A Safety, Tolerability, and Efficacy Study of BMN 190 in Pediatric Patients < 18 Years of Age With CLN2 Disease

Phase 2

Completed

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

Interventions: Biological: BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
Biological: BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
Device: Intracerebroventricular access device
Device: Intraventricular access device

Registration Number: NCT02678689

Lead Sponsor: BioMarin Pharmaceutical

Brief Summary: This Phase 2 open-label, multicenter study will evaluate the safety, tolerability, and efficacy of BMN 190 intracerebroventricular (ICV) administration every other week (qow) for a period of 144 weeks, in patients with CLN2. The study is designed to assess disease progression in CLN2 patients treated with BMN 190 compared to natural history data from untreated historical controls.

Detailed Description: BMN 190 is a recombinant form of human tripeptidyl peptidase 1 (TPP1), the enzyme deficient in patients with CLN2 diseases (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. BMN 190 is designed to reduce the progressive, pathologic accumulation of lysosomal storage material. 190-203 is a Phase 2 open-label, multicenter study that will evaluate the safety, tolerability, and efficacy of BMN 190 in pediatric patients \< 18 years of age with CLN2 disease. Study drug dosing will be determined by the patient's age and administered via intracerebroventricular (ICV) infusion every other week (qow), for a duration of 144 weeks.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 14

Inclusion Criteria

Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood spot) in the fibroblasts and leukocytes available at Screening
Quantitative clinical assessment of the Hamburg motor-language aggregate score 3-6 at Screening on CLN2 disease motor-language scale, as defined in the Ratings Assessment Guideline
< 18 years of age at the time of informed consent
Written informed consent from parent or legal guardian and assent form subject, if appropriate
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.
Ability to comply with protocol required assessments (ICV implantation, drug administration, laboratory sample collection, electroencephalogram (EEG), electrocardiogram (ECG),magnetic resonance imaging (MRI), etc.)

Exclusion Criteria

Presence of another inherited neurological disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible)
Presence of another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) or interference with disease rating (autism) before Screening
Presence of percutaneous feeding tube placement prior to enrollment
Has received stem cell, gene therapy, or ERT
Presence of contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities)
Presence of contraindications for MRI scans (e.g., cardiac pacemaker, metal fragment or chip in the eye, aneurysm clip in the brain)
Episode of generalized motor status epilepticus within 4 weeks before the First Dose visit
Severe infection (e.g., pneumonia, pyelonephritis, or meningitis) within 4 weeks before the First Dose visit (enrollment may be postponed)
Presence of ventricular abnormality (hydrocephalus, malformation)
Presence of ventricular shunt
Has known hypersensitivity to any of the components of BMN 190
Has received any investigational mediation 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; a female subject judged by the investigator to be of childbearing potential will be tested for pregnancy

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.
BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	Intracerebroventricular access device	An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.
BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.
BMN190 recombinant human tripeptidyl peptidase-1 (rhTPP1)	Intraventricular access device	An age-appropriate dose of BMN 190 administered via intracerebroventricular (ICV) infusion every other week (qow) for a duration of 144 weeks.

Primary Outcome Measures

Name	Time	Method
Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score.	Baseline to Last assessment (Week 169)	Rate of decline in 0 to 6-point ML score, \& primary analysis was based on up to 3-1 matching of Study 190-901 evaluable participants with Study 190-203 ITT participants. Rate of decline =(-1)x(48x7)x(Ending score - Starting score)/(Ending date - Starting date) A positive rate of decline means that subject declined, a negative rate of decline means that subject improved. The combined motor/gait and language (ML) score, as derived from Hamburg CLN2 rating scale, immediately preceding first infusion. The combined ML score is determined as sum of 0-3 point motor(M) \& language(L) subscales where 0 represents no function, \& 3 represents normal function, \& can range from 0(severely impaired) to 6(normal). Thus,high scores describe better function \& low scores describe poor function. The starting assessment is baseline ML assessment \& ending assessment is last ML score \>0. Note for Study 190-901, baseline ML assessment is defined as assessment of matching to Study 190-203 subj.
Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0	Baseline to Last assessment (Week 169)	An unreversed 2-point decline is any decline of 2 points or more that had not reversed to a 1-point decline (or better) at last recorded observation. An unreversed score of 0 is a decline to 0 that had not increased to a score \>0 at last recorded observation ML score decline is measured by motor \& language domains on CLN2 rating scale. Combined motor/gait \&language (ML) score, as derived from Hamburg CLN2 rating scale, immediately preceding first infusion. Combined ML score is determined as sum of the 0-3 point motor(M)\&language(L) where 0 represents no function, \& 3 represents normal function, \& can range from 0 (severely impaired) to 6 (normal). Thus, high scores describe better function \& low scores describe poor function Model includes data up to week 169. Estimates from the model are presented for Wks 49, 97 \& 145 No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had unreversed 2-point decline/score of 0 at given time points.
Probability of Decline of Unreversed Motor-language (ML) Score of 0	Baseline to Last assessment (Week 169)	The combined motor/gait and language (ML) score, as derived from the Hamburg CLN2 rating scale, immediately preceding the first infusion. The combined ML score is determined as the sum of the 0-3 point motor (M) and language (L) subscales where 0 represents no function, and 3 represents normal function, and can range from 0 (severely impaired) to 6 (normal). Thus, high scores describe better function and low scores describe poor function. Model includes data up to week 169. Estimates from the model are presented for Weeks 49, 97 and 145. No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had unreversed decline/score of 0 at given time points
Rate of Decline in Individual Motor Domains	Baseline to Last assessment (Week 169)	Rate of decline = (-1) x (48 x 7) x (Ending score - Starting score)/(Ending date - Starting date). A positive rate of decline means that the subject declined, a negative rate of decline means that the subject improved. The 0-3 point motor (M) subscales, as derived from the Hamburg CLN2 rating scale, where 0 represents no function, and 3 represents normal function. Thus, high scores describe better function, and low scores describe poor function.
Rate of Decline in Individual Language Domains	Baseline to Last assessment (Week 169)	Rate of decline = (-1) x (48 x 7) x (Ending score - Starting score)/(Ending date - Starting date). A positive rate of decline means that the subject declined, a negative rate of decline means that the subject improved. The 0-3 point language (L) subscales, as derived from the Hamburg CLN2 rating scale, where 0 represents no function, and 3 represents normal function. Thus, high scores describe better function and low scores describe poor function. Patients with baseline score of 0 are excluded.

Secondary Outcome Measures

Name	Time	Method
Change From Baseline in ML Scale Score	Baseline to Week 49, Week 97, Week 145, & Week 169	The combined motor/gait and language (ML) score, as derived from the Hamburg CLN2 rating scale, immediately preceding the first infusion. The combined ML score is determined as the sum of the 0-3 point motor (M) and language (L) subscales where 0 represents no function, and 3 represents normal function, and can range from 0 (severely impaired) to 6 (normal). Thus, high scores describe better function and low scores describe poor function. Some participants did not have follow-up at all time points.
Probability of Decline of Disease Manifestation at Week 49 & 97	Baseline to Last assessment (Week 169)	Disease manifestation is defined as post-baseline consecutive measurements of M,L,V/S scores\<3, measured atleast 22days apart. Combined motor-language-vision-seizure(MLVS)score as derived from Hamburg CLN2 rating scale, is determined as sum of 0-3 point motor(M)language(L)visio(V)\&seizure(S) subscales where 0 represents no function,\&3 represents normal function,\&can range from 0(severely impaired)to12(normal).Thus, high scores describe better function \& low scores describe poor function. 901 subj weighted according to no.of matches:weights for 3,2,\&1 study 901 subj matched to a given study 203 subj are 1/3,1/2, \&1 times N901/N203 respectively. N901 is no.of 901 subj matched to 203 subj(ie.18)\&N203 is no.203 subj who had matches (i.e.7).203 subj who had matches were assigned weight of 1. No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had decline of disease manifestation at given time points
Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL)	Baseline to Last assessment (Week 169)
Probability of Decline of Disease Manifestation at Week 145	Baseline to Week 145	Disease manifestation is defined as post-baseline consecutive measurements of M,L,V/S scores\<3,measured atleast 22days apart Combined MLVS score,as derived from Hamburg CLN2 rating scale,is determined as sum of 0-3 point motor(M)language(L)vision(V)\&seizure(S) subscales where 0 represents no function,\&3 represents normal function,\&can range from 0(severely impaired) to 12(normal).Thus,high scores describe better function\&low scores describe poor function 901 subj weighted according to no.of matches:weights for 3,2,\&1 study 901 subj matched to given study 203 subj are 1/3,1/2, \&1 times N901/N203 respectively.N901 is no.of 901 subj matched to 203 subj(ie.18)\&N203 is no.203 subj who had matches(i.e.7).203 subj who had matches were assigned weight of 1 Model includes data upto wk169.Estimates from model are presented for Wk145 No.analyzed is no.of subj out of overall no.of participants analyzed who have not been censored/had decline of disease manifestation at given time point
Changes From Baseline in MLV Scale Score	Baseline to Week 49, Week 97, Week 145, & Week 169	The combined motor-language-vision (MLV) score, as derived from the Hamburg CLN2 rating scale, is determined as the sum of the 0-3 point motor (M), language (L) \& vision (V) subscales where 0 represents no function, and 3 represents normal function, and can range from 0 (severely impaired) to 9 (normal). Thus, high scores describe better function and low scores describe poor function. Some participants did not have follow-up at all time points.
Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score.	Baseline to Week 49, Week 97, Week 145, & Week 169	The combined motor-language-vision-seizure (MLVS) score, as derived from the Hamburg CLN2 rating scale, is determined as the sum of the 0-3 point motor (M) and language (L) vision (V) and seizure (S) subscales where 0 represents no function, and 3 represents normal function, and can range from 0 (severely impaired) to 12 (normal). Thus, high scores describe better function and low scores describe poor function. Some participants did not have follow-up at all time points.
Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL)	Baseline to Last assessment (Week 169)
Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (mL)	Baseline to Last assessment (Week 169)
Change From Baseline to Last Assessment: Whole Brain Apparent Diffusion Coefficient Value	Baseline to Last assessment (Week 169)	The apparent diffusion coefficient (ADC) represents the calculated diffusion coefficient of water molecules in the direction of the applied gradients measured during diffusion MRI, a technique used to explore the architecture and microstructural properties of both the white and gray matter of the brain.

Trial Locations

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