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

Phase 1

Completed

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

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

Registration Number: NCT02485899

Lead Sponsor: BioMarin Pharmaceutical

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	BMN 190	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.
BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	Intracerebroventricular (ICV) access device	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.

Primary Outcome Measures

Name	Time	Method
Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Up to Week 289	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).
Probability of Unreversed Motor-language (ML) Score of Zero.	Up to Week 289	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).

Secondary Outcome Measures

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

Trial Locations

Locations (4): Universitaetsklinikum Hamburg-Eppendorf
🇩🇪
Hamburg, Germany
Nationwide Children's Hospital
🇺🇸
Columbus, Ohio, United States
Great Ormond Street Childrens Hospital
🇬🇧
London, United Kingdom
Children's Hospital Bambino Gesù,IRCCS
🇮🇹
Rome, Piazza, Italy