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

Phase 1

Completed

• Conditions: Jansky-Bielschowsky Disease; Batten Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2; CLN2 Disease
• Interventions: Biological: BMN 190

• Registration Number: NCT01907087
• Lead Sponsor: BioMarin Pharmaceutical

Brief Summary

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

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.

Study Timeline

• Study First Submitted: 2013-07-19
• Study First Submitted QC: 2013-07-22
• Study First Posted: 2013-07-24
• Study Start: 2013-09
• Primary Completion: 2015-11
• Study Completion: 2015-11
• Results First Submitted: 2018-02-15
• Results First Submitted QC: 2018-05-08
• Results First Posted: 2018-06-11
• Status Verified: 2019-03
• Last Update Submitted: 2019-03-06
• Last Update Posted: 2019-03-08

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 24

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BMN190	BMN 190	recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)

Primary Outcome Measures

Name	Time	Method
Motor-Language (ML) Scale Score During 300 mg Dosing Period	Baseline, Week 49/Last Assessment	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.

Secondary Outcome Measures

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

Trial Locations

Locations (5)

University Hamburg-Eppendorf; 🇩🇪 Hamburg, Germany

Bambino Gesù Children's Hospital; 🇮🇹 Rome, Italy

Guy's & St. Thomas NHS Foundation Trust; 🇬🇧 London, United Kingdom

Great Ormond Street Hospital for NHS Foundation Trust; 🇬🇧 London, United Kingdom

Nationwide Children's Hospital; 🇺🇸 Columbus, Ohio, United States