This amendment included the following major changes: • The system for grading adverse event (AE) severity was changed from Division of Acquired Immunodeficiency Syndrome to NCI CTCAE based on a regulatory request. • Addition of rules for stopping dosing in an individual participant or all study participants.

All changes in country-specific Protocol Amendment 2 were incorporated in this global amendment, with one clarification (see first bullet below). This amendment included the following major changes: • Further clarified the first criterion in the definition of growth failure. • Amended the definition of extreme prematurity from < 32 weeks gestational age at birth to < 36 weeks gestational age at birth. • Added birth weight to the list of demographic information to be collected. • Allowed the dose (mg) of sebelipase alfa to be determined based on a participant's last available weight measurement if weight could not be obtained on the day of the infusion due to the participant's condition. • Allowed for a screening period of < 7 days, to minimise the delay in treatment initiation, which could be important for severe cases. • Allowed for replacement of participants who had received fewer than 4 infusions of sebelipase alfa.

This global amendment included the following: • Clarifications to safety reporting guidelines made to comply with local regulations. • Nonclinical and clinical information for sebelipase alfa was also updated.

This amendment merged study LAL-CL03 with its extension study, LAL-CL05, under a single protocol. Study LAL-CL03 was originally designed as a safety trial with a limited 4-month treatment period. After additional nonclinical chronic toxicology data and extended clinical experience in adults became available, the Sponsor opened LAL-CL05 as an extension study, to permit participants who had been receiving treatment in LAL-CL03 (or under an expanded access program) to continue receiving sebelipase alfa without interruption, and to evaluate the long-term safety and efficacy of sebelipase alfa in these participants, including an analysis of survival. In addition, all changes in country-specific Protocol Amendment 4 and Protocol Amendment 5 were incorporated in this global amendment.

This amendment included the following major changes: • Added the option of a qow dosing schedule for participants who were on treatment for at least 96 weeks and had been on a stable dose for at least 24 weeks. • Modified the definition of suboptimal response to distinguish between early (first 3 months of treatment) and late (beyond 3 months of treatment) suboptimal response -- and added criteria for late suboptimal response. • Added anti-drug antibody (ADA) and tryptase testing in participants who experienced a moderate or severe infusion associated reaction (IAR). • Clarified that continuation of hospitalisation for trial purposes in participants who were already hospitalised at the start of the study due to severity of disease, would not be considered a serious adverse event (SAE).

This amendment was written to allow enrollment of a participant who had not yet met the criteria for growth failure if (a) the investigator has substantial clinical concerns based on evidence of the rapid disease progression requiring urgent medical intervention and (b) the participant had an older (biological) sibling who had a documented rapidly progressive course of LAL Deficiency with growth failure before 6 months of age. This exception was included as a footnote to the growth failure inclusion criterion, and further specified the process the Investigator was to follow to obtain approval for enrollment of such a participant.

This amendment included the following major change: • Modified the language introduced in Amendment 8. Specifically, the footnote to the growth failure inclusion criterion was revised to remove the requirement that the participant have an older (biological) sibling who had a documented rapidly progressive course of LAL Deficiency with growth failure before 6 months of age.

This amendment included the following major changes: • Extended the treatment period for each participant up to maximum of 4 years. • Refined the definition of suboptimal response, and specified that the evaluation of the suboptimal response was done in consultation with the SC. • Added an optional dose increase to 5 mg/kg qw for any participant who had a continued suboptimal response at 3 mg/kg (after at least 4 infusions) in association with the presence of neutralising antibodies. • Added annual magnetic resonance imaging, monthly weights after Week 24, and an optional liver biopsy.

This amendment included the following changes: • Extended dosing period to up to 5 years. • Removed the terminology “suboptimal response” and replaced with criteria for dose escalation. • Added the collection of serum lipid, serum liver, hematology, chemistry, ferritin, and high-sensitivity C-reactive protein labs prior to any dose change and serum lipid and serum liver 4, 8, and 12 weeks following any dose change. • Removed the terminology “total and functional area scores” relating to the Denver II. • Modified safety end points characterizing ADAs to remove reference to immunoglobulin G, seroconversion, and tolerization. • Removed infusion duration time, infusion rate table, and added in the final concentration of the infusion. •Antidrug antibody collection time points were updated from every 24 weeks following Week 24 to every 12 weeks following Week 24. •Revised the text on infusion associated reaction (IAR) management. •Revised the stopping rules to remove stopping rule for an individual participant for grade 1 and 2 IARs, for grade 4 AEs. •Removed specific stopping rule to pause dosing in all participants in the case of 3 or more participants with similar SAEs and in 3 or more participants with recurrent, unmanageable severe or higher IARs.

This amendment included the following minor changes: • Updated to the Sponsor information and SAE Reporting information (updated where to report SAEs, such as phone numbers)