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

Conditions

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

Keywords

Late infantile Neuronal Ceroid Lipofuscinosis Type 2, LINCL, NCL2, CLN2, Jansky-Bielschowsky disease

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.

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FV 1183. Long-Term Safety and Efficacy of Intraventricular Enzyme Replacement Therapy in CLN2 Disease: 2-Year Results from an Ongoing Multicenter Extension Study

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Interventions

BIOLOGICALBMN 190

300 mg Intracerebroventricular (ICV) infusion administered every other week for up to 240 weeks

DEVICEIntracerebroventricular (ICV) 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.

Study design

Allocation

NA

Intervention model

SINGLE_GROUP

Primary purpose

TREATMENT

Masking

NONE

Intervention 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.

Eligibility

Sex/Gender

ALL

Age

3 Years to 16 Years

Healthy volunteers

No

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.

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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
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
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
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
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

Countries

Germany, Italy, United Kingdom, United States

Participant flow

Recruitment details

190-201 was conducted at 5 clinic sites in Germany, Italy, the United Kingdom and the United States. One subject from one of the two 190-201 sites in the United Kingdom withdrew after 1 dose of BMN 190 and therefore this site was not activated in 190-202. The comparator group for determination of the primary efficacy outcome measures in this study was comprised of 42 Natural History (NH) subjects with CLN2 disease selected from the DEM-CHILD database (NCT04613089).

Pre-assignment details

190-202 is the extension of treatment & follow-up for subjects enrolled in Study 190-201. The ITT analysis population was comprised of the 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (completed 48 weeks in 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). The safety analysis population in Study 190-202 was comprised of the 24 subjects in Study 190-201 who had an ICV access device implanted.

Participants by arm

Arm	Count
190-202 (300 mg) 190-202 Intent to Treat (ITT)/Efficacy Population (n = 23): The 23 subjects who completed the 190-201 study and enrolled in the 190-202 study (i.e., completed 48 weeks in Study 190-201, met all other 190-202 study inclusion criteria and to whom none of the 190-202 study exclusion criteria applied). 190-202 Safety Population (n = 24): All study subjects who had an ICV access device implanted in Study 190-201.	24
Natural History Comparator 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 control group (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.	42
Total	66

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Protocol-Specified Withdrawal Criterion Met	2
Overall Study	Withdrawal by Parent/ Guardian	4
Overall Study	Withdrawal by Subject	1

Baseline characteristics

Characteristic	Total	Natural History Comparator	190-202 (300 mg)
300 mg Baseline ML Score	4.1 units on a scale STANDARD_DEVIATION 1.05	4.5 units on a scale STANDARD_DEVIATION 0.77	3.5 units on a scale STANDARD_DEVIATION 1.18
Age, Continuous	4.3 years STANDARD_DEVIATION 1.17	4.0 years STANDARD_DEVIATION 0.92	5.0 years STANDARD_DEVIATION 1.29
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	23 Participants	0 Participants	23 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	42 Participants	42 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) Black or African American	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	42 Participants	42 Participants	0 Participants
Race (NIH/OMB) White	23 Participants	0 Participants	23 Participants
Sex: Female, Male Female	32 Participants	17 Participants	15 Participants
Sex: Female, Male Male	34 Participants	25 Participants	9 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 24
other Total, other adverse events	24 / 24
serious Total, serious adverse events	21 / 24

Outcome results

Primary

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).

Time frame: Up to Week 289

Population: BMN 190-202: 24 subjects were enrolled in 190-201 at 5 clinic sites worldwide. One subject terminated from 190-201 after a single infusion and is not included in the Intent-to-Treat (ITT) population for 190-202. Study 190-202 final efficacy results include pooled data from the complete dataset from Study 190-201 \& Study 190-202 for all subjects who received \>1 dose (N=23).~NH: 42 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description below.

Arm	Measure	Group	Value (NUMBER)
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 49	0.13 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 97	0.22 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 145	0.22 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 193	0.26 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 241	0.40 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 289	0.54 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 241	1.00 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 49	0.48 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 193	0.97 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 97	0.91 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 289	1.00 Probability of decline
Natural History Comparator	Probability of Unreversed 2-point Decline in Motor-language (ML) Score or Score of 0	Probability of decline: Week 145	0.97 Probability of decline

p-value: <0.000195% CI: [0.06, 0.33]Cox Proportional Hazards model

Primary

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).

Time frame: Up to Week 289

Population: BMN 190-202: 24 subjects were enrolled in 190-201 at 5 clinic sites worldwide. One subject terminated from 190-201 after a single infusion and is not included in the Intent-to-Treat (ITT) population for 190-202. Study 190-202 final efficacy results include pooled data from the complete dataset from Study 190-201 \& Study 190-202 for all subjects who received \>1 dose (N=23).~NH: 42 subjects from DEM-CHILD database satisfying the criteria listed in the Arm/Group description below.

Arm	Measure	Group	Value (NUMBER)
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 49	0.00 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 97	0.00 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 145	0.00 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 193	0.05 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 241	0.05 Probability of decline
BMN 190-202 (300 mg)	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 289	0.15 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 241	0.97 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 49	0.03 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 193	0.94 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 97	0.38 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 289	1.00 Probability of decline
Natural History Comparator	Probability of Unreversed Motor-language (ML) Score of Zero.	Probability of decline: Week 145	0.78 Probability of decline

p-value: <0.0001Cox Proportional Hazards model

Secondary