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

NCT01907087 | Completed Phase 1 Results DMC

• 1 other identifier: 190-201
• Study Type: interventional
• Target: 24
• Locations: 4 countries
• Sites: 5

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.

Conditions

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

Keywords

Late infantile Neuronal Ceroid Lipofuscinosis Type 2; LINCL; NCL2; CLN2; Jansky-Bielschowsky disease

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (5)

• Percentage Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Whole Brain Volume

  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

  Baseline, Week 49

• 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 Change From Baseline of Magnetic Resonance Imaging (MRI) at Week 49 During 300 mg Dosing Period: Volume of Cerebrospinal Fluid

  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

  Baseline, Week 49

Study Arms (1)

BMN190

EXPERIMENTAL

recombinant human tripeptidyl peptidase-1 (rhTPP1/cerliponase alfa)

Biological: BMN 190

Interventions

BMN 190 BIOLOGICAL

30-300 mg ICV infusion administered every other week for at least 48 weeks.

Also known as: recombinant human tripeptidyl peptidase-1 (rhTPP1), cerliponase alfa

BMN190

Eligibility Criteria

• Age: 3 Years - 15 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (5)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

University Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Bambino Gesù Children's Hospital

Rome, 00165, Italy

Location

Guy's & St. Thomas NHS Foundation Trust

London, SE1 7EH, United Kingdom

Location

Great Ormond Street Hospital for NHS Foundation Trust

London, WC1N 3JH, United Kingdom

Location

Related Publications (4)

• Specchio N, Gissen P, de Los Reyes E, Olaye A, Camp C, Curteis T, Griffiths A, Butt T, Cohen-Pfeffer J, Slasor P, Sisic Z, Jain M, Schulz A. Exploring concurrent validity of the CLN2 Clinical Rating Scale: Comparison to PedsQL using cerliponase alfa clinical trial data. PLoS One. 2024 May 22;19(5):e0302382. doi: 10.1371/journal.pone.0302382. eCollection 2024.

  PMID: 38776275 DERIVED

• Schulz A, Specchio N, de Los Reyes E, Gissen P, Nickel M, Trivisano M, Aylward SC, Chakrapani A, Schwering C, Wibbeler E, Westermann LM, Ballon DJ, Dyke JP, Cherukuri A, Bondade S, Slasor P, Cohen Pfeffer J. Safety and efficacy of cerliponase alfa in children with neuronal ceroid lipofuscinosis type 2 (CLN2 disease): an open-label extension study. Lancet Neurol. 2024 Jan;23(1):60-70. doi: 10.1016/S1474-4422(23)00384-8.

  PMID: 38101904 DERIVED

• 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.

  PMID: 33980287 DERIVED

• 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.

  PMID: 29688815 DERIVED

MeSH Terms

Conditions

Neuronal Ceroid-Lipofuscinoses

Interventions

cerliponase alfa

Condition Hierarchy (Ancestors)

Heredodegenerative Disorders, Nervous System; Neurodegenerative Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Lipidoses; Lipid Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Limitations and Caveats

10 subjects were assigned in 1 of 3 cohorts in Dose Escalation Period for a 4-22 weeks treatment of 30, 100, and/or 300 mg. 9 subjects completing the Dose Escalation Period, plus 14 new subjects, were administered a stable dose of 300mg for 48 weeks.

Results Point of Contact

• Title: Peter Slasor/Sr Director, Biostatistics, Global Clinical Sciences
• Organization: BioMarin Pharmaceutical Inc.

PSlasor@bmrn.com

415-506-6765

Study Officials

• David Jacoby

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2013
• First Posted: July 24, 2013
• Study Start: September 1, 2013
• Primary Completion: November 1, 2015
• Study Completion: November 1, 2015
• Last Updated: March 8, 2019
• Results First Posted: June 11, 2018

Record last verified: 2019-03

Locations

US (1); GB (2); DE (1); IT (1)