Protocol, version 2.0 • Reduced the threshold for conditional power of interim study stopping rule • Clarified the unblinded PK/PD group for the interim analysis • Clarified PEF and ACT testing • Added language for abnormal liver laboratory findings to incorporate Hy’s law in applicable protocol sections • Updated the device on which subjects would complete the WI NRS and SD NRS (i.e., changed from paper form to an ePRO device) • Updated the schedule of assessments with respect to eDiary, full physical examinations, 12-lead ECG, blood sample collection for hematology and biochemistry, urinalysis, ACT, and PEF • Deleted mention that electrocardiogram machines would be provided • Clarified that descriptive statistics would be calculated for all individual popPK derived parameters • Designated the CRO and that an unblinded group would be used for the interim analysis • Updated the website for the Centers for Disease Control

Protocol, version 3.0 • Removed exclusion criterion 8d (pertained to PEF) • Described PEF as supplemental information as opposed to an exclusion criterion • Updated the schedule of assessments footnotes to capture PEF testing and deleted a repetitious footnote • Clarified the AESI of new asthma—that reduction in PEF value needed to be sent to adjudication only if there were suggestive asthma signs and/or symptoms and absence of another disease as a cause

Protocol, version 4.0 • Allowed enrollment of subjects who had CKD with moderate pruritus • Changed inclusion criterion 3 to reflect that 60 days is a suitable duration to cover 2 single-pool Kt/V measurements as opposed to 45 days • Decreased the WI NRS score from ≥7.0 to ≥5.0 in inclusion criterion 5 and provided the rationale for this change • Changed wording describing WI NRS from “reduction” to “improvement” • Adjusted ranges in subgroup analyses to accommodate moderate pruritus • Allowed rescheduling up to 72 hours from the screening window in exceptional circumstances • Allowed for subjects who failed prior to Protocol Version 4.0 to rescreen if their WI NRS was ≥5.0

Protocol, version 5.0 • Updated the Sponsor’s address • Removed the interim analysis • Allowed seasonal, emergency, and COVID vaccines • Further described the details of the estimand for the primary efficacy endpoints and further clarified how the intake of rescue therapy would be included in the definition of the binary composite response • Provided more detail for the WI NRS/SD NRS calculation • Corrected the multiplicity adjustment for primary and key secondary efficacy endpoints • Clarified the handling of missing data, added sensitivity analyses for the primary endpoint, and defined the mITT, PP and observed case analyses as supplementary (rather than sensitivity) as per ICH E9 (R1) addendum on estimands and sensitivity analysis • Specified that dose selection would be based on the final analysis, as the interim analysis was removed • Specified that the impact of body weight on efficacy would be evaluated at the end of the study • Added IGA of CKD-aP skin status to unscheduled visit(s) in the schedule of assessments • Provided an EMEA email address for reporting an AESI, SAE, or pregnancy

Protocol, version 6.0 • Added the biostatistician as an approver • Updated primary efficacy estimand and attributes to address treatment discontinuation due to lack of efficacy or adverse event/death related to study drug • Corrected the follow-up visit window • Clarified that missing data for dichotomous efficacy endpoints would be imputed using multiple imputations under missing at random assumption for the primary/main analyses; ‘non-responder’ imputation would be used as a sensitivity analysis