Batten Disease, CLN2 Disease, CLN2 Disorder, Jansky-Bielschowsky Disease, Late-Infantile Neuronal Ceroid Lipofuscinosis Type 2
Conditions
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.
Interventions
BIOLOGICALBMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
DEVICEIntracerebroventricular 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.
Sponsors
BioMarin Pharmaceutical
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 17 Years
Healthy volunteers
No
Inclusion criteria
Enrollment is complete. 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL) | Baseline to Last assessment (Week 169) | — |
| Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL) | Baseline to Last assessment (Week 169) | — |
| 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 |
| 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. |
| Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (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 |
| 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. |
| 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. |
Countries
Germany, Italy, United Kingdom, United States
Participant flow
Recruitment details
Study 190-203 was conducted at 4 clinic sites:One each in Germany, Italy, the United Kingdom and the United States. The comparator group for determination of the primary efficacy outcome measures in this study was comprised of 29 Natural History (NH) subjects with late-infantile neuronal ceroid lipofuscinosis disease, also known as classical late-infantile CLN2, cLINCL, or Jansky-Bielschowsky disease, a form of Batten Disease (CLN2) disease selected from the DEM-CHILD database (NCT04613089).
Pre-assignment details
A total of 14 participants were enrolled and treated in study 190-203. 13 participants completed the study, and 1 participant withdrew to receive treatment commercially. The 190-203 study required enrollment of at least 10 participants, including at least 5 participants with a combined ML score \>= 5 points (mild or pre-symptomatic disease), at least 5 participants with a ML score \< 5points (moderate disease), and at least 5 participants \< 2 years of age.
Participants by arm
| Arm | Count |
|---|---|
| BMN 190-203 BMN 190 was administered by continuous Intracerebroventricular (ICV) infusion at the rate of 2.5 mL/hour for approximately 4 hours every 14 (+/-3) days, preferably in the morning. The recommended dose of BMN 190 is according to the participant's age: Birth to \< 6 months: 100 mg, 6 months to \< 1 year: 150 mg, 1 year to \< 2 years: 200 mg (first four doses), 300 mg (subsequent doses) \>=2 years: 300 mg. The treatment continued for the duration of at least 144 weeks or until all procedures were completed or the participant discontinued from the study.
BMN 190 recombinant human tripeptidyl peptidase-1 (rhTPP1)
Intracerebroventricular 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. | 12 |
| Natural History Comparator:190-901 Participants The NH comparator population consisted of subjects from the DEM-CHILD database who satisfied the 190-203 inclusion criteria. The Study 190-901 evaluable population was required to have:
* At least one assessment ML \>= 3
* At least two ML assessments in the range 1 - 6 and at least 6 months apart | 29 |
| Total | 41 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Participant chose to receive commercial drug in their home country | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Natural History Comparator:190-901 Participants | BMN 190-203 |
|---|---|---|---|
| Age at disease onset (years) | 2.5 years STANDARD_DEVIATION 0.83 | 2.6 years STANDARD_DEVIATION 0.82 | 2.1 years STANDARD_DEVIATION 0.82 |
| Age, Continuous | 2.7 years STANDARD_DEVIATION 1.09 | 2.7 years STANDARD_DEVIATION 1.09 | 2.7 years STANDARD_DEVIATION 1.12 |
| CLN2 language scale score at Baseline | 2.4 Score on a scale STANDARD_DEVIATION 0.86 | 2.4 Score on a scale STANDARD_DEVIATION 0.93 | 2.6 Score on a scale STANDARD_DEVIATION 0.67 |
| CLN2 motor-language (ML) score | 5.0 score on a scale STANDARD_DEVIATION 1.37 | 5.0 score on a scale STANDARD_DEVIATION 1.38 | 5.0 score on a scale STANDARD_DEVIATION 1.41 |
| CLN2 motor-language-vision-seizure (MLVS) score | 10.4 Score on a scale STANDARD_DEVIATION 2.42 | 10.2 Score on a scale STANDARD_DEVIATION 2.7 | 10.9 Score on a scale STANDARD_DEVIATION 1.56 |
| CLN2 motor scale score at Baseline | 2.6 score on a scale STANDARD_DEVIATION 0.63 | 2.6 score on a scale STANDARD_DEVIATION 0.54 | 2.4 score on a scale STANDARD_DEVIATION 0.79 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 11 Participants | 0 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 29 Participants | 29 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown or Not Reported | 29 Participants | 29 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 12 Participants | 0 Participants | 12 Participants |
| Sex/Gender, Customized Female | 23 Participants | 15 Participants | 8 Participants |
| Sex/Gender, Customized Male | 18 Participants | 14 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 14 |
| other Total, other adverse events | 14 / 14 |
| serious Total, serious adverse events | 12 / 14 |
Outcome results
Primary
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)
Population: Matched ITT BMN 190-203: Two subjects in 190-203 ITT population (N=14) were excluded from the 190-203 ITT analysis with matching (N=12) who did not match with any 190-901 subjects on the matching criteria. The matching criteria at baseline were: • Equal ML score • Age within 3 months • Genome: equal number of common alleles (c.622C→T, c.509.1G→C)~Matched 190-901 Natural history population: 29 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score. | 0.15 change in score/48 wk | Standard Deviation 0.243 |
| Natural History Comparator: 190-901 Participants | Motor Language (ML) Scale: Rate of Decline in the 0 to 6-point ML Score. | 1.30 change in score/48 wk | Standard Deviation 0.857 |
p-value: <0.0001t-test, unequal variance
Primary
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)
Population: Matched ITT BMN 190-203: Two subjects in 190-203 ITT Population (N=14) were excluded from the 190-203 ITT analysis with matching (N=12) who did not match with any 190-901 subjects on the matching criteria. The matching criteria at baseline were: Equal ML score, age within 3 months and genome with equal number of common alleles (c.622C→T, c.509.1G→C).~Matched 190-901 Natural history population: 29 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMN 190-203 | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 49 | 0.0 Probability of decline |
| BMN 190-203 | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 97 | 0.0 Probability of decline |
| BMN 190-203 | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 145 | 0.0 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 49 | 0.03 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 97 | 0.149 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Decline of Unreversed Motor-language (ML) Score of 0 | Probability of decline: Week 145 | 0.336 Probability of decline |
p-value: 0.003295% CI: [0, 0]Cox Model Wald Test
Primary
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)
Population: Matched ITT BMN 190-203: Two subjects in 190-203 ITT Population(N=14) were excluded from the 190-203 ITT analysis with matching (N=12) who did not match with any 190-901 subjects on the matching criteria. The matching criteria at baseline were: Equal ML score, age within 3 months and genome with equal number of common alleles(c.622C→T, c.509.1G→C).~Matched 190-901 Natural history population: 29 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMN 190-203 | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 49 | 0.0 Probability of decline |
| BMN 190-203 | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 97 | 0.083 Probability of decline |
| BMN 190-203 | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 145 | 0.167 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 49 | 0.141 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 97 | 0.397 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Unreversed 2-Point Decline in Motor-language (ML) Score or Score of 0 | Probability of decline: Week 145 | 0.774 Probability of decline |
p-value: <0.000195% CI: [0.021, 0.393]Cox Model Wald Test
Primary
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)
Population: Matched ITT BMN 190-203: Two subjects in 190-203 ITT Population (N=14) were excluded from the 190-203 ITT analysis with matching (N=12) who did not match with any 190-901 subjects on the matching criteria. The matching criteria at baseline were: Equal ML score, age within 3 months and genome with equal number of common alleles (c.622C→T, c.509.1G→C).~Matched 190-901 Natural history population: 29 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Rate of Decline in Individual Language Domains | 0.10 change in score/48 wk | Standard Deviation 0.146 |
| Natural History Comparator: 190-901 Participants | Rate of Decline in Individual Language Domains | 0.77 change in score/48 wk | Standard Deviation 0.715 |
p-value: <0.0001t-test, unequal variance
Primary
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)
Population: Matched ITT BMN 190-203: Two subjects in 190-203 ITT Population (N=14) were excluded from the 190-203 ITT analysis with matching (N=12) who did not match with any 190-901 subjects on the matching criteria. The matching criteria at baseline were: Equal ML score, age within 3 months and genome with equal number of common alleles (c.622C→T, c.509.1G→C).~Matched 190-901 Natural history population: 29 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Rate of Decline in Individual Motor Domains | 0.05 change in score/48 wk | Standard Deviation 0.12 |
| Natural History Comparator: 190-901 Participants | Rate of Decline in Individual Motor Domains | 0.59 change in score/48 wk | Standard Deviation 0.496 |
p-value: <0.0001t-test, unequal variance
Secondary
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.
Time frame: Baseline to Week 49, Week 97, Week 145, & Week 169
Population: 190-901 participants weighted according to no. of matches: weights for 3,2,\&1 study 190-901 participant matched to a given Study190-203 participant were1/3,1/2,\&1 times N901/N203, respectively. N901 was no. of 190-901 participants matched to 190-203 participants (ie,29) \&N203 was no. of 190-203 participants who had matches (ie,12).190-203 participants who had matches were assigned weight of 1.~Each participant in Study 190-901 had their scores imputed to time points using linear interpolation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 190-203 | Change From Baseline in ML Scale Score | Change from Baseline to Week 49 | -0.0 score on a scale | Standard Deviation 0.57 |
| BMN 190-203 | Change From Baseline in ML Scale Score | Change from Baseline to Week 97 | 0.0 score on a scale | Standard Deviation 0.43 |
| BMN 190-203 | Change From Baseline in ML Scale Score | Change from Baseline to Week 145 | -0.4 score on a scale | Standard Deviation 0.78 |
| BMN 190-203 | Change From Baseline in ML Scale Score | Change from Baseline to Week 169 | -0.4 score on a scale | Standard Deviation 0.67 |
| Natural History Comparator: 190-901 Participants | Change From Baseline in ML Scale Score | Change from Baseline to Week 169 | -3.7 score on a scale | Standard Deviation 2.39 |
| Natural History Comparator: 190-901 Participants | Change From Baseline in ML Scale Score | Change from Baseline to Week 49 | -0.8 score on a scale | Standard Deviation 1.05 |
| Natural History Comparator: 190-901 Participants | Change From Baseline in ML Scale Score | Change from Baseline to Week 145 | -3.1 score on a scale | Standard Deviation 1.61 |
| Natural History Comparator: 190-901 Participants | Change From Baseline in ML Scale Score | Change from Baseline to Week 97 | -1.6 score on a scale | Standard Deviation 1.22 |
Secondary
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)
Population: Intent-to-treat (ITT) population.~One subject did not have any follow-up MRI data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Change From Baseline to Last Assessment: Whole Brain Apparent Diffusion Coefficient Value | 0.0 mm^2/s | Standard Deviation 0.04 |
Secondary
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
Population: 190-901 participants weighted according to no. of matches: weights for 3,2,\&1 study 190-901 participant matched to a given Study190-203 participant were1/3,1/2,\&1 times N901/N203, respectively. N901 was no. of 190-901 participants matched to 190-203 participants (ie,29) \&N203 was no. of 190-203 participants who had matches (ie,12).190-203 participants who had matches were assigned weight of 1.~Each participant in Study 190-901 had their scores imputed to time points using linear interpolation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 190-203 | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 49 | -0.1 score on a scale | Standard Deviation 0.74 |
| BMN 190-203 | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 97 | -0.1 score on a scale | Standard Deviation 0.51 |
| BMN 190-203 | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 145 | -0.7 score on a scale | Standard Deviation 1.06 |
| BMN 190-203 | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 169 | -0.7 score on a scale | Standard Deviation 1.1 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 169 | -4.5 score on a scale | Standard Deviation 3.04 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 49 | -1.0 score on a scale | Standard Deviation 1.31 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 145 | -3.9 score on a scale | Standard Deviation 1.98 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in MLV Scale Score | Change from Baseline to Week 97 | -2.1 score on a scale | Standard Deviation 1.71 |
Secondary
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
Population: 190-901 participants weighted according to no. of matches: weights for 3,2,\&1 study 190-901 participant matched to a given Study190-203 participant were1/3,1/2,\&1 times N901/N203, respectively. N901 was no. of 190-901 participants matched to 190-203 participants (ie,29) \&N203 was no. of 190-203 participants who had matches (ie,12).190-203 participants who had matches were assigned weight of 1.~Each participant in Study 190-901 had their scores imputed to time points using linear interpolation
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| BMN 190-203 | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 49 | -0.2 score on a scale | Standard Deviation 0.86 |
| BMN 190-203 | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 97 | -0.1 score on a scale | Standard Deviation 0.51 |
| BMN 190-203 | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 145 | -0.6 score on a scale | Standard Deviation 0.99 |
| BMN 190-203 | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 169 | -0.6 score on a scale | Standard Deviation 1.03 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 169 | -6.4 score on a scale | Standard Deviation 3.43 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 49 | -1.5 score on a scale | Standard Deviation 1.39 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 145 | -5.5 score on a scale | Standard Deviation 2.48 |
| Natural History Comparator: 190-901 Participants | Changes From Baseline in the 0-12 Point MLVS Motor, Language, Vision, and Seizure Subscales (MLVS) Score. | Change from Baseline to Week 97 | -3.0 score on a scale | Standard Deviation 1.78 |
Secondary
Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL)
Time frame: Baseline to Last assessment (Week 169)
Population: Intent-to-treat (ITT) population.~One subject did not have any follow-up MRI data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Percentage Change From Baseline to Last Assessment: Volume of Cerebrospinal Fluid (mL) | 0.7 Percentage | Standard Deviation 13.18 |
Secondary
Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL)
Time frame: Baseline to Last assessment (Week 169)
Population: Intent-to-treat (ITT) population.~One subject did not have any follow-up MRI data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Percentage Change From Baseline to Last Assessment: Volume of Total Cortical Gray Matter (mL) | -10.3 Percentage | Standard Deviation 13.86 |
Secondary
Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (mL)
Time frame: Baseline to Last assessment (Week 169)
Population: Intent-to-treat (ITT) population.~One subject did not have any follow-up MRI data available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| BMN 190-203 | Percentage Change From Baseline to Last Assessment: Volume of Total White Matter (mL) | 5.4 Percentage | Standard Deviation 20.86 |
Secondary
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
Population: Matched ITT BMN190-203:2 subj in 190-203 ITT Pop(N=14) were excluded from 190-203 ITT analysis with matching(N=12) who did not match with any 190-901 subj on matching criteria. Matching criteria at baseline were:Equal ML score, age within 3 months \& genome with equal no. of common alleles(c.622C→T, c.509.1G→C).~Matched 190-901 Natural history pop:29 subj from DEM-CHILD database satisfying criteria listed in Arm/Group descp.~No.of subj analyzed for 190-901=0 \& hence this arm is not included
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BMN 190-203 | Probability of Decline of Disease Manifestation at Week 145 | 0.429 Probability of decline |
Secondary
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)
Population: Matched ITT BMN190-203:2 subj in190-203 ITT Population(N=14)were excluded from 190-203 ITT analysis with matching(N=12)who did not match with any190-901 subj on matching criteria.Matching criteria at baseline were:Equal ML score,age\<3 months\&genome with equal no.of common alleles(c.622C→T,c.509.1G→C).~Matched190-901 Natural history population:29 subj from DEM-CHILD database satisfying criteria listed in Arm descp~Model includes data upto wk169.Estimates from model are presented for Wks 49\&97
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| BMN 190-203 | Probability of Decline of Disease Manifestation at Week 49 & 97 | Probability of decline: Week 49 | 0.143 Probability of decline |
| BMN 190-203 | Probability of Decline of Disease Manifestation at Week 49 & 97 | Probability of decline: Week 97 | 0.286 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Decline of Disease Manifestation at Week 49 & 97 | Probability of decline: Week 97 | 0.762 Probability of decline |
| Natural History Comparator: 190-901 Participants | Probability of Decline of Disease Manifestation at Week 49 & 97 | Probability of decline: Week 49 | 0.405 Probability of decline |
p-value: 0.008195% CI: [0.059, 0.735]Cox Model Wald Test