A Safety, Tolerability, and Efficacy Study of Intracerebroventricular BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease

Study Overview
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Brief Summary
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This Phase 2 open-label, multicenter study will evaluate the safety, tolerability, and efficacy of BMN 190 intracerebroventricular (ICV) administration every other week (qow) for a period of 144 weeks, in patients with CLN2. The study is designed to assess disease progression in CLN2 patients treated with BMN 190 compared to natural history data from untreated historical controls.

Detailed Description
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BMN 190 is a recombinant form of human tripeptidyl peptidase 1 (TPP1), the enzyme deficient in patients with CLN2 diseases (also known as classical late-infantile CLN2, cLINCL, or Jansky-Bielschowsky disease), a form of Batten Disease. As an enzyme replacement therapy (ERT), BMN 190 is designed to help restore TPP1 enzyme activity. BMN 190 is designed to reduce the progressive, pathologic accumulation of lysosomal storage material. 190-203 is a Phase 2 open-label, multicenter study that will evaluate the safety, tolerability, and efficacy of BMN 190 in pediatric patients < 18 years of age with CLN2 disease. Study drug dosing will be determined by the patient's age and administered via intracerebroventricular (ICV) infusion every other week (qow), for a duration of 144 weeks.

Official Title
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A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease

Conditions
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Jansky-Bielschowsky Disease, Batten Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2, CLN2 Disease, CLN2 Disorder

Intervention / Treatment
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* Biological: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
* Device: Intraventricular access device


Participation Criteria
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Eligibility Criteria
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Enrollment over the age of 2 years is complete. Inclusion Criteria: Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood spot) in the fibroblasts and leukocytes available at Screening Quantitative clinical assessment of the Hamburg motor-language aggregate score 3-6 at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline < 18 years of age at the time of informed consent Written informed consent from parent or legal guardian and assent form subject, if appropriate Males and females who are of reproductive age should practice true abstinence, defined as no sexual activity, during the study and for 6 months after the study has been completed (or withdrawal from the study). If sexually active and not practicing true abstinence, males and females of reproductive age must use a highly effective method of contraception while participating in the study. Ability to comply with protocol required assessments (ICV implantation, drug administration, laboratory sample collection, EEG, ECG, MRI, etc.) Exclusion Criteria: Presence of another inherited neurological disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible) Presence of another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) or interference with disease rating (autism) before Screening Presence of percutaneous feeding tube placement prior to enrollment Has received stem cell, gene therapy, or ERT Presence of contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities) Presence of contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain) Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed) Presence of ventricular abnormality (hydrocephalus, malformation) Presence of ventricular shunt Has known hypersensitivity to any of the components of BMN 190 Has received any investigational mediation within 30 days before the first infusion of study drug or is scheduled to receive any investigational drug other than BMN 190 during the course of the study Has a medical condition or extenuating circumstance that, in the opinion of the investigator, might compromise the subject's ability to comply with the protocol required testing or procedures or compromise the subject's well being, safety, or clinical interpretability Pregnancy any time during the study; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy

Ages Eligible for Study
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Minimum Age: 0 Years
Maximum Age: 17 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)<br>An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks. | Biological: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)<br> <br> * Other names: Brineura®;Device: Intraventricular access device<br>* Surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere is required for administration of study drug.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and severity of adverse events as assessed by CTCAE v 4.0 |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Change in the 0-6-point Motor/Language (ML) score on the Hamburg CLN2 rating scale |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Immunogenicity of BMN 190 in CSF and serum |  | Up to 144 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in the total Hamburg CLN2 rating scale |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Change in clinical laboratory tests |  | Up to 144 weeks | 
| Change in CSF and Plasma laboratory parameters |  | Up to 144 weeks | 
| Vital signs |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Physical examination |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Neurological examinations |  | Up to 144 weeks | 
| Electrocardiogram (ECG), 3 or 5-lead, 12-lead |  | Up to 144 weeks + 6 month follow up post last study treatment | 
| Change in Brain Volumes as Assessed by Cranial Magnetic Resonance Imaging (MRI) |  | Up to 144 weeks | 
| Assess time to disease manifestation for asymptomatic patients |  | Up to 144 weeks |