A Study to Evaluate the Safety, Tolerability, PK and PD of Intracerebroventricular GC1123 in Patients With MPS Ⅱ

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of intracerebroventricular GC1123 in patients with MPS Ⅱ who have central nervous system involvement and are receiving treatment with intravenous drug

Detailed Description
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This study is designed as prospective, open-label, ascending dose phase I study. Safety, tolerability, pharmacokinetic, and pharmacodynamic properties of repeat-dose treatment of ICV-administered investigational product will be studied in patients undergoing standard treatments. Patients will undergo cerebrospinal fluid (CSF) reservoir device implantation surgery on their scalps, and the reservoirs will be used to administer GC1123 to the cerebral ventricles monthly (every 28 days). The planned administering doses are 30 mg and 45 mg. After the 2nd dose on the 6th (last) patient in Group 1, Data and Safety Monitoring Boards (DSMB) will evaluate the safety and tolerability data of GC1123 to determine dose escalation if dose limiting toxicity (DLT) occurs in less than 2 out of 6 patients.

Official Title
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Phase 1, Open-Label, Ascending Dose Study to Evaluate the Safety, Tolerability, PK and PD of Intracerebroventricular GC1123 in Patients With MPS Ⅱ Who Have Central Nervous System Involvement and Are Receiving Treatment With Intravenous Drug

Conditions
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Mucopolysaccharidosis II, Hunter Syndrome

Intervention / Treatment
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* Biological: GC1123


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patient who has been diagnosed with severe MPS Ⅱ (Hunter syndrome) Patient, aged 1.5 years (18 months) to 18 years at the time of the screening Patient who has received and tolerated a minimum of 6 month of treatment with weekly intravenous treatment, and who has received 80% of the total planned infusions within that time frame. Patient who is capable of undergoing neurosurgery, which has been confirmed by neurosurgeons and anesthesiologist. Patient eligible to execute patient evaluation activities during the clinical trial period, as assessed by the investigator Patient whose parents or legal representative are willing to participate in this clinical trial and provide written informed consent form Exclusion Criteria: Patient who has been administered with intrathecal Idursulfase in the past Patient with a history of bone marrow transplantation or cord blood transplant Patient with a history of ventriculoperitoneal shunt or other intracranial surgeries Patient with end-stage multiple organ dysfunction syndrome or other severe diseases Patient who is exposed to malignant neoplasm Patient who has received treatment with any investigational drug or device within 30 days prior to study entry Patient who had experienced hypersensitivity or anaphylaxis to ingredients of the investigational product Patient with a history of bronchotomy/tracheostomy, or patient with acute respiratory disease at the time of screening Patient who is ineligible to participate in the clinical trial due to laboratory test results or other reasons, as determined by the investigator

Ages Eligible for Study
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Minimum Age: 18 Months
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GC1123 30mg<br>30 mg of IP will be administered every 28 days for 6 patients enrolled in Group 1 | Biological: GC1123<br>* ICV-administered Hunterase, Idursulfase-ß<br>|
| Experimental: GC1123 30mg + GC1123 45mg<br>30 mg of IP will be administered twice every 28 days for 2 patients enrolled in Group 2 45 mg of IP will be administered twice, and any DLT occurrence will be followed-up until 4 weeks after the 2nd 45 mg dose on the 2nd patient. DSMB will determine whether to proceed the administration after reviewing safety and tolerability data from 1) and 2). Group 2 will continue to receive 45 mg of IP administration | Biological: GC1123<br>* ICV-administered Hunterase, Idursulfase-ß<br>|
| Experimental: GC1123 45mg<br>45 mg of IP will be administered every 28 days for 4 patients enrolled in Group 3 | Biological: GC1123<br>* ICV-administered Hunterase, Idursulfase-ß<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and frequency of serious adverse events (SAEs) | Incidence and frequency of serious adverse events (SAEs) after administration of ICV-Hunterase (GC1123) for each group | Every 28 days from Week 1 through study completion (average of 6 months) | 
| Frequency and characteristics (severity, outcome, etc.) of adverse events | Frequency and characteristics (severity, outcome, etc.) of adverse events after administration of ICV-Hunterase (GC1123) for each group | Every 28 days from Week 1 through study completion (average of 6 months) | 
| Presence of clinically significant abnormal echocardiography results | Presence of clinically significant abnormal echocardiography results after administration of ICV-Hunterase (GC1123) for each group | Week 1 to study completion, an average of 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) parameters - Cmax | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - Tmax | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - AUClast | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - AUCinf | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - t1/2 | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - CL/F (or CL) | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - Vd/F (or Vd) | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacokinetic (PK) parameters - Bioavailability (F) | Pharmacokinetic (PK) parameters of ICV-Hunterase (GC1123) in serum and CSF | Week 2 to Week 22 and Week 30 | 
| Pharmacodynamic (PD) parameters - Heparan Sulfate (HS) in CSF | Pharmacodynamic (PD) parameters of ICV-Hunterase (GC1123) | Every 28 days from Week 1 through study completion (average of 6 months) | 
| Pharmacodynamic (PD) parameters - Heparan Sulfate (HS) in serum | Pharmacodynamic (PD) parameters of ICV-Hunterase (GC1123) | Every 28 days from Week 1 through study completion (average of 6 months) | 
| Pharmacodynamic (PD) parameters - Urine Glycosaminoglycan (GAG) | Pharmacodynamic (PD) parameters of ICV-Hunterase (GC1123) | Every 28 days from Week 1 through study completion (average of 6 months) | 
| Presence of anti-drug antibodies (ADAs) | Presence of anti-drug antibodies (ADAs) in CSF and serum, and neutralizing antibodies of ICV-Hunterase (GC1123) | Week 1 to Week 14, Week 26 (Group2 only), study completion (average of 6 months) |