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

Study Overview
=================
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).

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

Conditions
-----------------
Mucopolysaccharidosis Type II, Metabolic Diseases

Intervention / Treatment
-----------------
* 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


Participation Criteria
=================
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.
Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Adult: GNR-055<br>GNR-055: 1.0-2.0-3.0 mg/kg | Drug: GNR-055 1.0-2.0-3.0 mg/kg<br>* Weekly IV infusion (lyophilized powder) 1.0-2.0-3.0 mg/kg<br>* Other names: GNR-055;|
| Experimental: Paediatric: GNR-055 2.0 mg/kg<br>GNR-055 2.0 mg/kg | Drug: GNR-055 2.0 mg/kg<br>* Weekly IV infusion (lyophilized powder) 2.0 mg/kg<br>* Other names: GNR-055;|
| Experimental: Paediatric: GNR-055 3.0 mg/kg<br>GNR-055 3.0 mg/kg | Drug: GNR-055 3.0 mg/kg<br>* Weekly IV infusion (lyophilized powder) 3.0 mg/kg<br>* Other names: GNR-055;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| 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 | 
| Neurocognitive functions assessment | Changes over time in neurocognitive functions after multiple-dose administration of GNR-055 | Baseline to Week 12, 26, and 52 | 
| 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 | 
| Serum neuromarkers | Changes in levels of serum neuromarkers after multiple-dose administration of GNR-055 | Baseline to Week 24, and 52 | 
| CSF neuromarkers | Changes in levels of CSF neuromarkers after multiple-dose administration of GNR-055 | Baseline to Week 24, and 52 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
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