Summary of changes: - Inclusion 5 criterion amended to reflect that the decision to discontinue iron-chelation therapy should not be reliant on the willingness of the patient for pediatric patients aged 6-<18 years. The amendment reflected the need for the principal investigator and the patient’s parents to determine if stopping iron-chelation therapy is appropriate for the patient. - In light of the recent approval of the Paediatric Implementation Plan by the European Medicines Agency, Section 11.1 was amended to add further information on the sample size considerations for the pharmacokinetic cohorts.

Summary of changes: - Based on the FBS0701-CTP-12 data and the need for higher doses to ensure net negative iron balance, the maximum dose was increased to 60mg/kg/day. - New data from study FBS0701-CTP-12 were added to Section 3.3 of the protocol (summary of clinical studies). - Pituitary gland MRI assessments were added. - The frequency of height measurements and complete physical examinations was reduced. -The frequency of complete physical examinations was reduced. - The requirement for an ECG on Day 1 for chronic dosing patients was removed. - Fasting glucose assessments were added at Day 1, Week 24, and Week 48/EOT. - Trough plasma drug concentration measurements were added at Week 12 and Week 24. - The preliminary analysis of data from study FBS0701-CTP-4 in Sections 3.1 (rationale for development) and 3.3 (summary of clinical studies) of the protocol was revised. - Details of the FBS0701-CTP-15 extension protocol were added. - Animal toxicology data and potential risks text in Section 3.4 of the protocol (potential risks to human subjects) were corrected.

Summary of changes: - Section 6.7.5 amended to allow physicians with safety concerns to closely monitor any patient who had his or her dose increased to greater than 40mg/kg/day. The suggested frequency of every 2 weeks was deemed sufficient to monitor for any potential untoward signs of toxicity, including renal changes, owing to the increased dose. - The rationale for and safety of the proposed doses in Section 3.5.1 were amended to provide additional information and data in support of the safety of the proposed maximum dose (up to 60 mg/kg/day once daily).

Summary of changes: - It was clarified that AE collection was to commence at the signing of the consent/giving of assent as per Shire’s requirement. - The sponsor details were updated: FerroKin Biosciences Inc was replaced with Shire Development LLC. The original FerroKin protocol numbers were updated to Shire protocol numbers as follows: SPD602-101 replaced FBS0701-CTP-03; SPD602-201 replaced FBS0701 CTP-04; SPD602-102 replaced FBS0701-CTP-12; SPD602-202 replaced FBS0701-CTP-07; and SPD602-301 replaced FBS0701-CTP-15. - The pregnancy and AE reporting requirements were revised to 24 hours. - The stopping rules and rescue therapy section were revised and replaced to reflect current opinion for removal of subjects from investigational product or therapy. - Information on gastrointestinal events deemed possibly or probably related to SSP-0040184 was added to Section 3.3 of the protocol (summary of clinical studies). - Text in Section 9.3 of the protocol (DNA and RNA analysis) was replaced with Shire standard wording. - Wording in Section 10 of the protocol (AE and SAE assessment) was replaced with Shire standard wording. - Section 12 of the protocol (investigational product accountability) was updated to include Shire standard language.

Summary of changes: -The compound name was changed from SSP-004184 to SSP-004184AQ in all sections except the pharmacokinetic sections. - The description of investigational product was updated to include: provided as a magnesium salt (SSP-004184AQ). SSP-004184 is the free acid or active form. - Liver and pancreas were added to abdominal R2* MRI assessments to clarify the measurements required. - The AE and SAE collection time during chronic phase was reduced from 28 days after the last dose to 7 days after the last dose. - The pregnancy reporting time in the chronic dosing phase was reduced from 28 after the last dose to 7 days after the last dose. - The Week 52 EOS Visit was replaced by a Week 49 visit; the overall study duration therefore decreased from 417 days to 396 days. - A neurological examination was added to the study assessments to reflect current thinking on safety data capture; information on extended neurological examinations was added to Section 3.4 of the protocol (potential risks to human subjects) to reflect this change. - Cardiac LVEF was added to the exclusion criteria (criterion 12) and to the withdrawal criteria. - The baseline period (including the baseline MRI window), which was previously -14 to -7 days, was changed to -28 to -8 days. - Exclusion criterion 5 was amended to add that significant biliary disorder, e.g., chronic cholecystitis, would also exclude a subject from study entry, to reflect current clinical thinking. - A description of the data monitoring committee activities was added. - Details of possible drug interactions were added. - Information was added regarding events of potential interest to match neurological examination requirement. - Information was added regarding AEs of potential interest, including paraesthesia and hypoesthesia. Clarification was added that both the medical monitor and the Shire physician were to review and discuss SAE cases with the principal investigator.

Summary of changes: - Exclusion criterion 5 was updated with removal of “chronic cholecystitis” to reflect IB version 7.0. - The contraception text within inclusion criterion 9 was revised to state that female subjects were required to have negative pregnancy tests, abstain from sexual activity, or use acceptable methods of contraception. The detailed discussion of contraceptives was removed and a cross-reference included to a newly created reproductive potential section (Section 6.3). - It was clarified that exclusion criterion 12 only applied to LVEF below (not outside) the locally determined normal range or in subjects with LVEF <50%. - It was clarified that echocardiograph is acceptable for LVEF measurement if MRI information is not available. - Primary endpoint 2 was amended to include LVEF as an example parameter. - A new section was included on reproductive potential, which included the following information: hormonal contraceptives were no longer considered approved forms of contraception when used alone and a second adequate method of contraception was required; hormonal contraceptives could be less efficient in the presence of SPD602 due to its potential induction of CYP3A4; and females of child-bearing potential had to agree to use acceptable contraception if they became sexually active during the study and for 30 days following the last dose of investigational product. - Text was added to Section 6.8.7 of the protocol (concomitant and prohibited treatments or therapies) to discuss that SPD602 is a potential inducer of CYP2B6 and CYP3A4 mRNA in vitro and that there may be potential drug interactions with these substrates in vivo.