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.
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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
14
Surgical implantation of an MRI compatible ICV access device in the lateral ventricle of the right hemisphere is required for administration of study drug.
Nationwide Children's Hospital
Columbus, Ohio, United States
Universitaetsklinikum Hamburg-Eppendorf
Hamburg, Germany
Children's Hospital Bambino Gesù,IRCCS
Rome, Piazza, Italy
Great Ormond Street Childrens Hospital
London, United Kingdom
Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score.
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.
Time frame: Baseline to Last assessment (Week 169)
Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0
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.
Time frame: Baseline to Last assessment (Week 169)
Probability of Decline of Unreversed Motor-language (ML) Score of 0
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
Time frame: Baseline to Last assessment (Week 169)
Rate of Decline in Individual Motor Domains
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.
Time frame: Baseline to Last assessment (Week 169)
Rate of Decline in Individual Language Domains
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.
Time frame: Baseline to Last assessment (Week 169)
Probability of Decline of Disease Manifestation at Week 49 & 97
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
Time frame: Baseline to Last assessment (Week 169)
Probability of Decline of Disease Manifestation at 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
Time frame: Baseline to Week 145
Change From Baseline in ML Scale Score
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.
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Time frame: Baseline to Week 49, Week 97, Week 145, & Week 169
Changes From Baseline in MLV Scale Score
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.
Time frame: Baseline to Week 49, Week 97, Week 145, & Week 169
Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score.
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.
Time frame: Baseline to Week 49, Week 97, Week 145, & Week 169
Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL)
Time frame: Baseline to Last assessment (Week 169)
Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL)
Time frame: Baseline to Last assessment (Week 169)
Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (mL)
Time frame: Baseline to Last assessment (Week 169)
Change From Baseline to Last Assessment: Whole Brain Apparent Diffusion Coefficient Value
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.
Time frame: Baseline to Last assessment (Week 169)