(continued) - Added: If pregnancy occurs at any time during the Crossover Period in which the subject receives NaPBA (Section 7.1.8) - Added: The use of corticosteroids, valproic acid, or haloperidol may increase plasma ammonia level. Therefore, ammonia levels should be monitored closely, as deemed appropriate by the Investigator, if the subject is on one of these medications. Probenecid may inhibit the renal excretion of metabolites of RAVICTI, including PAGN and PAA, and therefore this potential should be considered when assessing PK results. - Added: NaPBA is contraindicated for use during pregnancy. Therefore, if a subject is pregnant at any time during the Crossover Period in which they receive NaPBA, the subject must be withdrawn from the study - Deleted: The Clinical Global Impression - Efficacy Index is a 4 point rating scale that assesses the therapeutic effect of the treatment by the Investigator and subject as: • 1 unchanged to worse • 2 minimal effect • 3 moderate effect • 4 marked effect And the side effects rated by the Investigator and subject as: • None • Some but do not significantly interfere with patient's functioning • Significantly interferes with patient's functioning and outweighs therapeutic effect - Deleted: 1Assess compliance and/or method of drug administration if the following below range U-PAGN concentrations from morning spot urine samples are observed, based on patient’s body surface area (BSA) - Updated SCHEDULE OF ASSESSMENTS

Added: - Treatment options for subjects following completion of the Protocol: European Sites: After completion of the Safety Extension, subjects at European sites will be given the option to consent and enroll in a long term study and receive study drug until it becomes commercially available in European countries. US Sites (as applicable): After completion of the Safety Extension and at the discretion of the Investigator, subjects at US sites may, if eligible, receive RAVICTI using commercial supply. Added: - 8-hour amino acid sampling at Hour 0 (pre-dose) and Hour 8 (post-dose) - For subjects taking NaBz at study entry who had NaBz treatment withdrawn during Crossover Period 1, the NaBz treatment may be resumed during the Safety Extension Period at the discretion of the Investigator. The dose of NaBz cannot be greater than the equivalent dose of RAVICTI. Please see protocol Section 5.2.2.1 for dose equivalents of RAVICTI. Added: - All females of childbearing potential and all sexually active males must agree to use an acceptable method of contraception throughout the study. Appropriate contraceptive methods include hormonal contraceptives (oral, injected, implanted, or transdermal), tubal ligation, intrauterine device, hysterectomy, vasectomy, or double barrier methods. Abstinence is an acceptable form of birth control, though appropriate contraception must be used if the subject becomes sexually active. Edited: - Subject has received chronic treatment with RAVICTI® (glycerol phenylbutyrate) Oral Liquid or NaPBA longer than 14 days before within one year prior to enrollment o Temporary use of NaPBA for acute management of a hyperammonemic crisis in the past is acceptable. Added: - Pregnant or breast-feeding patients. Women of childbearing potential must have a pregnancy test performed at the Baseline Visit prior to the start of study drug.

(continued) - Added: Only at Baseline Visit (for subjects on NaBz only), Day 7 and 14, eight (8)-hour amino acid panel testing will occur at the following timepoints: Hour 0 (just before the first main meal after an overnight fasting or after 4-6 hours without high calorie and protein intake: i.e., 08:00 [8:00 am]); Hour 8 (~2–4 hours after lunch or the after second main meal: i.e. ~16:00 [4:00 pm] - Deleted: The Clinical Global Impression - Efficacy (CGI-E) Index is a 4 point rating scale that assesses the therapeutic effect of the treatment by the investigator and subject. - Deleted: • Rate of adverse events • Drug discontinuation due to adverse events • Subject preference for Study drug after completing Crossover Period 2 (Day14) • Palatability of Study drug (Hedonic Scale) - Deleted: • Changes in clinical global impression (CGI) scales (Investigator and Patient) • Rate of adverse events • Drug discontinuation due to adverse events • Neuropsychological assessments: Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL)/Adult Self Report (ASR) • EQ-5D-5L health status quality of life assessment - Deleted: • Drug preference - Added: • Subject preference for study drug after completing Crossover Period 2 (Day 14) • Palatability of study drug (Hedonic Scale) • Changes in clinical global impression (CGI) scales (Investigator and Patient) • Neuropsychological assessments: Child Behavior Checklist (CBCL) or Adult Behavior Checklist (ABCL) or Adult Self Report (ASR) • EQ-5D-5L health status quality of life assessment - Deleted: Based on analysis of all available data from clinical trials of RAVICTI using the lower 25 percentile as a cutoff, the Investigator should assess compliance and/or effectiveness of drug administration if the U-PAGN concentration is <8300 µg/mL for patients whose body surface area is at or less than 1.3 m2 and <5200 µg/mL if the BSA is greater than 1.3.

- Updates the sponsor from Hyperion Therapeutics to Horizon Therapeutics - Updates the names and contact information to reflect Horizon's responsible study personnel -Clarifies that adequate contraception methods must be used from the signing of informed consent until 30 days after the last dose of study drug - Adds known hypersensitivity to PBA or any of the excipients of the NaPBA/PBA formulations to the exclusion criteria - Adds an optional Long-Term Safety Extension (LTE) period to allow European subjects the option t remain on RAVICTI until it is available commercially - Provides additional details concerning the LTE period and adds the assessments for this period to the schedule of assessments in Appendix A - Adds the criteria for premature termination or suspension of the study - Clarifies that adverse events will be collected from the time of signing of the informed consent - Clarifies the sponsor's responsibility with regard to reporting SAEs/SUSARs in accordance with the European Directive 2001/20/EC

- Updates all sections related o the optional LTE to define it as a one year period of continued dosing for the purpose of ongoing collection of safety data for subjects who continue to derive benefit as determined by the investigator - Removes all references to the use of flavors with RAVICTI - Corrects minor typographical and formatting errors

- Changes the design for the initial dosing period from a crossover to a parallel arm - Adds information on the EMA approval of RAVICTI - Replaces Crossover Periods 1 and 2 with a single parallel arm Initial Treatment Period (4 weeks) - Adds a RAVICTI only Transition Period (1 week) - Adds a RAVICTI only Maintenance Period (8 weeks) - Changes the duration of the Safety Extension Period to 12 weeks - Removes the Optional Long Term Safety Extension Period - Removes pharmacokinetic (PK) analyses for sodium benzoate (NaBz) - Removes inclusion criterion of weight > 15 Kg - Limits analysis of serum phenylbutyric acid (PBA), phenylacetatic acid (PAA), and (phenylacetylglutamine) PAGN, as well as, urine PAGN to the End of Initial Treatment Period (EITP) visit - Modifies the definition of Treatment Success - Adjusts the PBA starting dose based on disease and treatment status at study entry - Adds a dose adjustment algorithm - Adds a process for product complaints - Changes the entity responsible for receiving SAE reports - Adds the maximum daily dose of study drug to all relevant sections - Adds a contact at 30 days post study to check for SAEs and pregnancy

- Corrects the prior summary of changes to include removal of the inclusion criterion of weight > 15 Kg - Clarifies that “normal” as used in the definition of Treatment Success means < the upper limit of normal (ULN) - Adds collection of plasma and urine for pharmacokinetic (PK) assessments whenever a subject presents at the study center with hyperammonemic crisis (HAC) or potential phenylacetic acid (PAA) toxicity and as feasible when subjects present at other health care facilities - Adds the signs and symptoms of PAA toxicity to section 1.2.1 - Revises the dose adjustment algorithm in section 3.8 to: o Add specificity regarding plasma ammonia > ULN when the subject is asymptomatic o Include the maximum daily doses of study drugs o Provide definitions of terms used in the algorithm - Adds dietary protein adjustment guidelines to section 5.6 and capture of dietary changes to each relevant visit - Corrects typographical and formatting errors

- Revises the inclusion criteria to allow subjects ≥ 2 months of age and older - Updates the age range for measurement of head circumference - Updates the age range for administration of CBCL - Includes a recommendation for step-wise reduction of the dose of phenylbutyric acid (PBA) - Adds stopping rule relating to adverse clinical and laboratory parameters - Adds stopping rule relating to pregnancy - Removes the statement in section 5.7 “The randomisation will be stratified by NaBz use at study entry” - Adds an anticipated dropout rate and rationale for sample size calculations

- Clarifies that NaPBA powder and NaPBA granules are the same product - Adds requirement to collect AST, ALT and total bilirubin at Unscheduled visits throughout the study when subjects experience hyperammonemia, HAC or PAA toxicity and when PK sampling occurs at unscheduled visits due to signs and symptoms of HAC or PAA toxicity - Corrects the prior summary of changes, protocol version 4 to protocol version 5 to include: Removal of the requirement for the subject to complete the Clinical Global Impression scale

- Updated Horizon signature page in line with Horizon internal procedures - Synopsis Study Procedures section, Protocol Sections 3.2.1, 6.1.3, 15.4.2, and Appendix A, Schedule of Assessments, updated to clarify the timing of randomisation ie. Following baseline assessments and confirmation of eligibility, up to and including Initial Treatment Period Day 1, subjects will be randomised - Amino Acid Panel for analysis at study visits has been updated - Treatment Success clarified to include: - specific timepoint (Hour 0) to assess glutamine levels - specific timepoint (Hour 0) to assess amino acids - specific Amino Acids which contribute to Treatment Success are listed: Essential amino acids and branch chain amino acids: threonine, phenylalanine, methionine, lysine, leucine, isoleucine, histidine, valine - Study Endpoints in Protocol Synopsis, Protocol section 2.2 and Protocol section 15.3 have been revised for consistency. - Section 15.4.2 mITT population has been updated per SAP - Updated sponsor contact for SAE reporting - Section 7: Updated SAE reporting process - Section 8: corrected order of priority for blood samples - Administrative Changes as appropriate

- Synopsis Dosage and Regimen Transition Period, Protocol Sections 3.4, 5.2.2.3, 6.1.4: Provides a visit window of 2 days from End of Initial Treatment Period (EITP) visit to assignment to the next study period in order to evaluate ammonia and amino acid results from EITP, for subjects in Treatment Arm 1 - Appendix A, Schedule of Assessments: added footnote #22 to EITP visit

- Administrative changes on pages 1 and 2 of this protocol document - Protocol Section 1, Prior studies with RAVICTI text replaced with the Benefit Risk Analysis from the EU PBRER (DL31Jan2019) section 18.2 - Protocol list of abbreviations, VHP removed - Synopsis, Protocol Section 3.3, 5.2.2.1: Clarifies the requirement to assign the initial dose of study drug according to the disease/treatment status on entry as set out in protocol section 3.3 - Synopsis, Protocol Section 15.1: Reduces the Number of Subjects to 18 - Protocol section 15.4: Removes age range for sub-groups, these will be defined in the Statistical Analysis Plan. - Synopsis, Protocol Section 4.1, 6, 9, 15.4, Reduces age at entry to Birth

- Administrative changes on pages 1, 2, 4 of this protocol document - Section 7.1.5.1. Added the fax and email address for reporting SAE

- Synopsis: Number of Subjects, Study Rationale: Updated to: 16 subjects - Synopsis; Sample Size and Statistical Considerations and Protocol Section 15.1: A sample size of 16 subjects rather than 18 will be enrolled. Approximately 12 subjects will complete the study - Administrative changes on pages 1, 2, 3, 4 - Protocol Section 15.2 Interim Analysis: updated to read: There will be no formal interim analysis. - Protocol Section 20: References; Lee 2015, corrected to Lee 2014