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

Study Overview
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Brief Summary
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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
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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.

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

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

Intervention / Treatment
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* Biological: BMN 190
* Device: Intracerebroventricular (ICV) access device


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 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.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)<br>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<br>* 300 mg Intracerebroventricular (ICV) infusion administered every other week for up to 240 weeks<br>* Other names: cerliponase alfa;Device: Intracerebroventricular (ICV) access device<br>* Surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere is required for administration of study drug.<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Late infantile Neuronal Ceroid Lipofuscinosis Type 2, LINCL, NCL2, CLN2, Jansky-Bielschowsky disease