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

A Multicenter, Multinational, Extension Study to Evaluate the Long-Term Efficacy and Safety of BMN 190 in Patients With CLN2 Disease

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.

Study Overview

• Status: Completed
• Conditions: Batten Disease; CLN2 Disease; Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2; Jansky-Bielschowsky Disease; CLN2 Disorder
• Intervention / Treatment: Biological: BMN 190; Device: Intracerebroventricular (ICV) access device

Detailed Description

BMN 190 is a recombinant form of human tripeptidyl peptidase 1 (TPP1), the enzyme deficient in patients with CLN2 disease (also known as classical late-infantile CLN2, cLINCL, or Jansky-Bielschowsky disease), a form of Batten Disease. As an enzyme replacement therapy (ERT), BMN 190 is designed to help restore TPP1 enzyme activity. 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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Hamburg, Germany, 20246
    • Universitaetsklinikum Hamburg-Eppendorf
• Italy
  • Piazza
    • Rome, Piazza, Italy, 00165
      • Children's Hospital Bambino Gesù,IRCCS
• United Kingdom
  • London, United Kingdom, WC1N 3JH
    • Great Ormond Street Childrens Hospital
• United States
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 14 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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.

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); 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; 300 mg Intracerebroventricular (ICV) infusion administered every other week for up to 240 weeks; Other Names: recombinant human tripeptidyl peptidase-1 (rhTPP1); cerliponase alfa; Device: Intracerebroventricular (ICV) access 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole Brain Volume	Percentage change from Baseline to Last Observation: Whole Brain volume	Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation
Volume of Cerebrospinal Fluid	Percentage Change from Baseline to last observation: Volume of cerebrospinal fluid	Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation
Volume of Total Cortical Gray Matter	Percentage Change from Baseline to last observation: Volume of total cortical gray matter	Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation
Total White Matter Volume	Percentage Change from Baseline to last observation: Total white matter volume	Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation
Whole Brain Apparent Diffusion Coefficient	Change from Baseline to last observation Whole brain apparent diffusion coefficient	Baseline (Week 1 of BMN 190-201) to Week 289 / Last observation

Collaborators and Investigators

• Sponsor: BioMarin Pharmaceutical
• Investigators: Study Director: Medical Monitor, MD, 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 (Actual): February 1, 2015
• Primary Completion (Actual): December 10, 2020
• Study Completion (Actual): December 10, 2020

Study Registration Dates

• First Submitted: April 24, 2015
• First Submitted That Met QC Criteria: June 29, 2015
• First Posted (Estimate): June 30, 2015

Study Record Updates

• Last Update Posted (Actual): August 24, 2022
• Last Update Submitted That Met QC Criteria: July 28, 2022
• Last Verified: July 1, 2022

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: 190-202

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: Yes