A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis (CLN2) Disease

Study Overview
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Brief Summary
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The purpose of this study is to determine whether BMN 190 is safe and effective in the treatment of patients with Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease.

Detailed Description
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The purpose of this study is to determine whether BMN 190 is safe and effective in the treatment of patients with Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) disease. This is an open label Phase 1/2 study conducted in patients with CLN2 disease. Efficacy measures (disease rating scale and MRI) will be compared to a natural history control. The study will be conducted under cGCP and patients will be closely monitored.

Official Title
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A Phase 1/2 Open-Label Dose-Escalation Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Intracerebroventricular BMN 190 in Patients With Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2 (CLN2) Disease

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

Intervention / Treatment
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* Biological: BMN 190


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of CLN2 determined by TPP1 enzyme activity (dried blood spot) available at study entry. If no genotype information is available, blood will be collected for CLN2 gene analysis at baseline. In addition, blood for TPP1 enzyme activity (dried blood spot) will be collected at baseline to be analyzed centrally Has mild to moderate disease documented by a two-domain score of 3- 6 on motor and language domains of the Hamburg Scale, with a score of at least 1 in each of these two domains Written informed consent from parent or legal guardian and assent from subject, if appropriate Has the ability to comply with protocol requirements, in the opinion of the investigator Seizures are stable in the judgement of the investigator Exclusion Criteria: Is less than 3 years old at enrollment Is 16 years old or older at enrollement Has another inherited neurologic disease, e.g. other forms of CLN or seizures unrelated to CLN2 (patients with febrile seizures may be eligible) Has another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) before study entry Requires ventilation support, except for noninvasive support at night Has received stem cell, gene therapy, or ERT for CLN2 Has contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities) Has contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain) Has generalized motor status epilepticus within 4 weeks before the First Dose visit, taking care that status epilepticus is on clinical examination and not only electroencephalogram (EEG) (enrollment may be postponed) Has severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed) Is prone to complications from intraventricular drug administration, including patients with hydrocephalus or ventricular shunts Has known hypersensitivity to any of the components of BMN 190 Has received any investigational medication 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

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 15 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<br>recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa) | Biological: BMN 190<br>* 30-300 mg ICV infusion administered every other week for at least 48 weeks.<br>* Other names: cerliponase alfa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motor-Language (ML) Scale Score During 300 mg Dosing Period | The progression of ceroid lipofuscinosis (CLN2) disease was assessed using adapted motor and language domains of the Hamburg rating scale (ML scale score). Motor and Language are each 0 - 3 point subscales in which 3 represents best function and 0 represents loss of function. The sum of the motor and language scores (ML score, 0-6 points) was used to evaluate the loss of function. | Baseline, Week 49/Last Assessment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume | Percentage changes in whole brain volume from the ITT population for the 300 mg dosing period | Baseline, Week 49 | 
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Total Grey Matter | Percentage changes in volume of total grey matter from the ITT population for the 300 mg dosing period | Baseline, Week 49 | 
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Total White Matter Volume | Percentage changes in total white matter volume from the ITT population for the 300 mg dosing period | Baseline, Week 49 | 
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid | Percentage changes in volume of cerebrospinal fluid from the ITT population for the 300 mg dosing period | Baseline, Week 49 | 
| Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Apparent Diffusion Coefficient | Percentage changes in whole brain apparent diffusion coefficient from the ITT population for the 300 mg dosing period | Baseline, Week 49 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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LINCL, Late infantile Neuronal Ceroid Lipofuscinosis Type 2, NCL2, CLN2, Jansky-Bielschowsky disease