An Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease

NCT02485899 | Completed Phase 1 Results DMC FDA Drug FDA Device

• 1 other identifier: 190-202
• Study Type: interventional
• Target: 23
• Locations: 4 countries
• Sites: 4

Brief Summary

The Phase 1/2 study (190-201) evaluated the efficacy and safety of a 300 mg dose of BMN 190 administered every other week (qow) to patients with CLN2. The dose and regimen for this study (190-202) are based on the results of the 190-201 study. The rationale for this phase 2 extension study is to provide patients who complete the 190-201 study with the option to continue BMN 190 treatment. The 190-202 study is an open label extension protocol to assess long-term safety and efficacy.

Conditions

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

Keywords

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

Outcome Measures

Primary Outcomes (2)

• Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0

  Motor and Language are each 0-3 point subscales in which 3 represents best function and 0 represents loss of function. Thus, the 0-6 point ML score was used as the primary mode of evaluation of loss of function. In 190-201, the primary endpoint was a responder endpoint: unreversed ML 2-point decline or score of 0 at Week 48 compared to the 50% rate expected in natural history using the 1-sample binomial test. For 190-202, the primary endpoint was revised to assess response over the full duration of follow-up. It is not clear, given the variable follow-up much greater than 48 weeks, what response rate is expected in natural history. For this reason, the assessment of the primary endpoint is based on comparing to natural history data and using the Kaplan-Meier method and Cox proportional hazards model with covariate adjustment (i.e., baseline ML score and age as continuous covariates, and genotype \[common alleles\] and sex as categorical covariates).

  Up to Week 289

• Probability of Unreversed Motor-language (ML) Score of Zero.

  Motor and Language are each 0-3 point subscales in which 3 represents best function and 0 represents loss of function. Thus, the 0-6 point ML score was used as the primary mode of evaluation of loss of function. In 190-201, the primary endpoint was a responder endpoint: unreversed ML 2-point decline or score of 0 at Week 48 compared to the 50% rate expected in natural history using the 1-sample binomial test. For 190-202, the primary endpoint was revised to assess response over the full duration of follow-up. It is not clear, given the variable follow-up much greater than 48 weeks, what response rate is expected in natural history. For this reason, the assessment of the primary endpoint is based on comparing to natural history data and using the Kaplan-Meier method and Cox proportional hazards model with covariate adjustment (baseline ML score, age, genotype \[common alleles\], and sex).

  Up to Week 289

Secondary Outcomes (5)

• Whole Brain Volume

  Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

• Volume of Cerebrospinal Fluid

  Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

• Volume of Total Cortical Gray Matter

  Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

• Total White Matter Volume

  Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

• Whole Brain Apparent Diffusion Coefficient

  Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Study Arms (1)

BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)

EXPERIMENTAL

All 190-202 study subjects administered BMN 190 300 mg by continuous Intracerebroventricular (ICV) infusion at a rate of 2.5 mL/hour for approximately 4 hours) every 14 days.

Biological: BMN 190; Device: Intracerebroventricular (ICV) access device

Interventions

BMN 190 BIOLOGICAL

300 mg Intracerebroventricular (ICV) infusion administered every other week for up to 240 weeks

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

BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)

Intracerebroventricular (ICV) access device DEVICE

Surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere is required for administration of study drug.

BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)

Eligibility Criteria

• Age: 3 Years - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Must have completed 48 weeks in Study 190-201.
• Is willing and able to provide written, signed informed consent. Or, in the case of patients under the age of 18 (or other age as defined by regional law or regulation), provide written assent (if required) and have written informed consent, signed by a legally authorized representative, after the nature of the study has been explained, and prior to performance of research-related procedures.
• 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.
• If female, of childbearing potential, must have a negative pregnancy test at the Screening Visit and be willing to have additional pregnancy tests done during the study.

You may not qualify if:

• Has had a loss of 3 or more points in the combined motor and language components of the Hamburg CLN2 rating scale between Baseline of Study 190-201 and the Study Completion visit in Study 190-201 and would not benefit from enrolling in the study in the Investigator's discretion.
• Has a score of 0 points on the combined motor and language components of the Hamburg CLN2 rating scale.
• Is pregnant or breastfeeding, at Baseline, or planning to become pregnant (self or partner) at any time during the study.
• Has used any investigational product (other than BMN 190 in 190-201), or investigational medical device, within 30 days prior to Baseline; or is required to use any investigational agent prior to completion of all scheduled study assessments.
• Has a concurrent disease or condition that would interfere with study participation, or pose a safety risk, as determined by the Investigator.
• Has any condition that, in the view of the Investigator, places the patient at high risk of poor treatment compliance or of not completing the study.

Sponsors & Collaborators

• BioMarin Pharmaceutical: lead

Study Sites (4)

Nationwide Children's Hospital

Columbus, Ohio, 43205, United States

Location

Universitaetsklinikum Hamburg-Eppendorf

Hamburg, 20246, Germany

Location

Children's Hospital Bambino Gesù,IRCCS

Rome, Piazza, 00165, Italy

Location

Great Ormond Street Childrens Hospital

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

Results Point of Contact

• Title: Trial Specialist
• Organization: BioMarin Pharmaceutical, Inc.

medinfo@bmrn.com

1-800-983-4587

Study Officials

• Medical Monitor, MD

  BioMarin Pharmaceutical

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• 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

Model Details: Because of practical (limited number of available patients) and ethical (neurosurgery in children with fatal neurologic disease) concerns, this study design could not involve contemporaneous, matched, randomized, blinded, or untreated control subjects. As such, data from the DEM-CHILD Multi-Center Clinical NCL Database at the University Medical Center in Hamburg, Germany (NCT04613089) was used as a control group (i.e., Natural History \[NH\] comparator) to determine the primary efficacy outcome measures for this study. The NH comparator was comprised of subjects from the DEM-CHILD database who satisfied the 190-201 inclusion criterion: Age ≥ 3, and at least one ML score ≥ 3 at age ≥ 3 years and further, who had at least two CLN2 assessments with values within the range 1 - 5 and at least 6 months apart.

Study Record Dates

• First Submitted: April 24, 2015
• First Posted: June 30, 2015
• Study Start: February 1, 2015
• Primary Completion: December 10, 2020
• Study Completion: December 10, 2020
• Last Updated: August 24, 2022
• Results First Posted: August 24, 2022

Record last verified: 2022-07

Locations

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