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

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

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.

Study Overview

• Status: Completed
• Conditions: Batten Disease; CLN2 Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2; Jansky-Bielschowsky Disease
• Intervention / Treatment: Biological: BMN 190

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 Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • University Hamburg-Eppendorf
• Italy
  • Rome, Italy, 00165
    • Bambino Gesù Children's Hospital
• United Kingdom
  • London, United Kingdom, SE1 7EH
    • Guy's & St. Thomas NHS Foundation Trust
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Hospital for NHS Foundation Trust
• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 3 years to 15 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BMN190; recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)	Biological: BMN 190; 30-300 mg ICV infusion administered every other week for at least 48 weeks.; Other Names: recombinant human tripeptidyl peptidase-1 (rhTPP1); cerliponase alfa

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: David Jacoby, BioMarin Pharmaceutical

Publications and helpful links

General Publications

• Gissen P, Specchio N, Olaye A, Jain M, Butt T, Ghosh W, Ruban-Fell B, Griffiths A, Camp C, Sisic Z, Schwering C, Wibbeler E, Trivisano M, Lee L, Nickel M, Mortensen A, Schulz A. Investigating health-related quality of life in rare diseases: a case study in utility value determination for patients with CLN2 disease (neuronal ceroid lipofuscinosis type 2). Orphanet J Rare Dis. 2021 May 12;16(1):217. doi: 10.1186/s13023-021-01829-x.
• Schulz A, Ajayi T, Specchio N, de Los Reyes E, Gissen P, Ballon D, Dyke JP, Cahan H, Slasor P, Jacoby D, Kohlschutter A; CLN2 Study Group. Study of Intraventricular Cerliponase Alfa for CLN2 Disease. N Engl J Med. 2018 May 17;378(20):1898-1907. doi: 10.1056/NEJMoa1712649. Epub 2018 Apr 24.

Study record dates

Study Major Dates

• Study Start: September 1, 2013
• Primary Completion (Actual): November 1, 2015
• Study Completion (Actual): November 1, 2015

Study Registration Dates

• First Submitted: July 19, 2013
• First Submitted That Met QC Criteria: July 22, 2013
• First Posted (Estimate): July 24, 2013

Study Record Updates

• Last Update Posted (Actual): March 8, 2019
• Last Update Submitted That Met QC Criteria: March 6, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: LINCL; CLN2; Late infantile Neuronal Ceroid Lipofuscinosis Type 2; NCL2; Jansky-Bielschowsky disease
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Neurodegenerative Diseases; Metabolism, Inborn Errors; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Lipidoses; Lipid Metabolism, Inborn Errors; Neuronal Ceroid-Lipofuscinoses
• Other Study ID Numbers: 190-201