Implemented following agreed measures from modified BMN 190 paediatric investigation plan as set out in European Medicines Agency decision(P/0248/2016)dated 05 September 2016. This global protocol amendment superseded the previously implemented original & US-specific versions of protocol: o Added secondary study objective to assess serial CSF & plasma PK on Day 1,& Weeks 25, 49, & 97 to characterize the PK profile at the recommended doses o Added secondary study objective to assess time to disease manifestation for asymptomatic participants to better characterize the development of symptoms not captured by change in the CLN2 ML scale o Per Agency request, removed inclusion criterion requiring the participant to have at least 1 sibling with confirmed CLN2 disease who was enrolled in Study 190-201 o Added inclusion criterion requiring abstinence or a highly effective method of contraception while participating in the study & until 6 months after the study has been completed(or withdrawal from the study) o Modified BMN 190 dosing plan from 300mg administered every 14 days(+/-3 days)to dosing every 14 days (+/-3 days) according to the participant’s age: ▪ birth to <6 months:100mg ▪ 6 months to <1 year:150mg ▪ 1 year to <2 years:200mg(first 4 doses),300 mg(subsequent doses) ▪ >=2 years:300mg This change was implemented in order to describe dosing for participants who may be enrolled & are younger than 2 years of age o Changed timing of Hamburg CLN2 disease rating scale administration from once every 12 weeks to once every 4 weeks in order to have more frequent assessments of clinical function; the complete Hamburg CLN2 scale(motor, language, vision, & seizure subscales)will be administered for each assessment. Rating scale assessments will be videotaped every 12 weeks o Added follow-up plan that all participants will be offered participation in a follow-up registry that will assess long-term safety & efficacy of BMN 190 for patients receiving commercial drug

o Clarified that vital signs (SBP, DBP, heart rate, respiration rate, and temperature) will be measured within 30 (±5) minutes before infusion start (or restart), every 30 (±5 minutes) during infusion, 0.5 hours (±5 minutes), 1 hour (±5 minutes), and 4 hours (±15 minutes) after infusion end, and then every 4 hours (±15 minutes) for the next 16 hours. o In order to collect more accurate blood pressure measurements, added that blood pressure will be measured in the upper arm using an appropriately sized blood pressure cuff. If the participant’s blood pressure is abnormal (as compared to site-specific reference ranges), a manual blood pressure will be obtained by a trained healthcare professional. o Added that in participants with present or past bradycardia, conduction disorders, or with structural heart disease, an ECG (12-lead) (heart rate, rhythm, intervals, axis, conduction defects, and anatomic abnormalities) will be performed within 30 minutes before the start of infusion (±5 minutes), at 2 hours (±15 minutes) during infusion, within 15 (±5) minutes after infusion end, and 12 hours (±3 hours) after infusion end for each study drug administration. o Clarified that a standard ECG (12-lead) will be performed at the first infusion and every 24 weeks thereafter within 15 (±5) minutes after infusion end. o Added cardiovascular and ECG adverse events as AESI that require reporting to BioMarin Pharmacovigilance (BPV), irrespective of severity, seriousness, or causality within 24 hours of a study site awareness. o Clarified that in the event that the ICV device is replaced, the next infusion will occur at least 14 days and no more than 28 days after surgery. o Added dose selection rationale supporting the uniform infusion rate of 2.5 mL/hour for all participants, thus requiring shorter total infusion times for participants administered doses lower than 300 mg.

Implemented Regulatory Agency recommendation to increase ECG monitoring to further characterize possible acute cardiac effects of BMN 190; and to enroll at least 5 participants < 2 years of age. Significant changes were as follows: o For the first infusion of BMN 190, continuous ECG monitoring (3- or 5-lead) will be performed for all participants. The ECG should begin 15 (± 5) minutes prior to infusion start, continue through infusion of BMN 190, and end after infusion of flushing solution. In the event that the participant has already received the first infusion of BMN 190, the next infusion will be monitored as above. If a 12-lead ECG is required during this time, continuous monitoring should be interrupted in order to obtain the 12-lead ECG. o Revised 12-lead ECG assessment to occur 30 (± 5) minutes after infusion end for all participants to provide adequate time for the infusion of flushing solution and completion of telemetry prior to the 12-lead ECG assessment. o Added requirement that at least 5 participants < 2 years of age are enrolled. o Added requirement that all removed or replaced implantable ICV devices must be returned to BioMarin in order to evaluate the material integrity of the reservoir, and any other devices (as defined in the protocol) should also be returned.

Extended the study duration from 96 to 144 weeks and clarified study procedures during the extended study duration. Significant changes were as follows: o Modified the study duration to 144 weeks globally. The 48-week increase in treatment was implemented to increase the power of the study to show a treatment benefit for the study drug and to obtain additional safety data. o Revised Schedule of Events to indicate study procedures that will be performed from Week 96 to 144. o Frequency of complete physical examination changed from every 24 weeks to every 48 weeks to decrease burden to the participants. The frequency of the brief physical exam remains unchanged (every 2 weeks). o Updates were made to the immunogenicity assessment section to include serum neutralizing antibodies (Nab) sample collection. This change was made in response to Regulatory Agency request to evaluate the presence of neutralizing antibodies to BMN 190 in serum. No changes are being made to the frequency or schedule of assessments.

o Added clarification that for participants who do not participate in an extension study or registry after last dose of study drug, 4-week device safety follow-up visit & 6-month safety follow-up visit will capture information regarding ongoing events at the time of last dose or new events related to study drug o Added that central laboratories(or a central reviewer)will be used to evaluate EEG scans in order to standardize review & data presentation, & limit siteassociated variability o Added CLN2 disease rating scale assessment to 4-week device safety follow-up visit & 6-month safety follow-up visit in order to ascertain whether there were any functional changes associated with any reported adverse events o Removed Infant-Toddler Quality of Life Questionnaire in order to decrease study burden & in acknowledgement that other Quality of Life questionnaires administered may be more relevant to this patient population o Removed EQ-5D-5L Questionnaire in order to decrease study burden & in acknowledgement that other Quality of Life questionnaires administered may be more relevant to this patient population o Clarified that EEGs should be performed every 24 weeks, including end of treatment visit o Added updated information that material degradation of ICV device reservoir has occurred after approximately 105 perforations of ICV device in benchtop testing, & has been observed in clinical trials with approximately 4 years of BMN 190 administration. Access device replacement should be considered prior to 4 years of regular administration of BMN 190; with decision made on an individual participant level based on medical judgment of investigator o Assessment of height & body weight has been changed from every 48 weeks to every 24 weeks to permit additional monitoring of growth milestones o Clarified that, in event of a device-related AE where device & its components should be returned to BioMarin for further testing, infusion pump does not need to be returned

Corrected an error in Protocol 190-203 Amendment 5 in which “Ophthalmology Assessments” (Baseline/First Infusion, Q48W, Study Completion/Early Termination) was inadvertently removed from the Schedule of Events (Table 9.1.1) and Study Procedures (Section 12). Ophthalmologic assessments for the 190-203 protocol should continue to be performed before the first infusion and every 48 weeks for the duration of the study.