1) Added text to clarify how decisions of adding new patients would be made. 2) Section 3.3.1: Language was added to clarify how many patients could be added to each cohort. 3) Addition of text to clarify that enrollment in Cohort 6 would be based on safety experience in Cohort 5 according to the Dose Escalation Rules. 4) Removed text for Cohort Dose Reduction specifying how dose would be reduced for the cohort receiving 40 mg/week. The dose for cohort receiving 40 mg/week would be reduced to 20 mg/week which was already shown to be safe. The option of 40 mg every two weeks was removed due to lack of clear criteria to determine frequency of dose reduction. 5) Section 3.4.1.1.1: Revision of text to Safety Criteria for dose reduction to remove inconsistency in protocol and added that Hgb values of >13 g/dL would be confirmed by a repeat test to align with study assessments. 6) Clarification that Hgb >13 g/dL would be considered if no transfusion was performed for >4 weeks as transfusion may result in Hgb values of >13 g/dL for more than 7 days. This change was made to distinguish the effect of transfusion on Hgb levels from effect of PTG-300. 7) Text was added to Pregnancy Testing to include specification for negative urine pregnancy test results for NTD and TD populations as they were inadvertently omitted in original protocol. 8) Endpoints revised. 9) Inclusion and Exclusion Criteria modified to more clearly define the enrollment-eligible population. 10) Concomitant medications revised. 11) Corrected typographical error specifying Doses 5 and onward can be administered at site or home. 12) Clarification of timing of PK/PD assessments, adjusted statistical analysis sections to correspond to protocol changes. 13) Revised Physical Examination to remove ultrasound assessment. 14) Section 5.2.3: Added Treatment Compliance section to provide detail about compliance monitoring. 15) Revised definition of study completion for clarity.

1) Table 1 for Schedule of Assessments – revised footnotes to reflect scheduled assessments and clarify timing of assessments to align with other safety assessments for coagulation testing. Other changes made for clarity and to correct typographical errors. 2) Dose Escalation Criteria revised to change description of cohort dose escalation to include the additional dose cohorts and change to Cohort 4b dose level. 3) Dose Reduction Stopping Criteria text changed to add responsibility of Safety Monitoring Committee (SMC) flexibility in study continuation criteria. 4) Table 4 changed to reflect requirement that dosing be suspended in cohort until SMC reviews safety data and makes recommendations. 5) Changed Synopsis text to specify that negative urine pregnancy tests are required to proceed with dosing throughout the study. 6) Number of patients revised to reflect changes to number of patients enrolled in the study (up to 192, minimum of 84) to account for potential cohorts and allow sponsor to treat additional patients (up to 24) to confirm safety, efficacy, and dose titration rules. 7) Inclusion and exclusion criteria were modified. 8) Investigational Product – Dose Level 4b in NTD and TD patients revised to add dosing option of 20 mg or 80 mg every 2 weeks and additional cohorts 7-11 to evaluate every two-week dosing and allow flexibility in dose selection. 9) Safety Assessment added to synopsis for internal consistency 10) Safety Assessment descriptions amended to remove specific timepoints for internal consistency with schedule of assessments and for clarity. 11) Pregnancy Reporting revised to add that pregnancy not considered AE or SAE. 12) Clinical Laboratory Abnormalities revised for clarity regarding what is an AE or SAE and clinical significance. 13) Statistical Analysis section revised to remove statement regarding missing data. This was added to Statistical Analysis Plan instead. Baseline period for transfusions was changed for accuracy.