult, Older Adult
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Contacts

Contact: Svetlana B. Korotkova, MD, PhD; +7(495) 988 47 94 ext 7096; sbkorotkova@generium.ru

Contact: Oksana A. Markova, MD, MSc; +7(495) 988 47 94 ext 7077; oamarkova@generium.ru

Locations

Russian Federation

State Autonomous Healthcare Institution of the Sverdlovsk Region Regional Children's Clinical Hospital; Recruiting

Ekaterinburg, Russian Federation, 620149

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); Not yet recruiting

Moscow, Russian Federation, 119333

V.I. Vernadsky Crimean Federal University; Recruiting

Simferopol, Russian Federation, 295007

Federal State Budgetary Educational Institution of Higher Education "St. Petersburg State Pediatric Medical University" of the Ministry of Health of the Russian Federation; Not yet recruiting

St. Petersburg, Russian Federation, 194100

State Budgetary Healthcare Institution Republican Medical Genetic Center; Recruiting

Ufa, Russian Federation, 450076

Sponsors and Collaborators

AO GENERIUM

Investigators

• Study Director: Oksana A. Markova, MD, MSc; AO GENERIUM

More Information

• Responsible Party: AO GENERIUM
• ClinicalTrials.gov Identifier: NCT05208281
• Other Study ID Numbers: IDB-MPS-II-III
• First Posted: January 26, 2022
• Last Update Posted: February 23, 2023
• Last Verified: February 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by AO GENERIUM:

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

Additional relevant MeSH terms:

Mucopolysaccharidosis II; Mucopolysaccharidoses; Metabolic Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Genetic Diseases, Inborn; Lysosomal Storage Diseases; Mucinoses; Connective Tissue Diseases; Mental Retardation, X-Linked; Intellectual Disability; Neurobehavioral Manifestations; Neurologic Manifestations; Nervous System Diseases; Genetic Diseases, X-Linked; Heredodegenerative Disorders, Nervous System