BioMarin 190-203

• Research type

  Research Study

• Full title

  A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 years of age with CLN2 Disease.

• IRAS ID

  226822

• Contact name

  Paul Gissen

• Contact email

  p.gissen@ucl.ac.uk

• Sponsor organisation

  BioMarin Pharmaceutical Inc.

• Eudract number

  2015-000891-85

• Duration of Study in the UK

  5 years, 5 months, 28 days

• Research summary

  Summary of Research
  BMN 190 is a recombinant form of human (tripeptidyl peptidase-1 (TPP1) used for the treatment of CLN2 disease. This disease is a pediatric rare genetic disorder, characterized by deficiency of lysosomal serine protease TPP1 (enzyme). In the absence of TPP1, abnormal harmful materials normally metabolized by this enzyme accumulate in many organs; accumulation in the central nervous system leads to the neurodegenerative symptoms and, ultimately death.

  BMN 190 is expected to restore TPP1 enzyme activity in the brain and alter the primary affect of disease progression. Given the urgent and severe unmet medical need in CLN2 disease and observations of safety and efficacy in animal models of CLN2 disease, clinical development of BMN 190 ERT is justified, BMN 190 has recently been approved for treatment by the European Medicines Agency, the group that decides which medications may be used to treat patients in the counties of the European Union.
  BMN 190 medication has been tested in children with CLN2 disease ≥ 3 years of age. Results from the previous study demonstrated a substantial disease improvement in children treated with BMN 190 compared with untreated historical controls. Based on clinical and nonclinical information, it appears that BMN 190 medication has the potential of postponing clinical decline for a significant period.
  This particular clinical trial is intended to further investigate the safety and tolerability of ICV-delivered BMN 190 in CLN2 patients. The safety of BMN 190 medication as a delay in disease progression will be evaluated relative to untreated patients (data from siblings affected by CLN2 disease and/or data from a CLN2 disease patient registry will be used).
  This is a Phase 2 open-label, multicenter study in pediatric patients < 18 years of age with CLN2 Disease. Eligibility will be determined and study enrollment will occur before patients are admitted to the hospital for surgical implantation of an ICV access device.
  The treatment period is at least 96 weeks. The study will enroll at least 10 patients, including at least 1 in the UK at Great Ormond Street Hospital.

  Summary of Results
  SYNOPSIS BioMarin Pharmaceutical Inc.
  Individual Study Table Referring to Part of the Dossier Volume: (##) Page: (##) Finished Product: BMN 190 Active Ingredient: recombinant human tripeptidyl peptidase-1 (rhTPP1) Protocol No. 190-203: A Phase 2, Open-Label, Multicenter Study to Evaluate Safety, Tolerability, and Efficacy of Intracerebroventricular BMN 190 in Pediatric Patients < 18 years of age with CLN2 Disease.

  Principal Investigators/Study Centers:
  Angela Schulz / Universitätsklinikum Hamburg-Eppendorf, Hamburg Germany Emily de los Reyes / Nationwide Children’s Hospital, Columbus, OH US Nicola Specchio / Bambino Gesù Children’s Hospital, Rome, Italy Paul Gissen / Great Ormond Street Hospital, London, UK

  Publication: None

  Study Duration: Surgery/ recovery for 14-28 days with Treatment for at least 144 weeks

  Development Phase: 2

  First Participant Enrollment: 22 January 2016

  Last Participant Visit: 20 April 2022

  OBJECTIVES:
  The primary objectives of this study were as follows:
  • To evaluate safety and tolerability of BMN 190 administered via intracerebroventricular (ICV) device • to evaluate treatment effectiveness as a delay in progression of motor-language (ML) score on the CLN2 clinical rating scale • to assess immunogenicity of BMN 190 in cerebrospinal fluid (CSF) and serum.

  Secondary objectives:
  • to characterize the pharmacokinetics (PK) of BMN 190 in CSF and plasma • to measure magnetic resonance imaging (MRI) parameters of disease progression • to assess impact of treatment on the total CLN2 clinical rating scale • to assess the time to disease manifestation for asymptomatic participants

  Exploratory objectives:
  • to assess development achievement
  • to assess abnormal involuntary movements • to evaluate retinal anatomy using optical coherence tomography (OCT) • to determine seizure onset, type and frequency • to determine change in seizure activity • to explore temporal relationships between administration of anti-epileptic treatments and incidence of convulsion adverse events (AEs) and changes in seizure scores • to assess quality of life (QoL) • to assess changes in electroencephalogram (EEG) • to assess changes in visual acuity • to analyze disease-related biomarkers from CSF and blood.

  Overall Study Plan:
  Study 190-203 was a Phase 2, open-label, multicenter study in pediatric patients < 18 years of age with CLN2 disease, confirmed by deficiency of TPP1 enzyme activity and mutation of the CLN2 gene. This study was a post-marketing commitment that primarily enrolled children < 3 years of age and required enrollment of at least 5 participants < 2 years of age. The study was designed to assess disease progression in CLN2 patients treated with BMN 190 compared to natural history data from untreated historical controls (data from a CLN2 disease patient registry and data from siblings with CLN2 disease, when available). Comparison of treatment with untreated controls was performed from the time of the initiation of study drug. Eligibility was determined and study enrollment occurred before participants were admitted to the hospital for surgical implantation of an ICV access device. Baseline values were recorded before the first infusion, which were to occur at least 14 days from surgery and no more than 28 days after surgery.
  Participants younger than 2 years started the study at the dose level appropriate for their age and transitioned to the dose level consistent with their age as they matured.
  The study was to enroll at least 10 participants: at least 5 participants with a CLN2 clinical rating scale ML score ≥ 5 points, at least 5 participants with a ML score < 5 points, and at least 5 participants < 2 years of age. The treatment period was at least 144 weeks.
  Participants in this study were required to have an ICV reservoir surgically implanted for administration of BMN 190.
  Age-specific dosing was initiated every 14 days (±3 days) from the date of first infusion.
  Because hypersensitivity reactions may be associated with enzyme replacement therapy (ERT) administration, participants were pretreated with an age-appropriate dose of antihistamine (and antipyretic, if appropriate) medication approximately 30 minutes (± 15 minutes) before infusion. Participants were pretreated, at the discretion of the investigator, with age-appropriate sedative medication approximately 30 minutes (± 15 minutes) before BMN 190 infusion according to institution’s standard practices.
  Efficacy was measured using the 0 to 6-point ML score on the CLN2 clinical rating scale as the primary endpoint. The 12-point total score (motor, language, vision, and seizure subscales) on the CLN2 clinical rating scale, time to disease manifestation (for asymptomatic participants), and MRI measures of disease progression were collected as secondary endpoints. Exploratory efficacy measures include developmental status, involuntary movements, retinal anatomy using OCT, seizure frequency, change in seizure activity (as measured by CLN2 clinical rating scale score), anti-epileptic treatment, quality of life metrics, changes in EEG, assessment of visual acuity, and analysis of disease-related biomarkers.
  The safety and tolerability of treatment was assessed by collection of AEs, vital signs, ECGs, and clinical laboratory tests. AEs were assessed by the investigator for severity, seriousness, and relationship to study drug and/or the ICV access device. An AE occurring within 24 hours of the start or restart of BMN 190 infusion was defined as a temporally-related event (TRE).
  In the event of a suspected anaphylactic reaction, serious hypersensitivity event, or severe hypersensitivity (defined as a hypersensitivity event of Grade 3 or higher), blood samples to assess C4, serum tryptase, and total IgE were to be collected within 1 hour of the event and tested; a blood sample to assess drug-specific IgE was to be collected no sooner than 8 hours after the event (or before the next infusion).
  In addition, the investigator was required to contact the BioMarin medical monitor within 1 business day if any AE was severe (Grade 3 or higher) or serious and required any of the following:
  • infusion interruption, discontinuation, or modification (not due to blocked line) • administration of intravenous (IV) fluids, steroids, or antihistamines • administration of oxygen Before subsequent infusions, the study site investigator and BioMarin medical monitor were to discuss the case and agree upon infusion modification or additional premedication, if necessary. Agreed upon dose modifications or introduction of additional premedication were to be documented in the Case Report Forms and source files.
  AEs were judged by relationship to study drug and to the ICV access device. Routine CSF surveillance was performed by clinical laboratories and microbial studies each time the reservoir was accessed. If an infection was suspected, blood and CSF samples were drawn for laboratory assessments. The subsequent course of therapy could include antibiotic therapy and catheter reposition or withdrawal. If BMN 190 treatment was suspended, BMN 190 could resume if no more than 4 consecutive doses were missed after the last given dose.
  Samples were also taken to evaluate BMN 190 immunogenicity in CSF and serum.

  Number of Participants:
  At least 10 participants were expected to be enrolled: at least 5 participants with a CLN2 clinical rating scale ML score ≥ 5 points, at least 5 participants with a ML score < 5 points, and at least 5 participants < 2 years of age.
  A total of 14 participants were enrolled and dosed with BMN 190 in Study 190-203, including 8 participants with ML score ≥ 5 points, 6 participants with ML score < 5 points, and 5 participants < 2 years of age.

  Diagnosis and Main Criteria for Inclusion:
  Pediatric patients (from birth to < 18 years of age) with confirmed CLN2 disease were eligible to participate in this study. Additional criteria for participation in this study are detailed below. Participants met the following entry criteria to enroll in the study.
  Inclusion Criteria:
  • Diagnosis of CLN2 disease as determined by TPP1 enzyme activity (dried blood spot) in the fibroblasts and leukocytes available at Screening. Note: Blood for TPP1 enzyme activity and CLN2 gene analysis must be collected and analyzed centrally.
  • Quantitative clinical assessment of the CLN2 clinical rating scale motor-language aggregate score 3-6 at Screening, 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 from participant, if appropriate • Males and females who were of reproductive age were required to practice true abstinence, defined as no sexual activity, during the study and for 6 months after study completion (or withdrawal from the study). If sexually active and not practicing true abstinence, males and females of reproductive age were required to 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, EEG, ECG, MRI, etc.)

  Exclusion Criteria:
  • Another inherited neurologic disease, e.g., other forms of CLN or seizures unrelated to CLN2 disease (patients with febrile seizures may be eligible) • Another neurological illness that may have caused cognitive decline (e.g., trauma, meningitis, hemorrhage) or interfere with disease rating (autism) before Screening • Percutaneous feeding tube placement prior to enrollment • Received stem cell, gene therapy, or ERT • Contraindications for neurosurgery (e.g., congenital heart disease, severe respiratory impairment, or clotting abnormalities) • 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 • Known hypersensitivity to any of the components of BMN 190 • Received any investigational medication within 30 days before the first infusion of study drug or was scheduled to receive any investigational drug other than BMN 190 during the course of the study • Had a medical condition or extenuating circumstance that, in the opinion of the investigator, might have compromised the participant’s ability to comply with the protocol required testing or procedures or might have compromised the participant’s well-being, safety, or clinical interpretability • Pregnancy any time during the study; a female participant judged by the investigator to be of childbearing potential was to be tested for pregnancy.

  Test Product, Dose and Mode of Administration, Batch Number: BMN 190 was administered by ICV infusion every 14 days (preferably in the morning) according to the participant’s age. Participants younger than 2 years started the study at the dose level appropriate for their age and transitioned to the dose level consistent with their age as they matured, as indicated in the table below.

  Age
  Dose
  Rate
  Infusion
  Time

  birth to < 6 months
  100 mg
  2.5 mL/hr
  1.3 hours (±0.5 hr)
  6 months to < 1 year
  150 mg
  2.5 mL/hr
  2 hours (±0.5 hr)
  1 year to < 2 years
  200 mg (first 4 doses)
  300 mg (subsequent doses)
  2.5 mL/hr
  2.5 mL/hr
  2.7 hours (±1 hr)
  4 hours (±1 hr)
  ≥2 years
  300 mg
  2.5 mL/hr
  4 hours (±1 hr)

  The 300 mg infusion was administered over 4 (± 1) hours at a rate of 2.5 mL/hr. Participants not receiving the full 300 mg dose (administered in a total volume of 10 mL) were to receive the appropriate volume at a rate of 2.5 mL/hr for over a shorter duration of time.
  Dosing could be adapted in the judgement of the investigator (and in consultation with the medical monitor) to manage AEs as outlined in the table above. Should the dose-limiting AE resolve in the opinion of the investigator, the dosing at the full specified dose could resume.
  In participants younger than 2 years, dosing could also be adjusted by the sponsor in consultation with the investigator and medical monitor based on results from PK analysis, as follows:
  • Within a participant, if the observed CSF AUC0-t exceeded the range of CSF AUC0-t characterized with the 300 mg dose in Study 190-201, the dose could be reduced to 50% of the recommended age-appropriate dose.
  • Within a participant, if the observed CSF AUC0-t was less than the range of CSF AUC0-t characterized with the 300 mg dose in Study 190-201, the dose could be increased to the recommended dose for the next oldest age group.

  BMN 190 Batch Numbers Used: L241028, L241030, L241037, L241043, L241058, L241082, L241090, L241096, L241133, L241153, L241184

  Duration of Treatment: Treatment was to continue for at least 144 weeks or until all procedures were completed or the participant discontinued from the study.

  Reference Therapy: Because practical and ethical concerns precluded contemporaneous or untreated control participants, comparisons were made with a historical, non-interventional external control group (Study 190-901), utilizing the data from the DEM-CHILD Multi-Center Clinical NCL Database at the University Medical Center in Hamburg, Germany.

  Criteria for Evaluation:
  Safety:
  • AEs and concomitant medication
  • routine clinical laboratory tests (hematology, chemistry, and urinalysis) • routine CSF surveillance (cell count, protein, glucose, and culture) • vital signs (systolic blood pressure [SBP], diastolic blood pressure [DBP], heart rate, respiration rate, and temperature) • physical examination • neurological examination • electrocardiogram (ECG), 3 or 5-lead, 12-lead • immunogenicity, includes anti-BMN 190 total antibodies (TAb) and neutralizing antibodies (NAb) in CSF; TAb, NAb, total IgE, and drug-specific IgE in serum

  Efficacy:
  • CLN2 clinical rating scale with videotaping: 0 to 12 point total score (motor, language, visions, and seizure subscales) o Change in seizure activity (clinical [0 to 3 point CLN2clinical rating scale, seizure subscale]) • Anti-epileptic treatment • Denver II Development Scale • Modified Unified Batten Disease Rating Scale Involuntary Movement Scale (mUBDRS-Involuntary Movement Scale) • Modified Unified Batten Disease Rating Scale Seizure Scale (mUBDRS-Seizure) • Time to disease manifestation for asymptomatic participants • Assessments of visual acuity

  Imaging:
  • Cranial MRI with measurements of atrophy and apparent diffusion coefficients • Optical coherence tomography (OCT) • Electroencephalogram (EEG)

  Quality of Life (QoL) Assessments:
  • PedsQL: Family Impact and infant/toddler/ young children modules • CLN2 disease-specific QoL • EuroQol Health Status (EQ-5D-5L)

  Pharmacokinetics:
  • Area under concentration-time curve from time 0 to infinity (AUC0-∞) • Area under concentration-time curve from 0 to the time of last measurable concentration (AUC0-t) • Maximum observed concentration (Cmax) • Time to reach Cmax (Tmax) • Elimination half-life (t½) • Clearance (CL) • Volume of distribution (Vz)

  Immunogenicity:
  • TAb and NAb in CSF; TAb, NAb, total IgE, and drug-specific IgE in serum

  Biomarkers:
  • Analysis of disease-related biomarkers from CSF and blood

  Statistical Methods:
  Efficacy:
  The efficacy analyses were based on the ITT population, which included all enrolled participants.
  There were 2 set of efficacy analyses: the Matched Set and the ITT Set. The Matched Set included 190-901 natural history participants (N = 29) matched up to 3-1 with 190-203 ITT participants (N = 12). The Matched Set was presented for the CLN2 scale analyses (M, L, V, S, ML, MLV, MLVS). The ITT Set included the 190-203 ITT population (N = 14) and was presented for all efficacy variables. Efficacy variables were summarized by visit unless otherwise specified.
  The primary efficacy endpoint was the rate of decline in the 0 to 6-point ML score and the primary analysis was based on matching with Study 190-901 patients. The matching was up to 3-1 matching of the Study 190-901 Evaluable population and the Study 190-203 ITT population. 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) Study 190-901 participants were weighted inversely to the number of Study 190-901 participant matched to a given Study 190-203 participant. The weights for 3, 2, and 1 Study 190-901 participants (s) matched to a given Study 190-203 patient were 1/3 ,1/2, and 1 respectively, and the weights were normalized to the number of Study 190-901 participants matched to Study 190-203 participants. Study 190-203 and Study 190-901 patients who were not matched were excluded from matched analyses.
  The MLV score (motor, language, and vision subscales) and MLVS score (motor, language, vision, and seizure subscales) on the CLN2 clinical rating scale, time to disease manifestation (for pre-symptomatic participants), and MRI measures of disease progression were assessed as secondary endpoints.
  Exploratory efficacy measures included:
  • Change in seizure activity (as measured by CLN2 clinical rating scale seizure score) • Quality of life assessments:
  o PedsQL Parent Report of Infants (1-12 Months) o PedsQL Parent Report of Infants (13-24 Months) o PedsQL - Parent Report for Toddlers (2-4 years) o PedsQL - Parent Family Impact Module o PedsQL Parent Report of Young Children (5-7 years) o PedsQL Child Report for Young Children (5-7 years) Self-report o CLN2 Disease-Specific QoL o Infant Toddler Quality of Life Questionnaire (ITQOL) (discontinued 17 December 2018 with implementation of Protocol Amendment 5) o EQ-5D-5L (discontinued 17 December 2018 with implementation of Protocol Amendment 5) • Denver II Developmental Scale • Modified Unified Batten Disease Rating Scale Involuntary Movement Scale (mUBDRS-Movement Scale) • Modified Unified Batten Disease Rating Scale Seizure Inventory (mUBDRS-Seizure Scale) • Retinal Anatomy using Optical Coherence Tomography (OCT) • Ophthalmologic Assessment • Visual Acuity Measures • CLN2 Vision Scale (V) Score • CLN2 Seizure Scale (S) Score • Anti-epileptic treatment • CSF/Blood Biomarkers • Electroencephalogram (EEG) Subgroup analyses were performed for the primary efficacy analyses (the baseline ML=6 and baseline ML < 6 subgroups). ML score and MRI parameters were summarized by visit for the age groups (< 2, < 3, and ≥3 years), similar to the overall population analysis.
  Pharmacokinetics:
  The PK analyses for Study 190-203 are detailed in the 190-203 final clinical pharmacology analysis plan (CPAP). The following parameters were evaluated by non-compartmental analysis in CSF and plasma:
  • Area under concentration-time curve from time 0 to infinity (AUC0-∞) • Area under concentration-time curve from 0 to the time of last measurable concentration (AUC0-t) • Maximum observed concentration (Cmax) • Time to reach Cmax (Tmax) • Elimination half-life (t½) • Clearance (CL) • Volume of distribution (Vz)

  Safety:
  Safety and tolerability assessments were performed at study baseline and every 2 weeks thereafter. Safety was assessed by examination of AEs (including serious adverse events [SAEs], hypersensitivity AEs, infusion-associated reactions, and AEs of special interest), clinical laboratory results (including chemistry, hematology, urinalysis, and CSF), vital signs, ECGs, EEGs, and immunogenicity.
  Safety variables were summarized descriptively. No formal inference was conducted. Descriptive summaries of safety data were provided by age category (specified below) as well as for the total safety population (N = 14):
  • Baseline age < 2 years
  • Baseline age < 3 years
  • Baseline age ≥ 3 years

  Immunogenicity:
  Immunogenicity assessments were performed at study baseline and every 12 weeks thereafter. Incidence and titer summary statistics were provided for serum TAb, CSF TAb, serum NAb, and CSF NAb in table format and included mean, median, standard deviation, and minimum/ maximum titer values at each study visit. Immunogenicity was summarized by visit as well as by change at study timepoint from baseline. Potential impact of anti-drug antibodies (ADA) on efficacy and safety was explored.
  In the event of serious or severe (≥Grade 3) hypersensitivity AE, a blood sample was to be collected no sooner than 8 hours after the event (or before the next infusion) for drug-specific IgE testing. Potential associations between immunogenicity results and hypersensitivity AEs were analyzed.

  Determination of Sample size:
  Sample size was determined on the basis of clinical judgment. Statistical power was not a consideration.

  Summary of Results:
  Participant Population:
  A total of 14 participants were enrolled in 190-203 and dosed with BMN 190, and 13 participants completed the study. One participant discontinued prematurely from the study due to the participant choosing to receive Brineura (BMN 190) commercially in their home country.
  The mean (SD) length of time on study was 171.6 (7.12) weeks. The mean (SD) length of time on study drug was 140.4 (5.96) weeks. Administration of drug during the 24-week safety follow-up period was not regarded as study drug.
  The study population included 8 females and 6 males. All participants were white. The mean (SD) age at enrollment was 3.0 (1.46) years (range 0.9 – 5.9 years), including 5 participants < 2 years of age, 3 participants 2 to < 3 years of age, and 6 participants ≥ 3 years of age.

  Efficacy:
  The Study 190-203 final efficacy results comprise over 3 years of treatment with BMN 190 in a population of 14 participants with CLN2 disease, including 8 participants < 3 years of age and 5 participants < 2 years of age at treatment initiation. The 14 participants in Study 190-203 were assessed on the CLN2 scales for a mean (SD) duration of 166 (5.9) weeks (range 146 – 170 weeks).
  The 190-203 study included a significant proportion of participants (7 participants, 50%) who started with age-appropriate normal ML scores of 6 points. In the 190-901 evaluable population (natural history patients), the first decline in the mean CLN2 clinical rating scale ML score occurs just after the third birthday, consistent with published literature (Nickel 2018). The efficacy analysis includes summary statistics of a population in which children older than 3 are expected to rapidly decline, and those less than 3 in which there is a predicted prodromal period before ML decline. Where possible, each 190-203 participant was matched to up to 3 unique 190-901 natural history comparators on the basis of age, CLN2 ML score and pooled genotype to allow comparative analysis.
  Twelve of 14 participants from 190-203 met criteria for matching with 29 evaluable 190 901 participants. At Baseline, the mean (SD) ML scale score was 5.0 (1.41) points in the matched ITT population and 5.0 (1.38) points in the matched 190-901 evaluable population. Two participants who did not match with any 190-901 participants on the ML score matching criteria had stable ML scores for the duration of BMN 190 treatment.
  In the primary endpoint analysis, rate of decline per 48 weeks in the 0 to 6-point ML score, there was a statistically significant attenuation of the rate of decline on the ML scale for the matched 190-203 ITT participants when compared with the rate of decline in untreated 190-901 evaluable participants, as demonstrated by a mean difference between groups (901-203) of 1.15 points (SE 0.174); 95% CI, 0.80, 1.50 points; p < 0.0001. These results show a significant treatment benefit for participants treated with BMN 190 compared with matched natural history participants.
  A supportive analysis of the primary endpoint, the Cox proportional hazards model of time to unreversed 2-point decline or score of 0 in ML score, demonstrated a statistically significant difference in matched 190-203 ITT participants as compared to matched 190-901 participants (hazard ratio, 0.091; 95% CI, 0.021 to 0.393; p < 0.0001). The 190-203 ITT participants were an estimated 11 times less likely to experience an unreversed 2-point decline or score of 0 in ML score than 190-901 evaluable participants.
  In the 190-203 ITT population, 10 of 14 participants (71.4%) showed no clinical progression on the ML scale from baseline to last assessment. One participant (7.1%) showed an overall 1-point improvement. Two participants (14.3%) lost a single point and 2 participants (14.3%) lost 2 points. In total, 12 of 14 (85.7%) treated participants in Study 190-203 had less than a 2-point decline.
  The observed trend for the majority of treated participants was stability of ML scores compared with matched 190-901 evaluable participants. Individual ML scores plotted for all 12 matched ITT participants from 190-203 had at least one Study 190-901 match with greater decline in ML score and no 190-901 match with less decline in ML score. Ten matched 190 203 participants had better performances than all of their 190-901 matches (24). Two 190-203 participants each had one 190-901 match who had a similar performance. These results demonstrate that all 12 matched participants from 190 203 benefited from treatment with BMN 190. The treatment effect was also durable over approximately 3 years of dosing.
  Subgroup analyses of the primary efficacy endpoint were performed in participants in Study 190-203 with ML score < 6 points and ML score = 6 and in age subgroups (< 2, < 3, ≥ 3 years), all with 190-901 matching.
  For participants with ML score < 6 points, the mean (SD) rate of decline in ML score was 0.33 (0.331) points per 48 weeks for matched 190-203 participants (N = 5) and 1.91 (1.072) points per 48 weeks for matched 190-901 participants (N = 11). The mean (SE) for the difference between treatments (901 –203) was 1.58 (0.355) points and the 95% CI was 0.81 to 2.35 points. Thus, for participants with active ML decline at baseline, there was a treatment benefit consistent with pivotal study, 190-201, in which participants had a baseline mean (SD) age of 5.0 (1.29) years (range: 3.3 to 9 years).
  For participants with ML score = 6 points, the mean (SD) rate of decline in ML score was 0.00 (0.000) points per 48 weeks for matched 190-203 participants (N = 7) and 0.76 (0.674) points per 48 weeks for matched 190-901 participants (N = 18). The mean (SE) for the difference between treatments (901 – 203) was 0.76 (0.159) points and the 95% CI was 0.42 to 1.09 points. No sustained decline was observed in study participants with baseline ML score of 6, whereas matched comparators had aggregate loss of function in the observed study period.
  The enrolled population consisted of 6 participants who were ≥ 3 years old; and 8 participants who were < 3 years old at baseline, 5 of which were < 2 years old at baseline.
  In participants ≥ 3 years of age, the mean (SD) rate of decline in ML score was 1.72 (1.222) points per 48 weeks for matched 190-901 participants (N = 9) and 0.38 (0.298) points per 48 weeks for matched 190-203 participants (N = 4). This mean difference of 1.34 points (901-203) was statistically significant (p= 0.0097).
  In participants < 3 years of age, the mean (SD) rate of decline in ML score was 1.09 (0.562) points per 48 weeks for matched 190-901 participants (N = 20) and 0.04 (0.101) points per 48 weeks for matched 190-203 participants (N = 8). This mean difference of 1.05 points (901-203) was statistically significant (p< 0.0001).
  In participants < 2 years of age, the mean (SD) rate of decline in ML score was 0.88 (0.574) points per 48 weeks for matched 190-901 evaluable participants (N = 13) and 0.00 (0.000) points per 48 weeks for matched 190-203 ITT participants (N = 5). This mean difference of 0.88 points (201-203) was statistically significant (p = 0.0002).
  Participants treated at baseline age < 3 years retained ML scores in the age range 4 – 6 years that exceeded ML scores of the participants with baseline age ≥ 3 years at ages 4 – 6 years. The treatment effect was larger for participants < 3 years of age than participants ≥ 3 years of age, with the most pronounced treatments effect observed in participants < 2 years of age.
  The greatest treatment effect on ML rate of decline was seen in participants ≥ 3 years as evidenced by the largest difference between natural history and treated participants. Although the largest treatment effect was seen in these older participants, participants < 2 years did not experience any ML decline and had ML scores of 6 points in the age range of 4-6 years while participants enrolling at age ≥ 3 years had ML scores < 6 points in the age range 4-6 years.
  The 7 pre-symptomatic participants (50%) in the 190-203 ITT population had ML scores of 6 points and MLVS scores of 12 points at baseline. An analysis of time to disease manifestation in these participants demonstrated that treated participants were less likely to decline on the MLVS scale than their 190-901 matches. The Cox proportional hazards model of time to disease manifestation demonstrated a 5-fold reduction in the likelihood of consecutive M / L / V / S score decline from 3 points in comparison with 190-901 evaluable participants (hazard ratio, 0.209; 95% CI, 0.059 to 0.735; p = 0.0081). At Week 145, all 18 participants from 190-901 with baseline MLVS = 12 had declined on the MLVS scale vs. 4 of 7 (43%) of participants in 190-203. Median (95% CI) time to disease manifestation was 67 (34, 94) weeks in 190-901 participants vs not reached in 190-203 participants.
  Evidence of efficacy was also demonstrated in aggregate scores using seizure and vision subscales (MLV and MLVS), in which there was marked attenuation of decline compared to matched natural history participants.
  MRI Findings:
  MRI volumetry from baseline to last assessment showed a 10.3% decrease in total cortical gray matter, with a stable white matter and CSF volume. The volume loss occurred in participants with score < 6points; and in the first 48 weeks of therapy, after which the MRI measurement remained stable during the study period. It is well described that CLN2 disease is a neurodegenerative disease with progressive supra and infratentorial volume loss and ventriculomegaly (Löbel 2016). This volume loss continues to occur even past when patients have lost all function. Overall, the small MRI measurement changes occurred within the first 48 weeks of treatment and remained stable during the rest of the study period. Pharmacokinetic/ Pharmacodynamic Conclusions:
  Overall, the PK and PK/PD results support the doses administered in this study, including the doses administered to participants < 3 years of age. CSF exposure was generally within the range characterized to be safe and effective in Study 190-201, and the exposure/response relationships with efficacy endpoints suggests the obtained exposure is on the plateau of the exposure/response curve. Plasma exposure in younger participants exceeded the range characterized in 190-201, however, the exposure/response analyses with common drug-related AEs did not indicate any significant correlations and the greater plasma exposure was not associated with changes in the safety profile of BMN 190.
  Extent of Exposure: All 14 participants enrolled in 190-203 had exposure to study drug. Mean (SD) BMN 190 exposure was 140.4 weeks (range 119.7 - 142.6 weeks) for all doses and 138.0 (6.80) weeks for the 300 mg dose (range: 119.7 - 142.6 weeks). The 5 participants < 2 years of age received 200 mg BMN 190 for a mean (SD) of 6.9 (5.15) weeks (range: 1.9 – 14.4 weeks) before escalating to the 300 mg dose.
  A total of 988 infusions were administered over the entire Study 190-203 dosing period. The mean (SD) number of infusions per participant at any dose was 70.6 (2.98).
  Four participants (28%) missed a total of 9 (2 COVID-19 related, 7 AE related) planned infusions during the entire dosing period: 1 participant (7%) missed 1 infusion, 1 participant (7%) missed 2 infusions, and 2 participants (14%) each missed 3 infusions.
  Of the planned infusions, 5 participants (36%) had a total of 28 infusions interrupted. Three participants (21%) had more than 1 interrupted infusion, including 1 participant with 2 interruptions and 1 participant with 8 interruptions. Three participants (21%) had 1 incomplete infusion.
  Safety:
  Overall, the data from 190-203 demonstrate that BMN 190 at a dose of 300 mg administered every 14 days by ICV infusion for a mean duration of 138.0 weeks (range 119.7 – 142.6 weeks) was generally well tolerated and had an acceptable safety profile in this population of 14 pediatric participants with CLN2 disease, including 8 participants < 3 years of age and 5 participants < 2 years of age (included in < 3 years of age subgroup). The 5 participants < 2 years of age received 200 mg BMN 190 for a mean (SD) of 6.9 (5.15) weeks (range: 1.9 – 14.4 weeks) before escalating to the 300 mg dose.
  • Adverse events (AEs) were manageable and did not lead to study drug discontinuation.
  • There were no deaths.
  • One event of Grade 3 anaphylactic reaction was reported in association with BMN 190 infusion. This anaphylactic reaction was characterized by tachycardia, bronchospasm, diarrhea, rash, and hypotension, resulted in interruption of the participant’s BMN 190 infusion and was reported as recovered/resolved after 2 days. The participant continued on BMN 190 treatment and tolerated subsequent doses without recurrence. This was the first event of anaphylactic reaction reported for BMN 190. Anaphylactic reaction was included with hypersensitivity reaction as an important identified risk in the RMP and product labeling.
  • The most common incidences of treatment-emergent AEs in the overall safety population (N = 14) were pyrexia (12 participants; 85.7%), upper respiratory tract infection (12 participants; 85.7%), extensor plantar response (7 participants; 50.0%), gastroenteritis (7 participants; 50.0%), and generalized tonic-clonic seizure (6 participants; 42.9%).
  • Most AEs were mild or moderate in severity (Grade 1 or 2). Ten participants experienced eighteen Grade 3 AEs. One participant had a Grade 4 AE of gastrointestinal fistula that was determined not to be related to BMN 190. Overall, there was no substantial difference in the incidence and event rates for severity of AEs between age subgroups (< 2, < 3, ≥ 3 years).
  • A total of 53 study drug-related AEs were reported in 11 participants (78.6%). The most commonly reported drug-related AEs were pyrexia, hypersensitivity, and body temperature increased. Out of 53 drug-related AEs, AE onset age was ≥ 3 years for 33 events and < 3 years for 20 events. No substantial difference was identified in the event rate based on AE onset age.
  • A total of 36 hypersensitivity events were reported in 10 (71.4 %) participants. Upon further medical review, it was identified that out of 36 events, 21 events assessed as related to BMN 190 were hypersensitivity reactions to study drug. The other hypersensitivity events not related to BMN 190 had alternative etiological factors. Out of these 21 hypersensitivity reactions, 20 events were hypersensitivity (PT) and 1 event was anaphylactic reaction. Hypersensitivity reactions were reported in 4 of 8 (50%) participants < 3 years of age as compared with no incidences in participants ≥ 3 years of age. Out of 21 related hypersensitivity events, AE onset age was < 3 years for 16 events and ≥ 3 years of age for 5 events. The AE onset age of both the Grade 3 events was less than 3 years (AE onset age of Grade 3 hypersensitivity event was 2.6 years and AE onset age of Grade 3 anaphylactic reaction was 1.1 years). Updates to the product labeling and RMP are being proposed to mention this information of hypersensitivity reaction from the 190-203 study. Considering the benefit-risk profile of BMN 190 in CLN2 disease, no significant safety concerns were identified for administration of BMN 190 in patients < 3 years of age. The current product label provides information and recommendations to minimize the risk of hypersensitivity reactions including anaphylaxis.
  • Participants with higher mean serum TAb titers reported hypersensitivity AEs of similar incidence and severity as participants with lower mean serum TAb titers. No drug-specific IgE positivity was detected in participants receiving BMN 190.
  • A total of 41 SAEs were reported in 12 participants in Study 190-203. Nine participants experienced 17 SAEs that were ≥ Grade 3 in severity. The SAEs reported more than once included pyrexia (7 SAEs in 4 participants), influenza (3 SAEs in 2 participants), pneumonia (3 SAEs in 1 participant), hypersensitivity (2 SAEs in 2 participants), adenoidal hypertrophy (2 SAEs in 2 participants), and dental caries (2 SAEs in 1 participant). A total of 10 SAEs in 7 participants were considered related to study drug, including 7 events of pyrexia in 4 participants, 2 events of hypersensitivity in 2 participants, and 1 event of anaphylactic reaction in 1 participant. An event of atrioventricular block second degree was assessed as non-serious by the investigator but was later upgraded to serious by BioMarin. The investigator assessed the event as not related to BMN 190; however, due to absence of alternative etiological factors and strong temporal relationship, BioMarin conservatively assessed the event possibly related to BMN 190. This event was considered a SUSAR. There was no substantial difference in the incidence and severity of SAEs between age subgroups (< 2, < 3, ≥ 3 years).
  • The most common TREs were pyrexia (30 events in 10 participants), hypersensitivity (20 events in 4 participants), partial seizures (6 events in 2 participants), and body temperature increased (4 events in 1 participant). Most TREs were mild to moderate in severity (CTCAE Grade 1 to 2). Four participants (28.6%) had a ≥ Grade 3 TRE. Grade 3 TREs included 1 event each of Escherichia urinary tract infection, status epilepticus, hypersensitivity, and anaphylactic reaction. All 4 of these events were also SAEs, and the events of hypersensitivity and anaphylactic reaction were SAEs considered related to study drug. There was no substantial difference in the incidence of TREs between age subgroups (< 2, < 3, ≥ 3 years).
  • Five participants experienced 9 device-related AEs. The most common device-related event was device leakage (4 events in 3 participants). Additional device-related events reported once each included propionibacterium test positive, device breakage, needle issue, headache, and medical device site irritation. There were 3 device-related SAEs in 3 participants, including single events of Grade 3 Propionibacterium test positive, Grade 2 device leakage (described as leak of CSF from ICV device), and Grade 2 medical device site irritation. There was no substantial difference in the incidence and severity of device-related AEs between age subgroups (< 2, < 3, ≥ 3 years). There were no ICV malfunctions or AEs leading to the removal and return of an ICV device.
  • Overall, 8 (57.1 %) participants experienced 74 AEs of convulsions. The most common convulsion AEs included partial seizures, generalized tonic-clonic seizure, and seizure. All convulsion AEs were Grade 1 or 2 in severity, with the exception of the Grade 3 event of status epilepticus. One participant experienced a single Grade 3 SAE of status epilepticus assessed by the investigator as not related to BMN 190. All convulsion events were assessed by the investigator as not related to BMN 190. Given that seizures are a common manifestation of CLN2 disease, the overall number of events is not surprising. There was no substantial difference in the incidence and severity of convulsion AEs between age subgroups (< 2, < 3, ≥ 3 years).
  • Three participants experienced 4 cardiovascular AEs, including hematoma in 1 participant, atrioventricular block in 1 participant, and hypertension and electrocardiogram abnormal in 1 participant. The event of Grade 1 atrioventricular block second degree was assessed as non-serious and not related to BMN 190 by investigator, but the event was assessed as serious and possibly related to BMN 190 by BioMarin. This event was considered a SUSAR. There was no difference in the cardiovascular events based on AE onset age.
  • No events of meningitis, hydrocephalus, or unexplained declines in ML scale performance were reported.
  • Upon the review of all clinical laboratory results (including chemistry, hematology, urinalysis, and CSF), vital signs, ECGs, and EEGs, no new safety concerns were identified.
  Immunogenicity: Anti-drug antibodies (ADA) or TAb were detected in the serum and CSF of 14/14 (100%) and 3/14 (21%) participants, respectively, by end of study. Neutralizing antibodies (NAb) were detected in serum and CSF of 6/14 (43%) and 0/14 (0%) participants, respectively.
  No drug-specific IgE positivity has been detected thus far in participants receiving BMN 190. Participants with higher mean serum TAb titers reported hypersensitivity AEs of similar incidence and severity as participants with lower mean serum TAb titers.
  No association was found between CSF ADA status and treatment outcome as measured by the ML scale. Since none of the CSF TAb positive participants developed a NAb response, there was no detectable impact of CSF NAb on treatment outcome. In CSF or serum ADA positive participants, higher mean TAb/ NAb titers were not associated with poorer treatment outcomes.
  The immunogenicity profile of BMN 190 in the study was consistent with and supportive of the positive benefit-risk profile of BMN 190 in this pediatric patient population with CLN2 disease.
  Conclusions: In conclusion, the results of this Phase 2 study demonstrated that BMN 190 at a dose of 300 mg administered every 14 days by ICV infusion for a mean duration of 138.0 weeks (range 119.7 – 142.6 weeks) was generally well tolerated and had an acceptable safety profile in this population of 14 pediatric participants with CLN2 disease, including 8 participants < 3 years of age (of which 5 were < 2 years of age). The reported AEs were consistent with the known safety profile of BMN 190, the participants’ underlying disease or concurrent conditions, and side effects of concomitant medications.
  BMN 190 attenuated disease progression in symptomatic participants, and in the pre-symptomatic participants, it delayed disease onset. Efficacy was durable over > 3 years of BMN 190 treatment. The primary efficacy analysis comparing Study 190-203 participants with matched natural history participants demonstrated a statistically significant attenuation of disease progression in BMN 190 treated participants, with a difference in mean ML slope (CI) of 1.15 (0.80, 1.50) points and a hazard ratio (CI) of 0.091 (95% CI, 0.021 to 0.393); p < 0.0001 for the event of an unreversed ML 2-point decline or score of 0. In addition, there are preliminary findings that early treatment, especially < 2 years of age may delay disease onset.
  The 190-203 clinical trial data provide additional evidence to support the positive benefit-risk profile of BMN 190 in CLN2 disease.

• REC name

  East of England - Cambridge South Research Ethics Committee

• REC reference

  17/EE/0301

• Date of REC Opinion

  5 Sep 2017

• REC opinion

  Further Information Favourable Opinion