Amendment 1 became effective without approval by the Independent ethics committee (IEC)/ Institutional review board (IRB)/Competent authority (CA). The amendment introduced minor changes to the Clinical Trial Protocol (CTP) as follows: - Minor corrections to the flow charts regarding the timing of Anit-drug antibody (ADA) sampling to align with the rest of the CTP - Clarified endpoint definitions to specify that that they should be measured in the study eye - Correction of the calculated relative dose increases - Removed electrocardiogram (ECG) interval measurement analytical methods and deleted stipulations for blinding of the central ECG lab with regards to interval measurements as no interval measurements were to be collected and ECGs were only to be checked for baseline conditions and adverse events (AEs) - Clarification of vascular occlusion dose-limiting events (DLE) definition - Updated the methods of SAE submittal to Boehringer Ingelheim (BI) - Clarified that no hypothesis testing was to be accomplished due to the exploratory nature of the trial - Minor typing error corrections

Amendment 2 became effective without approval by the IEC/IRB/CA. The amendment introduced minor changes to the CTP as follows: - Clarification of inclusion criteria 1, 2, and 7 with regards to the methods to be used for Wet age-related macular degeneration (wAMD) diagnosis, applicability to sinlge rising dose (SRD) vs multiple rising dose (MRD), and degree of fibrosis, respectively.

Amendment 3 became effective after approval by the IEC/IRB/CA. The amendment introduced substantial changes to the CTP as follows: - Minor corrections to wording to more accurately describe endpoints and criteria - Removal of biobanking for SRD part and clarification of height and weight measurement timing - Addition of pharmacokinetic (PK) and biomarker sampling at Visits 6, 7, and 8 and ADA sampling at Visit 8 for MRD cohort 1 - Update of drug profile with data from 10 treated SRD patients - Added an assessment of the impact of the COVID-19 pandemic on the trial and the overall impact on the benefit-risk assessment along with changes to trial conduct with regard to COVID-19 testing and individual participation in the trial - Several adaptations were introduced to more accurately describe respective endpoints - Clarified the safety monitoring committee (SMC) role in selection of doses to be used in the MRD part - Clarification with regard to the timing of prior vascular endothelial growth factor (VEGF) treatments prior to screening/randomisation

Amendment 3 (continued): - Clarification of the definition of child bearing potential and contraceptive requirements - ‘Qualified personnel’ were added as an alternative to the site pharmacist - Clarification that standard of care was allowed from Visit 5 (Follow up period) - Corrected the timeframe for dose limiting events - Clarification of criteria to accurately determine recurrence leading to the use of rescue medication by adding specific central subfield retinal thickness (CSFT) and best corrected visual acuity (BCVA) changes - Added PK and plasma derived biomarker assessments for 56, 84, and 112 days after the 3rd treatment for the MRD part - Clarification of timelines and requirements for ocular tonometry and the exchange of optional fluorescein angiography for optical coherence tomography-angiography (OCT-A) acquisitions during follow up - Increased Follow up period from 14 to 28 days - Added text allowing an informal preliminary analysis of efficacy data after the completion of Visit 5

Amenment 4 became effective after approval by the IEC/IRB/CA. The amendment introduced substantial changes to the CTP as follows: - Increased the time from the last injection of VEGF therapy prior to screening from 12 to 16 weeks and removed the requirement for patients to have had the first anti-VEGF treatment in the study eye within 18 months (inclusion criterion 2) in order to increase eligibility and recruitment to the trial - Clarified exclusion criteria regarding previous incidences of increased IOP, allowed yttrium aluminium garnet laser capsulotomy within 1 month prior to enrolment, and allowed previous participation in other trials for the treatment of wAMD if washout requirements were met in order to increase eligibility and recruitment to the trial

Amendment 5 became effective after approval by the IEC/IRB/CA. The amendment introduced major changes to the CTP through the addition of MRD cohort 2 (treatment naïve patients) as follows: - Integration of cohort 2 via the additions of Flow Chart III and eligibility criteria (including specific inclusion and exclusion criteria), integration of associated increase in the number of entered/treated patients and sample size calculation, adaptation of the tested doses (2 mg BI 836880 for cohort 2), and an update of the trial rationale. - Update of drug profile and dose escalation scheme with data from the completed SRD part, including the highest safe dose (2 mg BI 836880). - Update of benefit risk assessment considering published faricimab data. Integration of risks and a corresponding update to the informed consent form (ICF) with regard to the silicon oil coated needle caution statement by Becton Dickson. - Description of new drug formulation (40 mg/mL BI 836880 solution for injection) - Addition of optional safety visits within 1 week of treatment visits (Visits 2, 3, and 4) and description of remote monitoring calls. - Increase in pre-dose sampling PK blood sampling windows

Amendment 6 became effective after approval by the IEC/IRB/CA. The amendment introduced substantial changes to the CTP as follows: Clarification of sample size and the overlap of cohorts 1 and 2 - Reduction of required CSFT >330 μm to CSFT >300 μm inclusion criteria to increase eligibility and recruitment - Broadening of early treatment diabetic retinopathy study (ETDRS) inclusion criteria from ‘ETDRS visual acuity (VA) in the study eye between 70 and 24 letters inclusive’ to ‘between 75 and 24 letters inclusive (approximately 20/32 or 6/9.5)’for MRD cohort 1 in line with the positive safety data collected to date. - Added description of diluent and its use for both 40 mg/mL and 80 mg/mL formulations.

Amendment 7 became effective while the trial was on voluntary medical hold by the sponsor due to 2 incidences inflammatory eye disorders that were judged as related to BI 836880 by investigators. Amendment 7 implemented safety measures to mitigate the risk and ensure early detection of intraocular inflammation. The trial was resumed only after approval by the IEC/IRB/CA. The amendment included the addition of cohort 3 and other updates to the CTP as follows: - Integration of cohort 3 via the additions of Flow Chart IV and eligibility criteria (including specific inclusion and exclusion criteria), dose groups (cohort 3 dosed at 2 mg per treatment), an update of the trial rationale. - Descriptions of increased safety measures included: fluorescein angiography imaging during screening, wide angle colour fundus photos with vitreous haze assessment at every visit, and the requirement to report any intraocular inflammation events as adverse events of special interests (AESIs). Furthermore, certain exclusion criteria were amended to exclude patients with a high potential of developing ocular inflammation from MRD cohort 3. - Revised and clarified the patients entered, cohort sizes, and dose groups in MRD part. All remaining patients were allocated to cohort 3. Reiteration of replacement strategy. - Updated current summary of clinical safety data including descriptions of 2 serious adverse events (SAEs) reported in MRD cohort 1. Described evidence of efficacy detected during exploratory analysis of interim data in patients requiring frequent standard of care which were the target patient population for MRD cohort 3.

Amendment 7 (continued): Added the following MRD cohort 3 further exploratory endpoints to gather insight of the treatment effect: o Absence (yes/no) of intra-retinal or sub-retinal fluid (IRF, SRF) in the study eye at Week 16 (Visit 6, cohort 3 only) o Resolution (yes/no) of subretinal hyper-reflective material/retinal pigment epithelial detachment (SHRM/PED) in the study eye at Week 16 (Visit 6, cohort 3 only) o A responder analysis that was further modified in the trial statistical analysis plan (TSAP) - Reworded statistical sections to make clear that no statistical testing was planned for descriptive statistics. Updated/clarified analytical details regarding MRD cohort 3 including the addition of the evaluable responders’ analytical dataset. - Added new BI 836880 formulation where an initial trial formulation (CMC1) was switched to an intended final formulation (CMC2) for MRD cohort 3. - Amended the restrictions to concomitant treatment to clarify that standard of care (SoC) therapy could be administered if there is a worsening in disease before Visit 6, and as deemed medically appropriate during/after Visit 6 to make clear that investigators could treat patients with SoC during the follow up period even if patients did not meet time to recurrence or AESI criteria. - Clarified DLE criteria and amended AESI criteria for cohorts that received the maximum dose (2 mg BI 836880, MRD cohorts 2 & 3). - Clarified the evaluation of ECGs by site personnel to allow operational flexibility. - Clarified the requirement of written consent of the pregnant partner of a study participant for drug exposure reporting and pregnancy outcome. - Extended PK dose sampling window prior to 1st intravitreal (IVT) dose.