- Clarified study endpoints - Updated to use the 2011 Iron Disorders Institute (IDI) phlebotomy guidelines for patients with hereditary hemochromatosis (HH) - Updated to require standard-of-care phlebotomy for all randomized patients on Day 1. Thereafter, phlebotomy decisions by the investigator were to be assessed at Weeks 4, 8 and 12 per the 2011 IDI guidelines - Added a secondary endpoint to assess the number of phlebotomy events - Added HH diagnosis and genotype as part of medical history data collection - Added that complete iron lab samples should be drawn predose at the same time of day each visit, whenever possible - Added contraception language - Revised TSAT stratification factor - Amended statistical methods to align with the revisions to study endpoints

- Updated adverse event reporting to start at the time of consent - Revised statistical methods to align with the statistical analysis plan - Modified phlebotomy language to allow investigator to remove blood volume based on weight - Specified diabetes Type 2 exclusion criteria to exclude patients with poorly controlled diabetes - Amended a phlebotomy event in subgroups as either based on a phlebotomy or having a fasting TSAT > 45% - Update planned enrollment to at least 48 evaluable patients - Revised excluded medications and therapies - Revised the comparability group to include subgroups of interest

- Study design changed from double-blind to single-blind - Extended the screening period to 90 days - Added rescreening specifics - Blood collections for TSAT and other iron parameters were changed from weekly to extended durations - Dosage was revised to a more fixed design - Added glycemic control as an exploratory objective and change in hemoglobin A1c from baseline to Week 16 as an exploratory endpoint - Added additional endpoint and blood sample collection at Week 17 for complete iron studies - Revised inclusion criteria for serum ferritin from 150 to greater than or equal to 100 ng/mL to < 1,000 ng/mL - Updated exclusion criteria to exclude patients receiving chelation therapy within 7 days prior to the first dose of study drug - Updated exclusion criteria to exclude patients initiation phlebotomy therapy less than 3 months from first dose of study drug - Removed type 2 diabetes as an exclusion criteria - Removed clinically significant arrhythmias as an exclusion criteria - Specified the timing of certain screening evaluations - Removed requirement for a formal DMC - Revised randomizations by baseline of phlebotomy frequency over the last 12 months

- Revised primary endpoint to account for patients who received phlebotomy and patients who did not receive a phlebotomy after Week 1 - Added an iron parameter endpoint at Week 17 - Revised statistical methods - Added 10 mg/mL concentration to the IMP description - Corrected dose adjustment information - Added a safety monitoring committee - Added an interim analysis to evaluate initial data after the first 16 patients completed Week 16 assessments or had a phlebotomy after the SOC phlebotomy on Day 1 and before Week 16 - Added an exclusion criteria based on ECG findings and clinical significant arrhythmias - Added an exclusion criteria to exclude patients with poorly controlled Type 2 diabetes

- Amended the Efficacy Analysis Population to include those patients enrolled under global protocol version 4.0 or later only