A Phase 2, Prospective, Multicenter, Randomized, Double-Masked, Active-Controlled Study to Assess the Safety, Tolerability, and Evidence of Activity of a Repeat Intravitreal Injection of UBX1325 in Patients With Neovascular Age-Related Macular Degeneration (Wet AMD)
Phase: PHASE2
Conditions: Neovascular Age-related Macular Degeneration
Sponsor: Unity Biotechnology, Inc.

Clinical Study Protocol
UBX1325
UBX1325-03 
Version 4.0 
UNITY Biotechnology, Inc. 
1 
Confidential 
A Phase 2, Prospective, Multicenter, Randomized, 
Double-Masked, Active-Controlled Study to Assess 
the Safety, Tolerability, and Evidence of Activity of a 
Repeat Intravitreal Injection of UBX1325 in Patients 
with Neovascular Age-Related Macular Degeneration 
(ENVISION) 
Investigational Product(s) 
UBX1325 
Protocol Number 
UBX1325-03
Version Number
4.0 
Version Date 
13 January 2023 
IND Number 
145348 
Sponsor 
UNITY Biotechnology, Inc. 
Sponsor’s Legal 
Representative 
Sharon Klier, MD, MPH 
VP and Medical Director, Ophthalmology 
UNITY Biotechnology, Inc. 
285 East Grand Avenue 
South San Francisco, CA 94080 
 
Date 
Original Protocol:
26 August 2021, Version 1.0  
Protocol Amendment 1: 
15 December 2021, Version 2.0
Protocol Amendment 2: 
31 August 2022, Version 3.0
Protocol Amendment 3: 
13 January 2023, Version 4.0 
Confidentiality Statement 
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the Sponsor. You may disclose the contents of this document only to study 
personnel under your supervision, Institutional Review Boards (IRBs)/Independent Ethics 
Committees (IECs), or duly authorized representatives of regulatory agencies for this purpose 
and under the condition that they maintain confidentiality. The contents of this document may 
not be used in any other clinical study, disclosed to any other person or entity, and/or published 
without the prior written permission of the Sponsor. The foregoing shall not apply to disclosure 
required by any regulations; however, you will give prompt notice to the Sponsor of any such 
disclosure. All other nonpublic information provided by the Sponsor and any information that 
may be added to this document also is confidential and proprietary to the Sponsor and must be 
kept in confidence in the same manner as the contents of this document.

Clinical Study Protocol
UBX1325
UBX1325-03 
Version 4.0 
UNITY Biotechnology, Inc. 
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SUMMARY OF CHANGES: AMENDMENT 1 
The following summarizes the principal elements requiring that change be made to the protocol. 
Other minor modifications for administrative purposes have been made to provide clarity and 
are captured in the redlined document. 
The principal components of change to the study are described in the table below. 
Area of change
Rationale
Repeat dose arm added and instead of a 
sham control there is an active control 
[Synopsis] and [Section 4.2 Design 
Rationale] [Section 6.0 Study Conduct] and 
[Section 7.6 Administration of aflibercept] 
Repeat dose arm was incorporated after 
additional data from the First-in-Human study 
suggested that a single injection may not be 
sufficient to all patients. A repeat dose of 
UBX1325 can potentially be beneficial 
clinically with elimination of additional 
senescent cells. 
Active control arm replaced the sham control 
in order to make the standard of care 
consistent 
Increased duration of follow-up from 
16 weeks to 24 weeks 
Increased overall study duration from 20 to 
22 months 
[Synopsis] and [Section 6.0 Study Conduct] 
To assess longer term effect of study drug 
through repeat IVT injection of UBX1325. The 
number of study visits aligns with standard of 
care to see wet AMD patients every 4 weeks. 
Added Aflibercept run-in: Once patients meet 
inclusion/exclusion criteria, they will receive a 
single run-in injection of aflibercept 
approximately -8 to -4 weeks prior to Day 1 
[Synopsis] and [Section 6.0 Study Conduct] 
To homogenize the patient population
Updated primary objective to include 
biological activity and primary endpoints to 
include changes in BCVA from Baseline 
within group at any or all visits 
Secondary and exploratory objectives and 
endpoints were also updated 
[Synopsis] and 
[Section 3.0 Objectives and Endpoints] 
To align with current objectives following the 
interim results of the UBX1325-01 study 
Sample size increased and order of efficacy 
endpoints was shifted putting BCVA changes 
at the top. 
[Synopsis] and [Section 3 Objectives and 
Endpoints] and [Section 9.2 Determination of 
Sample Size] 
Sample size was recalculated based on the 
new primary efficacy endpoint and overall list 
of endpoints better aligns with key endpoints 
in future wet AMD studies 

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Area of change
Rationale
Increased number of sites from 20 to 25 
[Synopsis] 
To align with the sample size
Inclusion 2: applied to Screening and Day 1 
Inclusion 3: required 2-anti-VEGF in previous 
6 months with the last injection within 4-
8 weeks prior to Screening 
Inclusion 4: advised that Investigator 
discretion be utilized 
Removed original Exclusion 13 and listed 
cataract surgery in Exclusion 5 
Reworded Exclusion 8 to emphasize poorly 
controlled glaucoma 
Exclusion 11: History of topical steroid use for 
the SE or systemic steroid use for 6 months 
prior to Screening. The use of intravitreal 
steroids is prohibited. Inhaled and locally 
administered steroids are acceptable 
Reverted Exclusion for history of malignancy 
within the last 3 years to within the last 
5 years 
[Section 5.3 Inclusion Criteria] and 
[Section 5.4 Exclusion Criteria] 
Eligibility criteria revised to address 1 or more 
issues: 
- 
remove redundancies 
-
remove specific criteria put in place 
before additional safety data was 
ascertained in the First-in-Human 
study 
- 
clarify requirements 
-
better align with patient population
Safety updates based on available data from 
the First-in-Human study, UBX1325-01. 
[Section 2.4.4 Supportive Nonclinical Data] 
and [Section 2.4.5 Benefit:Risk Assessment] 
The summary of safety data was revised to 
reflect additional non-serious, non-drug 
related adverse events 
Added section on exploratory substudies 
[Section 3.1 Exploratory Substudies] 
Added flexibility for future potential 
substudies 
Clarified collection of historical medical and 
medication data, including all imaging and 
ophthalmological assessments 
[6.1.3 Medical History and Concomitant 
Medication Review] 
To obtain the retrospective view of the 
patient’s anti-VEGF response 
Revisions to schedule of events table
[Schedule of Events] and [Section 6.0 Study 
Conduct] 
To align with new endpoints and revised 
study schematic 

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Area of change
Rationale
Unmasked injector will need to be available 
for IVT injections (or sham procedures if 
applicable) at Visits 1, 3, 4 and 6. 
[Section 7.8 Masked and Unmasked Study 
Staff] 
This accounts for additional days when IVT 
injections/sham procedures would be 
conducted per revised study schematic 
Updated Statistical Methods 
[Statistical Methods] 
To align with revised objectives, sample size, 
and study design 

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UBX1325-03 
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SUMMARY OF CHANGES: AMENDMENT 2 
The following summarizes the principal elements requiring that change be made to the protocol. 
Other minor modifications for administrative purposes have been made to provide clarity and 
are captured in the redlined document. 
The principal components of change to the study are described in the table below. 
Area of change
Rationale
Clarifications include: 
 
Post-dose anterior and posterior 
segment evaluations and intraocular 
pressure are to be assessed in only the 
SE, not OU 
 
Data collection of anti-VEGF in the 
preceding 6 months from Screening 
should be in OU. 
 
Data collection in the preceding 6 
months from Screening of SD-OCT and 
visual acuity assessments should be in 
OU and supports BCVA and CST entry 
into EDC 
 
OCT-A/FA/FP should be assessed at 
Screening instead of Day 1 
 
Sham procedure is utilized to maintain 
double-masking, and masked team 
members are specified 
 
Therapies that would preclude an IVT 
injection or can potentially exhibit retinal 
toxicity such as tamoxifen, 
hydroxychloroquine and trastuzumab 
are prohibited 
 
Numbing of the eye should be per 
standard of care and utilized 
consistently for sham and IVT 
injections. Medications used for 
numbing should be documented as 
concomitant medication 
 
Fluorescein used for IOP and 
IVFA/OCT-A should be documented as 
concomitant medication 
 
Treatment for the fellow eye should be 
completed at least 7 days from 
treatment of the SE. Treatment of the 
fellow eye during Screening is permitted 
since aflibercept run-in is open label. 
Incorporate Protocol Clarification Memo #1 
dated 17Feb2022 and Protocol Clarification 
Memo #2 dated 25May2022. 

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Area of change
Rationale
Exceptions to taking temperatures 
orally are acceptable when COVID 
protocols are in place. Method for 
taking temperature should be consistent 
throughout the study. 
 
AEs and SAEs are collected after 
aflibercept run-in during Screening 
[Section 6.0 Study Conduct] and 
[Section 7.7 Administration of Sham 
Procedure] and [Section 7.10 Permitted and 
Prohibited Concomitant Treatments] and 
[Section 8.2.1 Timeframe for Collection] 
Extended the duration from 24 weeks to 
48 weeks 
Added 2 additional injections of UBX1325 at 
Weeks 24 and 28 in the UBX1325 arm 
Added coadministration of UBX1325 with 
aflibercept at Week 24 and 32 in the aflibercept 
arm 
[Synopsis] and [Section 3 Objectives and 
Endpoints] and [Section 6.0 Study Conduct] 
and [7.7 Coadministration of Aflibercept and 
UBX1325 or Sham]
To study the safety, tolerability, and 
biological activity of 2 additional UBX1325 
injections through 48 weeks, as well as 
coadministration of UBX1325 with 
aflibercept through 48 weeks. 
Efficacy parameters and retinal structure 
for the 2 additional UBX1325 injections 
through 48 weeks and coadministration of 
UBX1325 with aflibercept will also be 
studied. 
Elaborated on the dosing interval and schedule 
as well as findings of IVT administration of 
UBX1325 in combination with aflibercept from 
the GLP toxicology study in cynomolgus 
monkeys. 
[Section 2.4.4.3 Toxicology] 
To support coadministration of UBX1325 
with aflibercept 
Clarified that for Unscheduled Visit, 
tests/procedures can be performed as PI 
discretion whereas all tests/procedures should 
be performed. 
[Section 1.2 Schedule of Events] and 
[Section 6.1.1.16 Unscheduled Visit/Early 
Termination (ET)] 
To distinguish between tests/procedures
required between UnscheduledVisit and 
Early Termination Visit. 

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Area of change
Rationale
Removed “more than 2” from the exploratory 
endpoint looking at proportion of UBX1325 
treated patients who require anti-VEGF therapy 
[Synopsis] and [Section 3 Objectives and 
Endpoints] 
Details of the analysis will be outlined in the 
Statistical Analysis Plan. 
Added interim analysis may be performed at 
24 weeks and removed at 8 weeks 
[Section 9.8 Planned Interim Analysis] 
To align with extension of the study
 

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Version 4.0 
UNITY Biotechnology, Inc. 
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SUMMARY OF CHANGES: AMENDMENT 3 
The following summarizes the principal elements requiring that change be made to the protocol. 
Other minor modifications for administrative purposes have been made to provide clarity and 
are captured in the redlined document. 
The principal components of change to the study are described in the table below. 
Area of change
Rationale
Clarified the Primary Objective and Endpoint by
removing “Primary Safety” references and 
added that the endpoint is assessed following a 
repeat IVT injection of UBX1325 compared to 
active control (aflibercept) through Week 24  
Secondary Objectives and Endpoints, added 
“safety” in the Objectives description, removed 
duplicative BCVA endpoint and clarified that 
safety is assessed through Week 48   
 
[Synopsis] and [Section 3 Objectives and 
Endpoints]
Correct typographical errors and clarify 
endpoint assessments 
Clarifications include: 
 
The protocol SOE is correct that a 
complete PE is required at Screening, 
Visit 8/Week 24, Visit 14/Week 48 and 
Early Termination. Sites should conduct 
this complete PE and enter any 
abnormalities or changes in EDC 
 
Per previous protocol, "For visits with 
masked study drug, FE treatment is to 
be completed 7 days from SE treatment 
(e.g., D1, Week 4, 8, 16, 24, 28, 32, 
and 40)."   
This restriction is being removed from 
the protocol in the latter 24 weeks of the 
study to allow Investigators greater 
clinical discretion of when it is 
appropriate to treat the fellow eye.  At 
Visit 8/Week 24, Visit 9/Week 28, Visit 
10/Week 32 and Visit 12/Week 40, the 
SE treatment and FE treatment no 
longer require a separation window of 7 
days. Please ensure however that the 
FE treatment is done after SE 
treatment. 
Per protocol, AE collection begins after 
Incorporate Protocol Clarification Memo #3 
dated 11Oct2022 

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Area of change
Rationale
the aflibercept run-in, however, this 
should include the run-in injection. The 
“Relationship to Aflibercept 
Administration” AE field in EDC 
corresponds to this run-in dose of 
aflibercept at Screening only.  Please 
ensure that this relationship is assessed 
accordingly. 
[Section 1.2 Schedule of Events]  and [Section 
7.10.1 Permitted Treatments] and [Section 
8.2.1 Timeframe for Collection] 

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STATEMENT OF COMPLIANCE 
The study will be conducted in compliance with this clinical study protocol, Good Clinical 
Practices (GCPs) as outlined by International Conference on Harmonisation (ICH) E6(R2), and 
all applicable local and national regulatory requirements. Enrollment at any clinical study site 
may not begin prior to that site receiving approval from the IRB or Ethics Committee of Record 
(ECR) for the protocol and all materials provided to potential patients. Screening at a site may 
not begin prior to approval from the IRB/IEC and the Sponsor. 
Any amendments to the protocol or changes to the consent document will be approved by the 
IRB/IEC before implementation of that amendment. Reconsent of previously enrolled patients 
may be necessary, depending on the nature of the amendment. 
All personnel involved in the conduct of this study have completed Human Subjects Protection 
and GCP training, as outlined by their governing institution. 

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SPONSOR’S APPROVAL 
Title 
A Phase 2, Prospective, Multicenter, Randomized, Double-Masked, 
Active-Controlled Study to Assess the Safety, Tolerability, and Evidence 
of Activity of a Repeat Intravitreal Injection of UBX1325 in Patients with 
Neovascular Age-Related Macular Degeneration 
Protocol Number 
UBX1325-03 
Version Number
4.0
Version Date
13 January 2023 
The design of this study as outlined by this protocol has been reviewed and approved by the 
Sponsor’s responsible personnel as indicated in the signature table below. 
Sponsor’s Legal Representative
Name: 
Title: 
Signature:
Date:
Sharon Klier, MD, 
MPH 
VP and Medical 
Director, 
Ophthalmology 
 

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INVESTIGATOR’S AGREEMENT 
I have read the protocol, appendices, and accessory materials related to Study UBX1325-03 
and agree to the following: 
• To conduct this study as described by the protocol and any accessory materials 
• To protect the rights, safety, and welfare of the participants under my care 
• To provide oversight to all personnel to whom study activities have been delegated 
• To control all Study Drug provided by the Sponsor and maintain records of the disposition of 
those products 
• To conduct the study in accordance with all applicable local and national regulations, the 
requirements of the ethics committee of record for my clinical site, and Good Clinical 
Practices as outlined by ICH E6(R2). 
• To obtain approval for the protocol and all written materials provided to participants prior to 
initiating the study at my site 
• To obtain informed consent – and updated consent in the event of new information or 
amendments – from all participants enrolled at my study site prior to initiating any 
study-specific procedures or administering investigational products to those participants 
• To maintain records of each patient’s participation and all data required by the protocol 
Name 
Title
Institution 
 
Signature 
Date 
 

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TABLE OF CONTENTS 
SUMMARY OF CHANGES: AMENDMENT 1 ..............................................................................2 
SUMMARY OF CHANGES: AMENDMENT 2..............................................................................5
SUMMARY OF CHANGES: AMENDMENT 3 ..............................................................................8 
STATEMENT OF COMPLIANCE ..............................................................................................10
SPONSOR’S APPROVAL .........................................................................................................11 
INVESTIGATOR’S AGREEMENT .............................................................................................12
TABLE OF CONTENTS .............................................................................................................13 
LIST OF TABLES .......................................................................................................................16 
LIST OF FIGURES ....................................................................................................................17
LIST OF ABBREVIATIONS .......................................................................................................18 
1
SYNOPSIS .....................................................................................................................21 
1.1 
Study Schematic .........................................................................................................24 
1.2 
Schedule of Events .....................................................................................................24 
2
INTRODUCTION ............................................................................................................28 
2.1 
Overview of Age-Related Macular Degeneration ........................................................28 
2.2 
Standard of Care .........................................................................................................29 
2.3 
Target Indication and Population.................................................................................29 
2.4 
Scientific Rationale for UBX1325 as a Treatment for wet AMD ..................................29 
2.4.1
Role of Senescence in Retinal Disease ...................................................................30 
2.4.2
Disease-Relevant Senescence-Associated Secretory Phenotype from Senescent 
Retinal Cells .............................................................................................................31 
2.4.3
Description of UBX1325 ...........................................................................................32 
2.4.4
Supportive Nonclinical Data .....................................................................................33 
2.4.4.1 
Pharmacology .......................................................................................................33 
2.4.4.2 
Pharmacokinetics ..................................................................................................33 
2.4.4.3 
Toxicology .............................................................................................................34 
2.4.5
Benefit:Risk Assessment ..........................................................................................34 
2.4.5.1 
Previous Human Experience with Bcl-2 Inhibitors .................................................34 
3
OBJECTIVES AND ENDPOINTS ..................................................................................36 
3.1 
Exploratory Substudies ...............................................................................................37 
4
STUDY PLAN .................................................................................................................38 
4.1 
Study Design ...............................................................................................................38 
4.2 
Design Rationale .........................................................................................................38 

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4.2.1
Patient Population Selection ....................................................................................38 
4.2.2
Dose Rationale.........................................................................................................38
5
POPULATION ................................................................................................................39 
5.1 
Recruitment .................................................................................................................39 
5.2 
Definitions ...................................................................................................................39 
5.3 
Inclusion Criteria .........................................................................................................39 
5.4
Exclusion Criteria ........................................................................................................39
6
STUDY CONDUCT ........................................................................................................42 
6.1
Study Procedures........................................................................................................42
6.1.1
Study Screening and Treatment Periods .................................................................42 
6.1.1.1 
Screening Period (Day -56 to Day -28) .................................................................42 
6.1.1.2 
Visit 1 (Day 1) ........................................................................................................43 
6.1.1.3 
Visit 2 (Day 15) ......................................................................................................43 
6.1.1.4 
Visit 3 (Day 29) ......................................................................................................44 
6.1.1.5 
Visit 4 (Day 57) ......................................................................................................45 
6.1.1.6 
Visit 5 (Day 85) ......................................................................................................45 
6.1.1.7 
Visit 6 (Day 113) ....................................................................................................46 
6.1.1.8 
Visit 7 (Day 141) ....................................................................................................47 
6.1.1.9 
Visit 8 (Day 169) ....................................................................................................47 
6.1.1.10 
Visit 9 (Day 197) ....................................................................................................48 
6.1.1.11 
Visit 10 (Day 225) ..................................................................................................48 
6.1.1.12 
Visit 11 (Day 253) ..................................................................................................49 
6.1.1.13 
Visit 12 (Day 281) ..................................................................................................50 
6.1.1.14 
Visit 13 (Day 309) ..................................................................................................50 
6.1.1.15 
Visit 14 (Day 337) ..................................................................................................50 
6.1.1.16 
Unscheduled Visit/Early Termination (ET) ............................................................51 
6.1.2
Informed Consent .....................................................................................................52 
6.1.3
Medical History and Concomitant Medication Review .............................................52 
6.1.4
Physical Examination ...............................................................................................52 
6.1.5
Vital Signs and Body Weight ....................................................................................53 
6.1.6
Laboratory Tests ......................................................................................................53 
6.1.7
Pregnancy Test ........................................................................................................53 
6.1.8
Electrocardiography .................................................................................................53 
6.1.9
Ocular Evaluations ...................................................................................................53 

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6.1.10 
Rescue Criteria .........................................................................................................54 
6.1.11
End of Study.............................................................................................................54
6.2 
Discontinuation or Withdrawal .....................................................................................55 
6.2.1
Individual Patients ....................................................................................................55 
6.2.1.1 
Withdrawal from Study ..........................................................................................55 
6.2.1.2 
Replacement of Patients .....................................................................................55 
6.3
Study Termination .......................................................................................................55
7
STUDY INTERVENTIONS .............................................................................................56 
7.1
Description of Product.................................................................................................56
7.1.1
UBX1325 ..................................................................................................................56 
7.1.1.1 
Formulation, Storage, Preparation, and Handling .................................................56 
7.2 
Method for Assigning Patients to the Treatment Group ..............................................56 
7.3 
Randomization Code Creation and Storage ................................................................57 
7.4 
Administration of UBX1325 .........................................................................................57 
7.5 
Administration of Sham Procedure..............................................................................57 
7.6 
Administration of aflibercept ........................................................................................57 
7.7 
Coadministration of Aflibercept and UBX1325 or Sham .............................................58 
7.8 
Masked and Unmasked Study Staff ............................................................................58 
7.9 
Extent of Maintenance of Double-Masking ..................................................................58 
7.10 
Permitted and Prohibited Concomitant Treatments ....................................................58 
7.10.1 
Permitted Treatments ...............................................................................................58 
7.10.2 
Prohibited Treatments ..............................................................................................59 
8
SAFETY MONITORING .................................................................................................60 
8.1 
Definitions ...................................................................................................................60 
8.2 
Documenting Adverse Events .....................................................................................62 
8.2.1
Timeframe for Collection ..........................................................................................62 
8.2.2
Classification of Events ............................................................................................62 
8.3 
Reporting Adverse Events...........................................................................................62 
8.4 
Adverse Events of Special Interest .............................................................................63 
8.5 
Clinical Laboratory Findings ........................................................................................63 
8.6 
Pregnancy ...................................................................................................................64 
8.7 
Overdose or Misuse ....................................................................................................65 
9
STATISTICAL METHODS .............................................................................................66 
9.1 
General Considerations...............................................................................................66 

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9.2 
Determination of Sample Size .....................................................................................66 
9.3
Analysis Populations ...................................................................................................66
9.3.1
Full Analysis Set .......................................................................................................66 
9.3.2
Safety Analysis Set ..................................................................................................66 
9.4 
Demographics and Baseline Characteristics ...............................................................66 
9.5 
Efficacy Analysis .........................................................................................................66 
9.6
Safety Analysis............................................................................................................67
9.7 
Exploratory Analysis ....................................................................................................67 
9.8
Planned Interim Analysis.............................................................................................67
10 
ETHICAL CONSIDERATIONS .......................................................................................68 
10.1 
Good Clinical Practice .................................................................................................68 
10.2 
Ethics Review ..............................................................................................................68 
10.3 
Informed Consent ........................................................................................................68 
10.4 
Data Privacy ................................................................................................................68 
10.5 
Financial Disclosure ....................................................................................................69 
10.6 
Biological Specimens and Data ...................................................................................69 
11 
OVERSIGHT ..................................................................................................................70 
11.1 
Safety Assessment Committee ...................................................................................70 
11.2 
Quality Control and Assurance....................................................................................70 
11.2.1 
Monitoring and Audits ...............................................................................................70 
11.2.2 
Protocol Deviations ..................................................................................................70 
11.2.3 
Records ....................................................................................................................70 
11.2.3.1 
Data Capture and Management ............................................................................70 
11.2.3.2 
Records Retention .................................................................................................71 
12 
PUBLICATION POLICY .................................................................................................72 
13 
FINANCING AND INSURANCE .....................................................................................73 
14 
REFERENCES ...............................................................................................................74 
LIST OF TABLES 
Table 1 
Schedule of Events ............................................................................................25 
Table 2 
Grading for Adverse Events Not Covered in the NCI CTCAE ............................62 
Table 3 
Laboratory Parameters .......................................................................................64 

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LIST OF FIGURES 
Figure 1 
Schematic of Phase 2 Proof-of-Concept Study ..................................................24 
Figure 2 
Immunohistochemical Staining of p16+ Cells in Human Donors ........................30 
Figure 3 
Induction of Senescence and DR-Relevant Genes After Glucose Treatment ....32 
Figure 4 
Improved Vascular Leakage and Neovascularization by UBX1325 ...................33 

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LIST OF ABBREVIATIONS 
Abbreviation
Definition
AMD 
age-related macular degeneration
A/C IOL
Aphakia or Anterior Chamber Intraocular Lens
AE 
adverse event 
ADL
activities of daily living
ANOVA
analysis of variance 
AR 
adverse reaction
Bcl-2
B-cell lymphoma 2 
Bcl-xL 
B-cell lymphoma-extra large 
BCVA
best corrected visual acuity
CFP 
color fundus photography 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
CNV 
choroidal neovascularization 
COVID-19 
Coronavirus Disease 2019 
CST 
central subfield thickness 
CV 
coefficient of variation
DAPI 
4’,6-diamidino2-phenylindole 
DME 
diabetic macular edema 
DNA 
Deoxyribonucleic acid 
DR 
diabetic retinopathy
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ECR 
Ethics Committee of Record 
EDC 
electronic data capture 
ERG 
electroretinography 
ERM 
epiretinal membrane 
ET
early termination 
ETDRS 
Early Treatment Diabetic Retinopathy Study
FA
fluorescein angiography 
FDA 
Food and Drug Administration 
GA 
Geographic atrophy 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice
hERG 
human ether-à-go-go-related gene
HRMEC 
human retinal microvascular endothelial cells 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 

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Abbreviation
Definition
ICH 
International Conference on Harmonisation 
IEC
Independent Ethics Committee 
IHC 
immunohistochemistry
IND 
Investigational New Drug (application) 
IOP 
intraocular pressure 
IRB
Institutional Review Board
IRF 
Intraretinal fluid 
IV 
Intravenous 
IVT 
intravitreal 
LLVA
Low-luminance visual acuity
MedDRA
Medical Dictionary for Regulatory Activities
mfERG 
multifocal electroretinography 
MMRM 
mixed model for repeating measures 
mRNA
messenger ribonucleic acid 
N 
number of patients 
wet AMD 
neovascular age-related macular degeneration 
NCI CTCAE 
v4.03 
National Cancer Institute Common Terminology Criteria for Adverse 
Events version 4.03 
NOAEL 
no-observed-adverse-effect-level 
NOEL 
No-observed-effect-level 
NSnC 
non-senescent cells 
NV 
neovascularization 
NZW 
New Zealand White 
OCT 
optical coherence tomography 
OCT-A 
optical coherence tomography angiography 
OIR 
oxygen-induced retinopathy
OU 
both eyes
p16
p16 cellular biomarker 
p21
p21 cellular biomarker 
PDGF 
platelet-derived growth factor
PDT 
Photodynamic therapy
PK 
pharmacokinetic
POC 
Proof-of-Concept 
PS 80 
polysorbate 80 
RBC 
red blood cell 
RPE 
retinal pigment epithelium 
SAC 
Safety Assessment Committee 
SAD 
single-ascending dose 

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Abbreviation
Definition
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SAR 
suspected adverse reaction 
SASP 
senescence-associated secretory phenotype
SD-OCT 
spectral domain optical coherence tomography
SE
study eye
SnCs 
senescent cells
SRF 
Subretinal fluid
SOE 
Schedule of Events
SUSAR
suspected unexpected serious adverse reaction
TEAE
treatment emergent adverse event
TNF 
tumor necrosis factor
US 
United States
VEGF 
vascular endothelial growth factor 
WBC 
white blood cell
WHO 
World Health Organization 

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1 
SYNOPSIS 
Title 
A Phase 2, Prospective, Multicenter, Randomized, 
Double-Masked, Active-Controlled Study to Assess the Safety, 
Tolerability and Evidence of Activity of a Repeat Intravitreal 
Injection of UBX1325 in Patients with Neovascular Age-Related 
Macular Degeneration (wet AMD)
Phase
Phase 2 
Study Design 
This is a Phase 2 Proof-of-Concept (POC) study. Approximately 
46 patients will be enrolled and randomized 1:1 into the repeat 
IVT injections of UBX1325 or active-control (aflibercept) and 
coadministration of UBX1325 study arms, in order to assess the 
primary and secondary objectives. All patients will be followed for 
approximately 48 weeks. 
The injector will be unmasked. The evaluator, patient, and 
sponsor clinical study personnel remains masked throughout the 
study. 
Rationale 
This study is intended to assess safety, tolerability and biological 
activity of repeat IVT injections of UBX1325 in patients with wet 
AMD. 
Target Population 
This study will enroll patients  50 years of age with wet AMD with 
best corrected visual acuity (BCVA) between 70 to 20 Early 
Treatment Diabetic Retinopathy Study (ETDRS) letters 
(equivalent to 20/40 to 20/400 on the Snellen chart) at Screening 
Number of Patients 
Approximately 46 patients
Length of Participation 
Run-in: Once patients meet inclusion/exclusion criteria, they will 
receive a single run-in injection of aflibercept approximately -8 
to -4 weeks prior to Day 1 
On treatment: On Day 1, patients will be randomized to either 
the UBX1325 arm or the aflibercept arm. 
Patients randomized to the UBX1325 arm will receive UBX1325 
on Day 1, Weeks 4, 24, and 28; and sham procedure on Weeks 
8, 16, 24, 32, and 40. 
Patients randomized to the active-control aflibercept arm will 
receive aflibercept per active-control every 8 weeks starting from 
day 1 until Week 40. In addition, these patients will receive 
UBX1325 on Week 24 and Week 32; and a sham procedure at 
Week 4 and Week 28. 
On study: Up to a total of approximately 56 weeks (8-week 
screening period + IVT of aflibercept at -8 to -4 weeks + 48-week 
follow-up period) 

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Intervention 
Patients will 
IVT injection at Day 1, Week 4, 24, and 28 (total injection of 1
 
x 4 injections in a 48-week period), active-control (aflibercept) per 
label, same day administration of aflibercept followed by 
UBX1325 approximately 30 minutes later at Week 24 & Week 32, 
or sham procedure(s).
Primary Objective and 
Endpoint 
Objective: Assess the local and systemic safety, tolerability and 
biological activity following a repeat IVT injection of UBX1325 
compared to active control (aflibercept)
through Week 24
 
Endpoint: 
Ocular and systemic safety and tolerability of a repeat IVT 
injection of UBX1325 compared to active-control (aflibercept)  
evaluated by treatment emergent adverse events (TEAEs) 
through Week 24. 
 
Secondary Objectives 
and Endpoints 
Objectives: Assess safety, efficacy parameters, and retinal 
structure of patients following: 
• 2 IVT injections (Cycle 1) of UBX1325 compared to active 
control (aflibercept) every 8 weeks through Week 24. 
• 2 additional IVT injections (Cycle 2) of UBX1325 through 
Week 48 compared to Cycle 1 through Week 24 
• Coadministration of UBX1325 with aflibercept through Week 
48 compared to aflibercept alone through Week 24 
 
Endpoints: 
o Change in BCVA from Baseline over time 
o Change in CST from Baseline over time as assessed by 
SD-OCT and read by a Central Reading Center 
o Safety through Week 48 

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Exploratory Objectives 
and Corresponding 
Endpoints 
Objective: Explore anatomical and physiological responses of a 
repeat IVT injections of UBX1325 compared to active-control 
and/or coadministration with aflibercept. 
Endpoints: 
o Proportion of UBX1325 treated patients who require anti-
VEGF rescue treatments over time 
o Time to rescue injection(s) 
o Change in retinal fluid from Baseline over time as assessed 
by SD-OCT and read by a Central Reading Center 
o Proportion of patients with absence of exudation (subretinal 
fluid [SRF]/intraretinal fluid [IRF]/cystoid edema) at any or all 
visits 
o Change in choroidal neovascularization (CNV) leakage and 
lesion size from Baseline on FA 
o Change in CNV lesion size from Baseline on OCT-A 
o Changes in choroidal blood flow on OCT-A 
Number of Sites
Approximately 25 sites in the US 
Study Duration 
Approximately 31 months including start up 
Safety Assessment 
Committee 
A Safety Assessment Committee (SAC) will be established for 
adjudication of adverse events (AEs) or possible safety signals. 
The committee will meet on an ad hoc basis. 

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Table 1 
Schedule of Events 
Test/Procedure
Screening 
Day -56 to 
Day -28
Visit 1 
Week 
0 
Day 1
Visit 2 
Week 
2 Day 
15 ± 7
Visit 3 
Week 
4 
Day 29 
± 7
Visit 4 
Week 
8 
Day 57 
± 7
Visit 5 
Week 
12 
Day 
85 ± 7
Visit 6 
Week 
16 
Day 
113 
± 7
Visit 7 
Week 
20 
Day 
141 
± 7
Visit 8 
Week 
24 
Day 
169 
± 7
Visit 9 
Week 
28 
Day 
197 ± 7
Visit 10 
Week 
32 Day 
225 ± 7
Visit 11 
Week 
36 
Day 
253 ± 7
Visit 
12 
Week 
40 
Day 
281 
± 7
Visit 
13 
Week 
44 
Day 
309 
± 7
Visit 
14 
Week 
48 
Day 
337 
± 7
Unscheduled 
Visit/ETk
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics
X
Medical / Ophthalmic 
History
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication 
History/Concomitant 
Medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical 
ExaminationL
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Vital Signs and 
Weight 
Xa 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests: 
Hematology and 
Chemistry 
Xb 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
Pregnancy Test 
X (serum)b 
X 
(urine)c
 
X 
(urine)c
X 
(urine)c
 
 
 
X
(urine)c
 
 
 
 
 
X 
(urine)
X (urine) 
12-Lead ECG
Xb
X
X
X
BCVA 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Anterior Segment 
Evaluation 
Xd 
Xd 
X 
Xd
Xd 
X 
Xd 
X 
Xd 
Xd 
Xd 
X 
Xd 
X 
X 
X 
Posterior Segment 
Evaluation 
Xd 
Xd 
X 
Xd
Xd 
X 
Xd 
X 
Xd 
Xd 
Xd 
X 
Xd 
X 
X 
X 
IOP 
Xd 
Xd 
X 
Xd
Xd 
X 
Xd 
X 
Xd 
Xd 
Xd 
X 
Xd 
X 
X 
X 
SD-OCTe 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT-Ae 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
FAe 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Xf 
CFPe 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 

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Test/Procedure 
Screening 
Day -56 to 
Day -28 
Visit 1 
Week 
0 
Day 1 
Visit 2 
Week 
2 Day 
15 ± 7 
Visit 3 
Week 
4 
Day 29 
± 7 
Visit 4 
Week 
8 
Day 57 
± 7 
Visit 5 
Week 
12 
Day 
85 ± 7 
Visit 6
Week 
16 
Day 
113 
± 7 
Visit 7
Week 
20 
Day 
141 
± 7 
Visit 8
Week 
24 
Day 
169 
± 7 
Visit 9 
Week 
28 
Day 
197 ± 7 
Visit 10 
Week 
32 Day 
225 ± 7 
Visit 11 
Week 
36 
Day 
253 ± 7
Visit 
12 
Week 
40 
Day 
281 
± 7 
Visit 
13 
Week 
44 
Day 
309 
± 7 
Visit 
14 
Week 
48 
Day 
337 
± 7 
Unscheduled 
Visit/ETk 
mfERGe
X 
X 
X 
X 
X 
X 
Low-luminance 
visual acuityi 
X 
 
 
X 
X 
 
X 
 
X 
 
 
X 
 
 
X 
X 
Eligibility Criteria 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Aflibercept 
Administration 
Xg
IVT Injection and/or 
Sham Procedureh 
X 
X 
X 
X 
Xj
X 
Xj
X 
AE assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE = adverse event; BCVA = best corrected visual acuity; CFP = color fundus photography; ECG = electrocardiogram; ET = early termination; 
FA = fluorescein angiography; IOP = intraocular pressure; mfERG = multifocal electroretinography; OCT-A = optical coherence tomography 
angiography; SD-OCT = spectral domain optical coherence tomography 
a
Height should also be measured at Screening
b
Serum pregnancy test, labs and ECG results are not required prior to aflibercept administration during Screening. The results must be verified 
prior to Day 1 randomization. 
c
Pre-dose urine dipstick.
d
Procedure to be performed pre-dose OU and post-dose SE only. On coadministration days, these assessments should be done pre and at 
each post IVT injection or sham procedure.  
e 
CFP, FA, SD-OCT, and OCT-A and mfERG images should be transmitted to the Central Reading Center at each applicable visit. mfERG to be 
conducted as the first ocular evaluation at sites with the proper equipment available and completed prior to IVT injection  
f
To be completed only if assessment has not been done within the last 30 days.
g 
All patients will receive aflibercept as a run-in injection prior to being randomized on Day 1 
h 
IVT injection is either UBX1325 study drug/sham and/or aflibercept/sham, depending on the arm the patient is randomized to. Refer to Study 
Schematic Figure 1 and Pharmacy Manual. Sham procedure should be administered to maintain the integrity of double-mask. NOTE: After all 
IVT injections or sham procedures have completed, sites should follow their standard practice with administration of prophylactic antibiotics 
and document all medication given. 
i
LLVA to be conducted at sites with the proper equipment

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j 
Refer to section 7.7, before coadministration, IOP must be 30 mmHg. Administration of UBX1325 or sham needs to be no less than 
15 minutes apart and no longer than 2 hours unless there are safety concerns, in which case the site should contact the unmasked medical 
monitor. 
k 
For Unscheduled Visit, tests/procedures can be performed as PI discretion. For ET all tests/procedures need to be performed. 
l 
Complete physical examinations will be performed by a licensed physician (or a physician’s assistant or nurse practitioner) at Screening, Visit 
8 (Day 169), Visit 14 (Day 337) or ET. Aside from those timepoints, symptom-directed physical examinations are required to be performed as 
clinically indicated 
 
 

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2 
INTRODUCTION 
UBX1325 is a new molecular entity that is being investigated by UNITY Biotechnology, Inc. (the 
Sponsor) for the treatment of neovascular Age-Related Macular Degeneration (wet AMD) and 
other retinovascular diseases. 
Age-related macular degeneration (AMD) is a leading cause of severe, irreversible vision loss in 
people age 60 and over. The neovascular form (wet AMD) is an advanced stage, which is 
responsible for the most severe vision loss (Schlottmann et al., 2017). It is an acquired disease 
of the macula characterized by progressive visual impairment due to late-onset 
neurodegeneration of the photoreceptor-retinal pigment epithelial complex 
(Al-Zamil and Yassin 2017). 
As many as 11 million people in the US have some form of AMD. This number is expected to 
double to nearly 22 million by 2050. Age is a prominent risk factor for AMD. The risk of 
developing advanced AMD increases from 2% for those ages 50-59, to nearly 30% for those 
over the age of 75 (Bright Focus Foundation 2020). 
Despite success of anti-VEGF therapy, patients experience an increased burden of treatment 
due to frequent injections and multiple office visits to assess treatment response. This presents 
a burden on patients and providers and ultimately results in reduced patient adherence and an 
inconsistent response (Holz et al., 2016). Additionally, several retrospective studies have 
reported suboptimal responder rates for anti-VEGF agents to be as high as 10-15% 
(Otsuji et al., 2013; Suzuki et al., 2014). 
2.1 
Overview of Age-Related Macular Degeneration 
There are 2 forms of macular degeneration. All AMD starts as the dry form, also called 
nonexudative or atrophic AMD. The dry form is the most common type; about 90% of people 
with AMD have dry AMD. The wet form, known as exudative or neovascular, occurs in about 
10% of those with AMD. Neovascular AMD is the cause of 80 to 90% of the severe vision loss 
cause by AMD (Cheung and Easton 2013). 
Early stages of AMD usually are asymptomatic and are characterized by the presence of drusen 
and pigmentary alterations within 2 disc diameters of the fovea (Ferris et al., 2012). Advanced 
AMD includes geographic atrophy (GA) and wet AMD. While early and intermediate AMD cause 
only minimal visual acuity impairment, advanced AMD is the leading cause of blindness 
worldwide (van Lookeren Campagne et al., 2014). 
AMD is a multifactorial blinding disease. It has been previously demonstrated that oxidative 
stress, aging, DNA damage and ultraviolet radiation can lead to AMD by influencing the 
autophagy function of retinal pigment epithelial (RPE) cells, cellular senescence, and the 
immune-inflammatory response (Wang et al., 2019). 
wet AMD is typically diagnosed using a fundus photo by the presence of the following: RPE 
and/or retinal detachment, exudates (lipid degradation products), fibrovascular scars, and 
hemorrhage. FA and OCT can be used to further characterize the vascular lesions based on 
location (subfoveal, juxtafoveal, or extrafoveal) and presenting features of drusen, atrophy, and 
neovascularization (van Lookeren Campagne et al., 2014; Al-Zamil and Yassin 2017; 
Ferris et al., 2012). 
Choroidal neovascularization (CNV) in wet AMD is likely a secondary reaction. Stress or 
damage in the RPE and the associated immune responses are believed to promote the 
production of pro-angiogenic factors, thereby driving CNV. In addition, degenerative changes 

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within the choridal vasculature are another plausible cause of pathological angiogenesis 
(van Lookeren Campagne et al., 2014). 
Examination of early AMD lesions indicated that loss of vessels and/or reduction of perfusion in 
the choriocapillaris precedes the formation of pathological vessels. Vascular loss is often 
accompanied by the accumulation of macrophages and giant cells as well as early signs of 
angiogenesis such as endothelial cell and pericyte activation. These asymptomatic vascular 
changes may result in hypoxia and upregulate angiogenic factors in the choroid, leading to the 
formation of pathological vessels. Among the angiogenic factors investigated, VEGF-A is found 
to be a key factor in animal models and patients. Indeed, VEGF-A inhibitors have proven to be 
safe and effective in treating wet AMD (van Lookeren Campagne et al., 2014). 
2.2 
Standard of Care  
Macular photocoagulation was studied extensively in the 1970s. Laser photocoagulation 
showed efficacy with positive visual outcomes in certain lesions. However, the adoption of laser 
photocoagulation in the treatment of wet AMD is hampered by several issues, including a high 
recurrence rate; a risk of producing vision loss, especially with subfoveal membranes; and a 
limited visual improvement potential. In the era of anti-VEGF therapies, the role of direct 
photocoagulation as a major treatment approach for wet AMD is waning. If used, this treatment 
should be limited to treat very small lesions outside the central macula 
(Al-Zamil and Yassin 2017). 
Photodynamic therapy (PDT) was introduced in the late 1990s. It was used with a 
photosensitizer verteporfin administered intravenously to form reactive-free radicals that 
damage the vascular endothelium and induce occlusion of new vessels. The use of PDT has 
declined because of inadequate and unpredictable effects of PDT on CNV. Nowadays, the use 
of PDT is usually considered in combination with an anti-VEGF or steroid as a second line of 
therapy to nonresponders (Al-Zamil and Yassin 2017). 
There are 3 available anti-VEGF therapies in the US that are considered standard of care for 
wet AMD. However, not all patients benefit from the effect of these drugs and many respond 
sub-optimally. It has been hypothesized that this high rate of suboptimal responders is largely 
due to angiogenic factors and pathways other than VEGF playing a role in the disease 
progression. Long-term studies evaluating the efficacy of anti-VEGF agents have demonstrated 
that initial improvements in vision over the first 2 years are not always sustained over longer 
periods of time. This may be the result of under treatment in the real world setting or potentially 
the development of macular atrophy in these patients (Gahn and Khanani 2018). 
2.3 
Target Indication and Population 
This study will enroll patients 
50 years of age with wet AMD with BCVA of 70 TO 20 ETDRS 
letters (equivalent to 20/40 to 20/400 on the Snellen chart). 
2.4 
Scientific Rationale for UBX1325 as a Treatment for wet AMD 
The Sponsor hypothesizes that the accumulation of senescent cells (SnCs) in the retina 
contributes to retinal disease. UBX1325 is a phosphate pro-drug of the active parent molecule, 
UBX0601, an inhibitor of the anti-apoptotic protein Bcl-xL in the retina. Inhibition of Bcl-xL leads 
to induction of apoptosis, ultimately leading to cell death. IVT administration of UBX1325 in 
mouse oxygen-induced retinopathy (OIR) model decreased neovascular retinal area and 
avascular area, presumably due to restoration of healthy vasculature after elimination of 

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pathological SnCs. The effect of UBX1325 on mouse OIR model provides support for the 
treatment of neovascular diseases such as proliferative diabetic retinopathy and wet AMD. 
2.4.1
Role of Senescence in Retinal Disease
The principal feature of senescence, a regulated cellular program, is to induce a cell to enter a 
permanent state of cell cycle arrest. The first observation that human cells do not divide 
indefinitely was proposed in 1961 by the seminal work by Leonard Hayflick (Hayflick and 
Moorhead 1961). Several important features of the senescence program have since been 
elucidated. Exposure to damage-inducing stimuli such as oxidative stress, radiation, and 
ischemia are among factors associated with the induction of senescence. Several studies 
(Marazita et al., 2016; Lamoke et al., 2015; Ma and Wong 2016) have confirmed the correlation
between these stressors and angiogenic retinal disease. SnCs produce a set of proinflammatory 
factors, cytokines, chemokines, and others that are called senescence-associated secretory 
phenotype (SASP). Although many factors of SASP have been identified in wet AMD and 
diabetic retinopathy (DR), a list of the most relevant ones associated with each disease have 
been studied and identified with many of them having a proinflammatory role (Funk et al., 2009; 
Sato et al., 2018; Schori et al., 2018). 
Blasiak et al., 2017 demonstrated the role of SASP in RPE cells, photoreceptors, and 
choriocapillaris and postulated that in the central retina, RPE cells cannot be easily replaced by 
peripheral RPE cells leading to DNA damage response, autophagy, photoreceptor 
degeneration, and eventually, vision loss.
Evidence of SnCs in human retinopathies has focused on SASP and in vitro culture systems but
reports of p16+ immunohistochemistry (IHC) and cell-type identification are limited. Literature 
reports suggest presence of SnCs in aged primates (Mishima et al., 1999), and the proliferation 
potential of human RPE cells in vitro is suggested to be influenced by donor age 
(Flood et al. 1980). Recently, Lopez-Luppo et al., 2017 reported the presence of p16+ cells in 
the retinal vasculature of aged human donors and vessels associated with microaneurysms. 
Figure 2 
Immunohistochemical Staining of p16+ Cells in Human Donors
AMD = age-related macular degeneration; DAPI = 4’,6-diamidino2-phenylindole; DME = diabetic macular 
edema; DR = diabetic retinopathy; N = number of patients; p16 = p16 cellular biomarker. 
Retinal sections from human donor tissue were subject to immunohistochemical staining for p16. Cell 
nuclei were stained with DAPI, and % cells positive for p16 were calculated for each donor globe.
N = 27-43 per group.

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Immunohistochemical staining performed by the Sponsor, of retinal sections from patients with 
DR/diabetic macular edema (DME) and AMD indicates the presence of p16+ cells (Figure 2). 
When quantified and compared to age-matched normal tissue, a significant SnC burden was 
observed in both DR/DME and AMD globes. 
The Sponsor hypothesizes that there is a close relationship between senescence burden, 
measured by p16 IHC in the retina, the presence of SASP in the tissue, and clinical progression 
in patients with DR and DME. UBX1325 has the potential to remove SnCs from a tissue without 
altering the healthy resident cells in the eye and slow down the progression of the disease or 
even provide structural and functional recovery by addressing not just one target factor like 
VEGF, but a set of proinflammatory or growth factors present in the SASP. This approach would 
address more effectively the multifactorial character of the disease and may decrease the 
proportion of patients that respond either poorly or partially to anti-VEGF, the need for repeated 
treatments, and the long-term complications like fibrosis and macular atrophy. 
2.4.2 
Disease-Relevant Senescence-Associated Secretory Phenotype from 
Senescent Retinal Cells 
In addition to the cellular marker of senescence, elevated expression of several secreted factors 
has been associated with retinal diseases, which have been detected in the vitreous humor and 
aqueous humor from patients with ocular disease. Levels of mediators such as VEGF, tumor 
necrosis factor (TNF), IL-
-derived growth factor (PDGF), and IL-6 are significantly 
increased in the ocular fluids of DR and AMD globes (Bromberg-White et al., 2013; 
Boss et al., 2017; Ghodasra et al., 2016; Sato et al., 2018). In addition to p16, the Sponsor is 
focused on the association of disease-relevant SASP to our senescent cellular and in vivo 
animal models. Elimination of SnCs by UBX1325 may lead to a reduction in SASP by targeting 
the source, resulting in the restoration of homeostasis and retinal function. 
Human ocular cell types can be cultured and rendered senescent by a variety of different 
insults, including DNA-damaging treatment (e.g., irradiation) and disease relevant- conditions 
such as incubation in elevated glucose media. Human retinal microvascular endothelial cells 
(HRMEC) upregulate the production of important mediators such as VEGF and PDGF upon 
induction of senescence by glucose (Figure 3). As these molecules have been shown to be 
elevated in DR patients (Ghodasra et al., 2016; Klaassen et al., 2017), it stands to reason that 
senescent HRMEC in the retinas of patients may be the source of the elevated VEGF/PDGF 
that contribute to disease pathogenesis. 

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Figure 3 
Induction of Senescence and DR-Relevant Genes After Glucose 
Treatment
DR = diabetic retinopathy; HRMEC = human retinal microvascular endothelial cells; mRNA = messenger ribonucleic 
acid; NSnC = non-senescent cells; SnC = senescent cells; PDGF = platelet-derived growth factor; p16 = p16 cellular 
biomarker; p21 = p21 cellular biomarker; VEGF = vascular endothelial growth factor. 
Increased expression of several genes was observed by qRT-PCR in non-senescent HRMEC (NsnC) or HRMEC 
treated with elevated glucose (200 mM) in culture media for 2 weeks.
2.4.3
Description of UBX1325
UBX1325 is a phosphate pro-drug of the active parent molecule, UBX0601, which is cleaved 
rapidly in tissues by a ubiquitously present enzyme, a phosphatase. UBX1325 was designed to 
aid in solubility of UBX0601 as an ophthalmic formulation. In all nonclinical studies conducted, 
UBX1325, as a pro-drug, is administered in an appropriate formulation, then converted in vivo 
rapidly to UBX0601 in vivo for its potent inhibition of Bcl-xL in the retina. In this protocol, Study 
Drug refers to UBX1325.
The Bcl-2 gene family encodes more than 20 proteins that regulate the intrinsic apoptosis 
pathway and are fundamental to the balance between cell survival and death. Inhibition of 
particular members of the Bcl-2 family of apoptosis regulatory proteins disrupts the interactions 
with pro-apoptotic activators and effectors, resulting in cell death. SnCs utilize pro-survival 
mechanisms to remain viable and rely on particular members of the Bcl-2 family of apoptosis 
regulatory proteins members to persist and accumulate in tissues (Yosef et al., 2016). Binding 
of retinal Bcl-xL by UBX0601 in senescent HRMEC acts to promote caspase activation and the 
apoptotic cascade, ultimately leading to cell death (manuscript in preparation). 
In streptozotocin-induced DR mouse model, IVT administration of UBX1325 resulted in 
decreased vascular leakage at all doses tested (2 to 200 pmol) (Figure 4). Similarly, IVT 
administration of UBX1325 in the mouse OIR model resulted in decreased neovascularization
(Figure 4). Refer to the Investigator’s Brochure (IB) for additional details.

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Figure 4 
Improved Vascular Leakage and Neovascularization by UBX1325
ANOVA = analysis of variance; IVT = intravitreal; PS-80 = polysorbate 80
A) Increased retinal vascular leakage was measured by Evans Blue extravasation in diabetic mice (Vehicle) as 
compared to non-diabetic animals. All 3 dose levels of UBX1325 (2-200 pmol, IVT) significantly reduced vascular 
leakage. B) Neovascular area was determined from isolectin B4-stained images of OIR retinas. All 4 dose levels of 
UBX1325 (3-100 pmol, IVT) significantly reduced retinal neovascularization as compared to vehicle control animals.
2.4.4
Supportive Nonclinical Data
All nonclinical pharmacology, pharmacokinetic (PK), and toxicology, studies briefly described in 
this section were conducted by or for the Sponsor. More detailed information is provided in the 
current version of the IB.
2.4.4.1
Pharmacology
UBX1325 (pro-drug) and UBX0601 (active parent molecule), where appropriate, were studied in 
cellular and animal models of ocular disease to demonstrate activity in the retina. UBX1325 is a 
potent inhibitor of Bcl-2 family of apoptosis regulatory proteins, which results in initiation of 
apoptosis in HRMEC, in vitro. In 2 different mouse models of retinal dysfunction, UBX1325 
demonstrated inhibition of disease-relevant endpoints such as neovascularization (NV) and 
vascular leakage. UBX1325 is a  pro-drug of UBX0601, which is cleaved rapidly in tissues by a 
ubiquitously present enzyme, phosphatase.
2.4.4.2
Pharmacokinetics
Ocular tissue exposures of UBX1325 and UBX0601 following a single IVT injection of 50 µg of 
UBX1325 were well-characterized in rabbits following serial necropsy at 2, 24, 72, 168, 240, and 
336 hours, post-dose. UBX0601 half-lives in the vitreous humor, retina, choroid, and iris-ciliary 
body of rabbits were 48 hours, 34 hours, 47 hours, and 80 hours, respectively. The 
concentration of UBX0601 in the lens showed a slower rate of decline with an estimated half-life 
of 173 hours. Aqueous humor concentrations, which did not allow for PK estimates, appeared to 

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remain at a very low level 
1 following 
intraocular dose was minimal, usually below the lower limit of quantification in the assay 
(1 
 
2.4.4.3 
Toxicology 
ocular toxicity studies in New 
Zealand White (NZW) rabbits and monkeys with observation periods of up to 2 months following 
-week IVT cynomolgus monkey combination study with 
UBX1325 and aflibercept with a 4-week recovery period was completed. Also, in order to 
evaluate the potential for systemic toxicity, one-
UBX1325 was given as a once weekly IV dose to rats and dogs. The no-observed-effect-level 
no-
levels n
Cardiovascular, respiratory, and neurobehavioral safety pharmacology studies following IV 
dosing of UBX1325 did not show any impact on these parameters. Specifically, in the CV dog 
study, there were no effects on QTc. This result was consistent with UBX1325 and UBX0601 
not having clinically relevant effects on the human ether-à-go-go-related gene (hERG) channel. 
The combination of UBX1325 with aflibercept was well tolerated with no effects on IOP, ERGs, 
the cynomolgus monkey. There was no apparen
aflibercept concentrations. In addition, UBX1325 and UBX0601 were not genotoxic in in vitro 
 
In the 
-week IVT cynomolgus combination study, UBX1325 and aflibercept were dosed at 
a 2-week interval with no apparent signs of toxicity.  
Intravitreal administration of UBX1325 (on Study Day 15) in combination with aflibercept (on 
Study Days 1 and 29), was well tolerated. There was no 
or aflibercept-related clinical observations or changes in food consumption or body weight; no 
-related IOP changes or effects on ffERG or VEP; and no 
clinical or anatomic pathology ef
-related findings were limited to 
non-adverse and reversible findings noted ophthalmoscopically and on OCT. 
2.4.5 
Benefit:Risk Assessment 
2.4.5.1 
Previous Human Experience with Bcl-2 Inhibitors 
UBX1325 is in a class of agents known to inhibit certain members of the Bcl-2 family that are 
apoptosis regulatory proteins. Targeting this pathway has been extensively studied in 
connection with the search for new oncology medicines. Some tumor cells can become 
dependent on Bcl-2 for survival, which allows for specific targeting with inhibitors of Bcl-2. Bcl-2 
inhibitors have been investigated in the oncology setting indicating safety and tolerability when 
administered systemically in humans (Tse et al., 2008; Touzeau et al., 2014; 
Souers et al., 2013). To the best of the Sponsor’s knowledge, Bcl-2 inhibitors have not 
previously been investigated in an ocular setting. 
UBX1325 was administered to patients with advanced DME and wet AMD in the Phase 1 single 
ascending dose (SAD) study, UBX1325-01. UBX1325 was well tolerated with favorable safety 

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profile supporting further development. As of November 9, 2021 there were a total of 14 adverse 
events unrelated to study drug. Of those 14, 4 were non-ocular, non-serious, non-drug related 
adverse events in 2 wet AMD patients (1 patient contracted COVID-19 and 1 patient had a tooth 
extraction, blister on gums and constipation). The remaining 10 ocular, non-serious, non-drug 
related adverse events occurred in 9 patients (2 DME and 7 wet AMD). Nine were study eye 
related (progression of disease in 8 patients, 1 DME and 7 wet AMD) and 1 was non-study eye 
related (retinal detachment in 1 DME patient). There were no serious adverse events, 
dose-limiting toxicities, inflammation, or AEs that would preclude advancement into later-stage 
clinical development. 
The Sponsor is aware of the systemic toxicities associated with venetoclax, an 
-approved 
oral Bcl-2 selective 
acute myeloid leukemia. As a consequence of being in the same class of molecules, and in view 
of similar systemic toxicities noted in UBX1325 IV nonclinical studies, the Sponsor is planning to 
monitor for potential Bcl-2 inhibitor related toxicities (e.g., cytopenia) that may emerge from 
UBX1325 IVT treatment (Section 8). However, based on currently available exposure data from 
nonclinical studies following IVT dosing (Section 2.4.4.2) and the lack of measurable systemic 
exposure of UBX1325 and UBX0601 after a single IVT dose at all doses tested in patients in the 
Phase 1 SAD study, the Sponsor expects systemic exposure of UBX1325 following IVT 
treatment to be low in patients and, therefore, the potential to observe such systemic events is 
also low. 

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3 
OBJECTIVES AND ENDPOINTS 
Tier
Primary 
Objective and 
Endpoint  
Assess the local and 
systemic safety, tolerability
and biological activity 
following a repeat IVT 
injection of UBX1325 
compared to active control 
(aflibercept) through Week 24
Ocular and systemic safety and 
tolerability of a repeat IVT injection of 
UBX1325 compared to active-control 
(aflibercept) evaluated by treatment 
emergent adverse events (TEAEs) 
through Week 24 
Secondary
Objectives and 
Endpoints  
Assess efficacy parameters 
and retinal structure of 
patients following:  
•
2 IVT injections (Cycle 1)
of UBX1325 compared to
active-control (aflibercept)
every 8 weeks through
Week 24.
•
2 additional IVT injections
(Cycle 2) of UBX1325
through Week 48
compared to Cycle 1
through Week 24
•
Coadministration of
UBX1325 with aflibercept
through Week 48
compared to aflibercept
alone through Week 24
o
Change in BCVA from Baseline over
time
o
Change in CST from Baseline over
time as assessed by SD-OCT and
read by a Central Reading Center
o

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Exploratory 
Objectives and 
Corresponding 
Endpoints 
Explore anatomical and 
physiological responses of a 
repeat IVT injections of 
UBX1325 compared to active- 
control 
coadministration 
with aflibercept. 
o
Proportion of UBX1325 treated 
patients who require anti-
rescue treatments over time 
o
Time to rescue injection(s)
o Change in retinal fluid from Baseline 
over time as assessed by SD-OCT 
and read by a Central Reading 
Center 
o Proportion of patients with absence of 
exudation (subretinal fluid 
edema) at any or all visits 
o Change in choroidal 
neovascularization (CNV) leakage 
 
o Change in CNV lesion size from 
Baseline on OCT-A 
o Changes in choroidal blood flow on 
OCT-A 
3.1 
Exploratory Substudies 
At select sites, the Sponsor may propose exploratory substudies associated with this Protocol. If 
so, each substudy will be documented in a separate substudy protocol and will utilize separate 
 

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4 
STUDY PLAN 
4.1 
Study Design 
This is a Phase 2, prospective, multicenter, randomized, double-masked, active-controlled study 
to assess the safety, tolerability and evidence of activity of repeat IVT injections of UBX1325 in 
patients with wet AMD. Approximately 46 patients will be enrolled 1:1 to the repeat doses of 
UBX1325 or active-controlled (aflibercept) study arms, in order to assess the primary objective. 
All patients will be followed for approximately 48 weeks. 
See Section 7.8 for details on double-masking and site requirements. A schematic 
representation of the study design is presented in 
 1. 
4.2 
Design Rationale 
4.2.1 
Patient Population Selection 
Based on the in vitro and in vivo pharmacology and toxicology data (refer to the UBX1325 IB) 
and scientific rationale (see Section 2.4), the Sponsor asserts that UBX1325 can be tested for 
safety, tolerability and evidence of activity in wet AMD patients. 
Patients will be those who are 50 years of age or older and diagnosed as having wet AMD with 
BCVA in the SE of 70 to 20 
40 
on the Snellen chart). 
4.2.2 
Dose Rationale 
As of November 9, 2021, in patients with advanced DME and wet AMD in the SAD Phase 1 
study, UBX1325 was well tolerated with favorable acute safety profile supporting development; 
no dose-limiting toxicities in any of the dose cohorts, including the high do
The 
 
In terms of mechanism of action, of the drug and based on preclinical models, a single injection 
of UBX1325 is proposed to induce the selective elimination of SnCs. However, it is conceivable 
that a single injection is insufficient in eliminating all SnCs in the tissue, therefore elimination of 
additional SnCs with a repeat dose of UBX1325 can potentially be clinically beneficial. 
om choroidal vasculature is affected, optimum efficacy and 
durability may require a repeat dose so this Phase 2 aims to determine if the repeat will be 
clinically beneficial. 

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5 
POPULATION 
5.1 
Recruitment 
Approximately 46 patients are planned to enroll in this study. 
5.2 
Definitions  
Patients officially enter the Screening Period following provision of informed consent. 
A screen failure is a consented patient who has been deemed ineligible on the basis of 1 or 
more eligibility criteria or who has withdrawn consent prior to randomization. Screen failures 
may be rescreened. Patients will be permitted to re-screen once and in consultation with the 
Sponsor’s Medical Monitor. 
An enrolled patient is one who has been deemed eligible and has been randomized. 
5.3 
Inclusion Criteria 
To be included in this study, each individual must satisfy all of the following criteria: 
1.
Patients aged  50 years.
2.
Active CNV associated with age-
SD-OCT with presence of intraretinal or subretinal fluid at Screening and Day 1 with either
the CNV or fluid involving the center of the fovea
3.
Wet AMD patients who have had at least 2 anti-
SE in the preceding
6 months prior to Screening, with the last injection within 4-8 weeks of Screening
4.
BCVA in the SE 
the Snellen chart) at Screening. On Day 1, BCVA cannot be an improvement of 10 or more
letters from Screening
Note: if both eyes are eligible, Investigator discretion should be utilized.
5.
IOP 
23 mmHg in the SE.
6.
-OCT, and adequate
BCVA evaluation.
7.
Patients who have the capacity to give informed consent and who are willing and able to
comply with all study-related procedures and assessments.
5.4 
Exclusion Criteria 
If an individual meets any of the following criteria, he or she is ineligible for this study: 
8.
Concurrent disease in the SE or structural damage, other than wet AMD, that could
compromise BCVA, prevent BCVA improvement, require medical or surgical intervention
during the study period, confound interpretation of the results, or interfere with assessment
SE. This includes, but is not limited to, the following:
Clinically significant subretinal fibrosis

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Subfoveal lipid with atrophy involving center of fovea 
 
Cataract requiring surgery during the study period 
 
RPE atrophy or tear or rips involving the macula 
 
Presence of macular hole 
 
History of uveitis 
 
Vitreomacular traction 
 
Clinically significant epiretinal membrane (ERM) 
 
 
 
Other retinovascular disease (e.g., macular telangectasia) 
9. 
her eye in the past 12 weeks 
prior to Screening (mild blepharitis is acceptable) 
10. Subretinal hemorrhage with bleeding area 
4 disc area in the SE 
11. History of vitrectomy in the SE 
12. History of intraocular, periocular, or corneal surgery (including cataract surgery), in the SE 
within 3 months prior to Screening, or anticipated need for such surgery during the study 
13. History of panretinal photocoagulation or macular laser photocoagulation in the SE 
14. History of corneal transplant in the SE 
15. Patients with glaucoma who are poorly controlled in the opinion of the investigator or on 3 or 
more medications (whether administered as single agents or in combination formulations) 
16. Any condition, including laboratory findings and findings in the medical history or in 
screening or Day 1 assessments, that, in the opinion of the Investigator, constitutes a risk or 
contraindication for participation in the study or that could interfere with the study objectives, 
conduct, or evaluation or prevent the patient from fully participating in all aspects of the 
study 
17. Presence of severe myopia (-8 diopters or greater) in the SE 
18. History of topical steroid use for the SE or systemic steroid use for 6 months prior to 
Screening. The use of intravitreal steroids is prohibited. Inhaled and locally administered 
steroids are acceptable 
19. History of Visudyne® photodynamic therapy in the SE 
20. Significant media opacities, including cataract, which might interfere with visual acuity, 
assessment of toxicity, or fundus imaging 
21. Known allergy to any component (phosphate buffered saline and polysorbate 80) of the 
Study Drug or to any component of aflibercept, or a clinically relevant sensitivity to 
fluorescein dye  
22. 
tential who do not agree to 
use highly effective methods of birth control (e.g., progesterone-only hormonal 
contraception, double barrier, or intrauterine device) during the study and for 3 months 
following the last dose of Study Drug. Postmenopausal females (> 45 years old and without 

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menses for more than 1 year) and surgically sterilized females are exempt from these 
requirements. 
23. Male patients who do not agree to use a highly effective method of contraception during the
study and for 3 months following the last dose of Study Drug, if sexually active with a female
partner of childbearing potential.
24. Patients who within 3 months of screening received or are concurrently on another
investigational drug or vaccine study, including patients who previously received treatment
in a UBX1325 study. Coronavirus Disease 2019 (COVID-19) vaccinations are permitted
prior to or during the course of the study.
25. Any uncontrolled medical condition, in the opinion of the Investigator, would preclude
participation in this study, including, but not limited to, history of malignancy within the last
5 years, history of myocardial infarction within the last 6 months, or concomitant therapy
that, in the opinion of the Investigator, would preclude participation in this study.

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6 
STUDY CONDUCT 
The expected duration of study participation for patients will be approximately 56 weeks, which 
includes a 8-week screening period and 48 weeks of follow-up. 
The procedures outlined below and in the Schedule of Events (Table 1) will take place for all 
patients. 
6.1 
Study Procedures 
6.1.1 
Study Screening and Treatment Periods 
6.1.1.1 
Screening Period (Day -56 to Day -28) 
• Informed Consent 
• Demographics 
• Medical and Ophthalmic History 
• 
 
• Historical anti-
 for OU in the 6 months preceding Screening, 
where available 
• Physical Examination (Complete) 
• Vital Signs and Weight  
• Height 
• 
Chemistry* 
• Pregnancy Test (serum)* 
•
12-lead ECG* 
• BCVA 
• Anterior Segment Evaluation (pre-dose in OU and post-dose in SE of aflibercept) 
• Posterior Segment Evaluation (pre-dose in OU and post-dose in SE of aflibercept) 
• IOP (pre-dose in OU and post-dose in SE of aflibercept) 
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• 
 
• 
 
• 
-luminance visual acuity (to be conducted at sites with the proper equipment) 

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•
Eligibility Criteria
•
Aflibercept Administration
o
or patients currently receiving aflibercept, they will be maintained on that therapy;
for patients on other anti-
Screening
•
AE assessment
*NOTE: the results must be verified on Day 1 and are not required prior to aflibercept
administration during Screening
6.1.1.2 
Visit 1 (Day 1) 
•
Medical and Ophthalmic History
•
•
Vital Signs and Weight
•
Pregnancy Test (pre-dose urine dipstick)
•
BCVA
•
Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection in SE)
•
Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection in SE)
•
IOP (pre-IVT injection in OU and post IVT injection in SE)
•
SD-OCT
•
mfERG (to be conducted at sites with proper equipment available and done prior to IVT
injection)
•
Eligibility Criteria
•
IVT injection of UBX1325 or aflibercept
•
Prophylactic Antibiotics Post IVT Injection (optional)
•
AE assessment
6.1.1.3 
Visit 2 (Day 15) 
The following procedures will be done: 
•
Medical and Ophthalmic History

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• 
 
•
Vital Signs and Weight
• BCVA 
•
Anterior Segment Evaluation
• Posterior Segment Evaluation  
• IOP  
• SD-OCT 
• AE Assessment 
6.1.1.4 
Visit 3 (Day 29) 
• Medical and Ophthalmic History 
• 
 
• Vital Signs and Weight 
• Pregnancy Test (pre-dose urine dipstick) 
• BCVA 
• Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE) 
• Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE)  
• IOP (both pre-IVT injection in OU and post IVT injection or sham procedure in SE)  
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• 
 
• 
 
• mfERG (to be conducted at sites with proper equipment available and done prior to IVT 
injection or sham procedure) 
• 
-luminance visual acuity (to be conducted at sites with proper equipment available) 
• IVT injection of UBX1325 or sham procedure 

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• Prophylactic Antibiotics Post IVT Injection or sham procedure (optional) 
•
AE assessment
6.1.1.5 
Visit 4 (Day 57) 
• Medical and Ophthalmic History 
• 
 
• Vital Signs and Weight 
• Pregnancy Test (pre-dose urine dipstick) 
• BCVA 
• Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE) 
• Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE)  
• IOP (pre-IVT injection in OU and post IVT injection or sham procedure in SE)  
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• 
 
• 
 
•
mfERG (to be conducted at sites with proper equipment available and done prior to IVT 
injection or sham procedure) 
• 
-luminance visual acuity (to be conducted at sites with proper equipment available) 
• IVT injection of aflibercept or sham procedure 
• Prophylactic Antibiotics Post IVT Injection or sham procedure (optional) 
• AE assessment 
6.1.1.6 
Visit 5 (Day 85) 
• Medical and Ophthalmic History 
• 
 

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•
Vital Signs and Weight
•
BCVA
•
Anterior Segment Evaluation
•
Posterior Segment Evaluation
•
IOP
•
SD-OCT
•
AE Assessment
6.1.1.7 
Visit 6 (Day 113) 
•
Medical and Ophthalmic History
•
•
Vital Signs and Weight
•
BCVA
•
Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham
procedure in SE)
•
Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham
procedure in SE)
•
IOP (pre-IVT injection in OU and post IVT injection or sham procedure in SE)
•
SD-OCT
•
OCT-A (to be conducted at sites with proper equipment available)
•
•
•
-luminance visual acuity (to be conducted at sites with proper equipment available)
•
IVT injection of aflibercept or sham procedure
•
Prophylactic Antibiotics Post IVT Injection or sham procedure (optional)
•
AE assessment

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6.1.1.8 
Visit 7 (Day 141) 
• Medical and Ophthalmic History 
• 
 
• Vital Signs and Weight 
• BCVA 
•
Anterior Segment Evaluation
• Posterior Segment Evaluation 
•
IOP
•
SD-OCT 
• AE Assessment 
6.1.1.9 
Visit 8 (Day 169) 
• Medical and Ophthalmic History 
• 
 
• Vital Signs and Weight 
• Physical Examination (Complete) 
• 
 
• Pregnancy Test (urine dipstick) 
• 12-lead ECG 
• BCVA 
• Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injections 
or 
sham procedure in SE)  
• Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injections 
or 
sham procedure in SE)  
• IOP (pre-IVT injection in OU and post IVT injections 
or sham procedure in SE). 
 
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• 
 

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•
CFP
•
mfERG (to be conducted at sites with proper equipment available)
•
Low-luminance visual acuity (to be conducted at sites with proper equipment available)
•
IVT injection of UBX1325 and aflibercept or sham. Administration of UBX1325 or sham
needs to be no less than 15 minutes apart and no longer than 2 hours unless there are
safety concerns, in which case the site should contact the unmasked medical monitor.
•
Prophylactic Antibiotics Post IVT Injection or sham procedure (optional)
•
AE assessment
6.1.1.10 
Visit 9 (Day 197) 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Vital Signs and Weight
•
BCVA
•
Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham
procedure in SE)
•
Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham
procedure in SE)
•
IOP (pre-IVT injection in OU and post IVT injection or sham procedure in SE)
•
SD-OCT
•
IVT injection of UBX1325 or sham procedure
•
Prophylactic Antibiotics Post IVT Injection or sham procedure (optional)
•
AE assessment
6.1.1.11 
Visit 10 (Day 225) 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Vital Signs and Weight
•
BCVA

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• Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injections and/or 
sham procedures in SE)  
• Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injections and/or 
sham procedures in SE)  
• IOP (pre-IVT injection in OU and post IVT injections and/or sham procedures in SE). 
 
• SD-OCT 
•
IVT injection of UBX1325 or sham and aflibercept or sham. Administration of UBX1325 
or sham needs to be no less than 15 minutes apart and no longer than 2 hours unless 
there are safety concerns, in which case the site should contact the unmasked medical 
monitor. 
• Prophylactic Antibiotics Post IVT Injection or sham procedure (optional) 
• AE assessment 
 
6.1.1.12 
Visit 11 (Day 253) 
• Medical and Ophthalmic History 
• Medication History/Concomitant Medications 
• Vital Signs and Weight 
• BCVA 
• Anterior Segment Evaluation  
• Posterior Segment Evaluation  
•
IOP
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• FA 
• CFP 
• mfERG (to be conducted at sites with proper equipment available) 
• Low-luminance visual acuity (to be conducted at sites with proper equipment available)  
• AE assessment 
 

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6.1.1.13 
Visit 12 (Day 281) 
• Medical and Ophthalmic History 
• Medication History/Concomitant Medications 
• Vital Signs and Weight 
• BCVA 
•
Anterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE)  
• Posterior Segment Evaluation (pre-IVT injection in OU and post IVT injection or sham 
procedure in SE)  
• IOP (pre-IVT injection in OU and post IVT injection or sham procedure in SE)  
• SD-OCT 
• IVT injection of aflibercept or sham procedure 
• Prophylactic Antibiotics Post IVT Injection or sham procedure (optional) 
• AE assessment 
6.1.1.14 
Visit 13 (Day 309) 
• Medical and Ophthalmic History 
• Medication History/Concomitant Medications 
• Vital Signs and Weight 
• BCVA 
• Anterior Segment Evaluation 
• Posterior Segment Evaluation 
• IOP 
• SD-OCT 
• AE assessment 
6.1.1.15 
Visit 14 (Day 337) 
• Medical and Ophthalmic History 

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•
Medication History/Concomitant Medications
•
Vital Signs and Weight
•
Physical Examination ( Complete)
•
Laboratory Tests: Hematology and Chemistry
•
Pregnancy Test (urine dipstick)
•
12-lead ECG
•
BCVA
•
Anterior Segment Evaluation
•
Posterior Segment Evaluation
•
IOP
•
SD-OCT
•
OCT-A (to be conducted at sites with proper equipment available)
•
FA
•
CFP
•
mfERG (to be conducted at sites with proper equipment available)
•
Low-luminance visual acuity (to be conducted at sites with proper equipment available)
•
AE assessment
6.1.1.16 
Unscheduled Visit/Early Termination (ET) 
For Unscheduled Visit, tests/procedures can be performed as PI discretion. For ET, all 
tests/procedures need to be performed. 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Complete Phyisical Examination for ET & Symptom Directed Physical Examination for
Unscheduled Visit
•
Vital Signs and Weight
•
Laboratory Tests: Hematology and Chemistry
•
Pregnancy Test (urine dipstick)

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• 12-lead ECG 
•
BCVA 
• Anterior Segment Evaluation 
•
Posterior Segment Evaluation
• IOP 
• SD-OCT 
• OCT-A (to be conducted at sites with proper equipment available) 
• FA (if not done within the last 30 days) 
• CFP 
• Low-luminance visual acuity (to be conducted at sites with proper equipment available)  
• AE Assessment 
6.1.2 
Informed Consent 
It is the responsibility of the Investigator to obtain signed written consent for the study from each 
patient prior to participating in the study to provide for the protection of the patients by following 
applicable regulations and institutional policies and procedures. The Informed Consent Form 
(ICF) used during the informed consent process must be reviewed by the Sponsor or designee 
and approved by the Institutional Review Board (IRB)/Independent Ethics Committee (IEC). 
6.1.3 
Medical History and Concomitant Medication Review 
A detailed medical history will be obtained by the Investigator or qualified designee. This will 
include a comprehensive medical history and a complete review of systems, with specific 
attention to inclusion and exclusion criteria. The historical anti-VEGF should be collected for OU 
in the preceding 6 months prior to Screening should be documented in the concomitant 
medication log. All historical imaging and ophthalmological assessments done for OU (when 
available) in the preceding 6 months prior to Screening should be entered into the designated 
eCRF. BCVA and CST values should be entered into EDC. Past medical history deemed by the 
Investigator as not clinically relevant to the patient’s overall health status or to his or her wet 
AMD will not be captured. Relevant medical history will be recorded in the electronic case report 
form (eCRF). 
All medications taken for wet AMD will be recorded in the eCRF Concomitant Medication Log. 
6.1.4 
Physical Examination 
Physical examination includes assessments of the skin, head and neck, lungs, heart, abdomen, 
lymph nodes, extremities, and body weight. Height will be measured at Screening only. 
Complete physical examinations will be performed by a licensed physician (or a physician’s 
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from those timepoints, symptom-directed physical examinations are required to be performed as 
clinically indicated. 
6.1.5 
Vital Signs and Body Weight 
Vital signs (blood pressure, respiratory rate, pulse rate, and oral temperature) will be obtained in 
the sitting position. The patient must be in the sitting position for 5 minutes prior to obtaining 
vital signs. In regard to COVID, if the site has a COVID related protocol, exceptions can be 
made to collect forehead temperature readings. Sites must remain consistent with how that data 
is collected across all study visits for a study participant. 
Vital signs and body weight assessment will be performed at all study visits.
6.1.6 
Laboratory Tests 
The Laboratory Manual contains detailed instructions for the collection and preparation of 
samples, directions with respect to the utilization of specialized tubes and requirements for 
dispensing of aliquots, and storage and shipment of samples to the Sponsor’s designated 
central laboratory. 
6.1.7 
Pregnancy Test 
Serum pregnancy tests will be performed at Screening, and urine pregnancy tests will be 
performed pre-dose at Visit 1, Visit 3, Visit 4, Visit 8, Visit 14, and at Unscheduled Visits/ET for 
all females of childbearing potential. 
6.1.8 
Electrocardiography 
Evaluation will be performed at Screening for baseline reference, Visit 8, Visit 14, and at 
Unscheduled Visits/ET. 
6.1.9 
Ocular Evaluations 
BCVA: should be assessed using the ETDRS chart starting at 4 meters at Screening, on Visits 
1-14 and Unscheduled Visits/ET. BCVA should be done prior to IVT injection or sham procedure
or rescue treatment. See the Ophthalmic Manual for details.
Anterior Segment Evaluation: should be performed prior to pupillary dilation, unless that
contradicts the site Standard of Care. Any abnormalities of the anterior chamber,
eyelids, conjunctivae, pupil, iris, lens and cornea should be documented at Screening,
on Visits 1-14, and Unscheduled/ET. Any anterior chamber inflammation (cells and
flare), phakic status, and posterior lens capsule status should also be noted. Pre-IVT
injection or sham procedure should be completed in OU. Post IVT injection or sham
procedure should be completed in the SE only.
Posterior Segment Evaluation/Ophthalmoscope Examination: should be performed after
pupillary dilation to examine the vitreous body, optic nerve head, macula, posterior pole,
and peripheral retina at Screening, on Visits 1-14, and Unscheduled/ET. Any vitreous
inflammation (haze and cells) should also be noted. Pre-IVT injection or sham procedure
should be completed in OU. Post IVT injection or sham procedure should be completed
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IOP: should be measured using Goldmann Applanation tonometry at Screening, on
Visits 1-14 and Unscheduled/ET. IOP should be done pre and post IVT injection or sham
procedure or rescue treatment. The post assessment should be done 30 minutes
±15 minutes. Tonometry should be performed prior to pupillary dilation when possible.
o
On coadministration days on Week 24 and Week 32, IOP should be done pre
and post each IVT injection or sham procedure. Pre-IVT injection or sham
procedure should be completed in OU. Post IVT injection or sham procedure
should be completed in the SE only.
CFP: should be obtained at Screening, Visits 3, 4, 6, 8, 11, 14 and Unscheduled/ET.
SD-OCT: should be obtained at Screening, on Visits 1-14 and Unscheduled/ET.
OCT-A: to be conducted at sites with the proper equipment available and should be
obtained at Screening, Visits 3, 4, 6, 8, 11, 14 and Unscheduled/ET.
FA: should be obtained at Screening, Visits 3, 4, 6, 8, 11, 14 and Unscheduled/ET (if it
had not been done within 30 days prior).
mfERG: to be conducted as the first ocular evaluation, and at sites with proper
equipment available and should be obtained at Visits 1, 3, 4, 8, 11 and 14. mfERG
should be done pre IVT injection or sham procedure.
Low-luminance visual acuity: to be conducted at sites with proper equipment available
and should be obtained at Screening, on Visits 3, 4, 6, 8, 11, 14 and Unscheduled/ET.
CFP, SD-OCT, FA, OCT-A (if done) and mfERG (if done) images should be transmitted to the 
Central Reading Center at each applicable visit. 
6.1.10 
Rescue Criteria 
If at any visit after Week 8 (Day 57), patients exhibit increase in disease activity, defined as any 
of the following: new, or clinically relevant worsening of, IRF/SRF/cysts compared to Day 1, new 
blood or heme present compared to previous visit, decrease in BCVA by  10 ETDRS letters 
from peak (best VA) within-study level
 75 µm from trough (lowest), they can 
be rescued with aflibercept. Rescued patients will continue their visit schedule as safety follow-
up through Week 48. Prior to administration of rescue medication, or for any questions on 
rescue criteria, please contact the Medical Monitor or designee. Rescued patients continue with 
study visits per protocol. If additional visits are required outside of study visit windows, these will 
be considered unscheduled visits. 
6.1.11 
End of Study 
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6.2 
Discontinuation or Withdrawal 
6.2.1 
Individual Patients 
6.2.1.1 
Withdrawal from Study 
Patients can voluntarily withdraw from the study for any reason at any time. They are to be 
considered withdrawn if they state an intention to withdraw, fail to return for visits, or become 
lost to follow-up for any reason. Patients withdrawing from the study because of an AE should 
be followed for at least 30 days, until resolution of the AE, or until no further improvement is 
expected, whichever comes first. Patients withdrawing from the study should be encouraged to 
complete all assessments under the Unscheduled/ET visit described in Table 1. 
The Investigator may withdraw a patient from the study for any of the following reasons: 
A protocol violation occurs, 
A serious or intolerable AE occurs, 
The Sponsor or Investigator terminates the study, or 
The patient requests to be discontinued from the study. 
6.2.1.2 
Replacement of Patients 
Enrollment may be extended to replace patients who discontinued or are lost to follow up during 
the study. 
6.3 
Study Termination 
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason. If the Investigator suspends or terminates that site’s participation in the study, the 
Investigator will promptly inform the Sponsor and the IRB/IEC and provide a detailed written 
explanation. Upon study completion, the Investigator will provide the Sponsor with final reports 
and summaries as required by regulations. Upon study suspension, completion, or termination, 
the Investigator will return all Study Drug and other study materials to the Sponsor or designee 
or destroy the materials at the investigative site per the Sponsor’s instructions. 

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7 
STUDY INTERVENTIONS 
7.1 
Description of Product 
The Study Drug (UBX1325) to be provided to the clinical sites will be bulk packaged (sites will 
be supplied with adequate overage, which will be accounted for as part of Study Drug 
accountability). The term “Study Drug” when used throughout this protocol means UBX1325 in 
solution. Each vial and carton will be individually labeled. Study Drug labeling will include 
identification required by local law, drug identification, and dosage. The packaging and labeling 
of the Study Drug will be in accordance with the Sponsor’s standards and local regulations. The 
Study Drug was manufactured at Vetter Pharma Development Services USA, Skokie, IIlinois. 
7.1.1 
UBX1325 
7.1.1.1 
Formulation, Storage, Preparation, and Handling 
UBX1325 is formulated as a sterile, clear, colorless to pale yellow solution at a concentration of 
1 mg/mL in pH 7.4 phosphate buffered saline that contains 0.3% polysorbate 80 (PS 80), and 
will be provided in a glass vial, stoppered and crimp-sealed with a teal flip cap for IVT 
administration. Each vial contains 1 mg/mL of UBX1325 and is single-use only. UBX1325 must 
be stored at -20°C upon receipt. 
UBX1325 will be provided to the investigational site along with a Pharmacy Manual, which 
details clinical product presentation and dilutions to be prepared using aseptic technique. Sterile 
diluent (pH 7.4 phosphate buffered saline) will be provided in a glass vial with a white flip cap 
along with sterile syringes and sterile needles for the preparation of the Study Drug. Each vial of 
sterile diluent is single-use only. 
Post-dilution solutions for clinical administration will be held no more than 1 hour at room 
temperature. 
Storage and dose preparation of Study Drug will be conducted in accordance with instructions in 
the Pharmacy Manual and under aseptic conditions. 
The Investigator is responsible for drug accountability at the investigational site, appointing a 
qualified individual to oversee the storage, preparation, and dispensing of Study Drug, and 
keeping records of such activity in accordance with the requirements of the Sponsor. 
All used and unused Study Drug must be stored at site and stored in accordance with the 
directions given in the Pharmacy Manual. 
7.2 
Method for Assigning Patients to the Treatment Group 
After a patient has been identified as potentially eligible for the study, the patient will be invited 
to participate. If the patient agrees to study participation, written informed consent will be 
obtained before any study-specific procedures are performed. Patients who have consented to 
participate in the study will be assigned a screening number. 
After the patient has been consented and completed all screening procedures confirming 
eligibility, they may proceed to be randomized in a 1:1 ratio on Day 1 (Visit 1) to receive 
UBX1325 or aflibercept. 
Patients randomized to the UBX1325 arm will receive UBX1325 on Day 1 and Weeks 4, 24, 28 
and sham procedure on Weeks 8, 16, 24, 32, and 40. 

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Patients randomized to the aflibercept arm will receive aflibercept on Day 1, Weeks 8, 16, 24, 
32, 40 and sham procedure on Weeks 4 and 28. Coadministration of UBX1325 with aflibercept 
will occur at Weeks 24 and 32. 
Patients will be randomly allocated to receive treatment through the randomization system, 
which administers the randomization code generated by the Sponsor’s biostatistician or 
designee. Following receipt of the treatment assignment, the site staff will prepare the Study 
Drug as instructed by the Pharmacy Manual. Patients who are randomized but do not receive 
treatment may be replaced. 
7.3 
Randomization Code Creation and Storage 
Randomization personnel of the Sponsor or designee will generate the randomization schedule 
prior to the start of the study. An interactive web response system will be used for patient 
randomization. All randomization information will be stored in a secured area, accessible only by 
authorized personnel. 
7.4 
Administration of UBX1325 
UBX1325 is administered via IVT injection. Following the IVT injection, patients will be 
monitored for elevation of IOP, decreased optic nerve head perfusion, and for possible injection 
complications (e.g., vitreous hemorrhage, retinal tears, etc.). Additionally, patients should 
immediately report any symptoms suggestive of endophthalmitis, such as ocular pain, swelling, 
redness, haze and gradual loss of vision. 
Patients may be prescribed prophylactic antibiotic eye drops following any IVT injection or sham 
procedure per the site’s preferred practice patterns. Such drops, if prescribed, should be 
documented in the patient’s eCRF. 
Sites are to use numbing agents per their preferred practice and documented in the patient’s 
eCRF. Use of numbing agents should be consistent for IVT injections and sham procedures. 
7.5 
Administration of Sham Procedure 
Sham procedures will be performed to maintain double-masking on the study. A sham 
procedure involves a needleless, empty sterile syringe that touches the surface of the SE to 
mimic an IVT injection. The unmasked team will administer IVT injections or sham procedures 
according the patient’s randomization status and per Study Schematic in Figure 1. Please refer 
to the current Pharmacy Manual for details on how to prepare and administer the sham 
procedure. 
Patients may be prescribed prophylactic antibiotic eye drops following a sham procedure per the 
site’s preferred practice patterns. Such drops, if prescribed, should be documented in the 
patient’s eCRF. 
Sites are to use numbing agents per their preferred practice and documented in the patient’s 
eCRF. Use of numbing agents should be consistent for IVT injections and sham procedures.  
7.6 
Administration of aflibercept 
Aflibercept should be administered per standard of care.  

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7.7 
Coadministration of Aflibercept and UBX1325 or Sham 
On coadministration days (week 24 and week 32), aflibercept or sham should be administered 
first before UBX1325 or sham. 
IOP taken post aflibercept injection or sham should be equal to or less than 30 mmHg prior to 
administering UBX1325 or sham. Administration of UBX1325 or sham after aflibercept or sham 
should be no less than 15 mins apart and no longer than 2 hours unless there are safety 
concerns, in which case the site should contact the unmasked medical monitor. 
7.8 
Masked and Unmasked Study Staff 
This study will be double-masked. Patients, Investigators, visual acuity technicians, 
photographers, reading center personnel and the Sponsor are masked. Sites will have a 
qualified injector who is unmasked in order to perform the IVT injection (UBX1325 or aflibercept) 
or sham procedure, as well as certain post-injection assessments on Visits 1, 3, 4, 6, 8, 9, 10, 
and 12. Specifically post injection, the unmasked injector will do the anterior and posterior 
segment exams, IOP and AE assessment on the SE. Other supporting activities such as Study 
Drug preparation and Study Drug accountability will be performed by designated unmasked 
personnel. The Screening visit may be conducted by unmasked or masked personnel; however, 
unmasked personnel should not be involved in any other study procedures outside of visits 
when an IVT injection or sham procedure is required. It is important the randomization code is 
not revealed to anyone in order to maintain the integrity of the double-masking. 
7.9 
Extent of Maintenance of Double-Masking 
In addition to the patients and Investigators being masked, any Sponsor or designee team 
members who are actively engaged with the site will be masked. 
There will be no planned unmasking. If there is an unplanned or unintentional unmasking, the 
randomization system will be used to manage the roles and permissions with respect to the 
ability to break the masking. The Investigator must contact the Medical Monitor to discuss any 
need to unmask, unless medical emergency dictates otherwise. The randomization code and 
records related to the unmasking will be filed as essential study documents. 
A patient who has unplanned or unintentional unmasking during the study will be asked to 
continue in the study through Week 48 for safety follow-up (AE and concomitant medication 
reporting, vital signs, physical examinations and laboratory testing). 
7.10 
Permitted and Prohibited Concomitant Treatments 
7.10.1 
Permitted Treatments 
Permitted concomitant treatments in/for the SE and non-SE include: 
Sites should follow their standard of care for numbing the eye. Lidocaine, proparacaine,
etc. are permitted if consistently administered to all patients regardless of sham or IVT
injection and should be entered on the concomitant medication source log and in EDC.
o
This should be entered as PRN for each eye individually
Fluorescein used for IOP and IVFA/OCT-A needs to be documented as a concomitant
medication
o
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Treatment of the fellow eye (FE) during Screening is permitted given aflibercept run-in is
open label
o
For visits with masked study drug, FE treatment is to be completed 7 days from SE
treatment (e.g., D1, Week 4, 8, and 16)
o
For Visit 8/Week 24, Visit 9/Week 28, Visit 10/Week 32 and Visit 12/Week 40, the SE
treatment and FE treatment no longer require a separation window of 7 days. FE
treatment is done after SE treatment.
Topical antibiotics administered prophylactically with IVT injection or sham procedure,
and topical/systemic antibiotics used for AE treatment
Artificial tears
Steroid use is permitted only for the following conditions:
o
Topical (e.g., for atopic dermatitis treatment), inhaled (e.g., for asthma treatment), or
locally injected (e.g., for epidural or joint injection)
o
Topical use of steroids in the fellow eye
o
Topical use of steroids for treatment of inflammation in the SE (e.g., uveitis)
Concomitant intravitreal therapy in the non-SE is permitted but cannot be administered within 
7 days of treatment with masked Study Drug. 
7.10.2 
Prohibited Treatments 
There are no known contraindications to the administration of UBX1325 injection. 
Patients will not be permitted to receive treatments for the management of wet AMD in the SE, 
once randomized to this study, unless it is aflibercept as a rescue treatment (see 
Section 6.1.10). 
Systemic (oral, intramuscular, and intravenous) or intravitreal steroids are not allowed unless for 
an AE treatment. All systemic steroids are prohibited 6 months before Screening. 
Patients should not have received any therapy that would preclude an IVT injection or can 
potentially exhibit retinal toxicity (such as tamoxifen, hydroxychloroquine, and trastuzumab. 
Patients are prohibited from receiving any medication for the SE that, in the opinion of the 
Investigator and/or the Medical Monitor, may have an effect on the study results. 
Patients who have received brolucizumab as their anti-VEGF treatment prior to Screening may 
be eligible given there were no complications associated with its use and given it was not 
administered within 8 weeks prior to Visit 1. Historical use of brolucizumab is not excluded. 

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8 
SAFETY MONITORING 
At each visit, patients will undergo ophthalmologic evaluation and assessment for signs of 
potential toxicity. 
For all patients, all acquired data may be reviewed by the SAC. This process will be detailed in 
the SAC Charter. 
8.1 
Definitions 
AE: An AE is any untoward medical occurrence associated with the use of an
intervention in humans whether or not it is considered intervention related.
Suspected unexpected serious adverse reaction (SUSAR): A serious adverse
reaction (AR) that is unexpected based on current product information.
Serious adverse event (SAE): An event is considered “serious” if, in the view of either
the Investigator or the Sponsor, it results in any of the following outcomes:
-
Death
-
A life-threatening AE (An event is considered “life-threatening” if, in the view of either
the Investigator or Sponsor, its occurrence places the patient at immediate risk of
death. It does not include an AE or suspected AR that, had it occurred in a more
severe form, might have caused death.)
-
Inpatient hospitalization or prolongation of existing hospitalization
-
A persistent or significant incapacity or substantial disruption of the ability to conduct
normal life functions
-
A congenital anomaly/birth defect
-
Important medical events that may not result in death, be life-threatening, or require
hospitalization may be considered serious when, based upon appropriate medical
judgment, they may jeopardize the patient and may require medical or surgical
intervention to prevent one of the outcomes listed in this definition. Examples of such
medical events include allergic bronchospasm requiring intensive treatment in an
emergency room or at home, blood dyscrasias or convulsions that do not result in
inpatient hospitalization, or the development of drug dependency or drug abuse.
Causality or relatedness: AEs should be considered probably or possibly
treatment-related, unless they fulfill the following criteria (in which circumstances it
should be considered unlikely related or unrelated):
-
Evidence exists that the AE has an etiology other than the Study Drug (e.g.,
preexisting medical condition, underlying disease, intercurrent illness, or concomitant
medication), and/or
-
The AE has no plausible temporal relationship to administration of the Study Drug
(e.g., a new cancer diagnosed 2 days after first dose of Study Drug).
Relatedness to Study Drug will be graded as “probably,” “possibly,” “unlikely,” or “unrelated” 
as follows: 

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Probably related: The AE 
-
Follows a reasonable temporal sequence from drug administration
-
Abates upon discontinuation of the drug
-
Cannot be reasonably explained by the known characteristics of the patient’s clinical
state
Possibly related: The AE 
-
Follows a reasonable temporal sequence from drug administration
-
Could have been produced by the patient’s clinical state or by other modes of
therapy administered to the patient
Unlikely related: The AE 
-
Is most likely to be explained by the patient’s clinical state or by other modes of
therapy administered to the patient
Unrelated: The AE 
-
Does not follow a reasonable sequence from drug administration
-
Is readily explained by and considered by the Investigator to be an expected
complication of the patient’s clinical state, concurrent medical conditions, or by other
modes of therapy administered to the patient
AR: An AR is any AE caused by a drug.
Suspected adverse reaction (SAR): An SAR is any AE for which there is a reasonable
possibility that the drug caused the AE. For the purposes of the investigational new drug
(IND) safety reporting, “reasonable possibility” means there is evidence to suggest a
causal relationship between the drug and the AE. SAR implies a lesser degree of
certainty about causality than AR.
Unexpected: An event is considered unexpected if it is not listed in the IB, is not listed at
the specificity or severity that has been observed, or, if an IB is not required or available,
is not consistent with the risk information described in the General Investigational Plan or
elsewhere in the IND. Unexpected also refers to events that are mentioned in the IB as
occurring with a class of drugs or as anticipated from the pharmacological properties of
the drug but are not specifically mentioned as occurring with the particular drug under
investigation.
Severity or intensity: The severity of an event describes the degree of impact upon the
patient and/or the need for medical care necessary to treat the event. AEs reported for
patients participating in this study will be graded using the National Cancer Institute
Common Terminology Criteria for Adverse Events version 4.03 (NCI CTCAE v4.03). The
Investigator will grade the severity of each AE using, when applicable, the NCI CTCAE
v4.03. For AEs not included in the NCI CTCAE v4.03, the criteria outlined in Table 2
should be used as a general guideline.

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Table 2 
Grading for Adverse Events Not Covered in the NCI CTCAE 
Severity
Description
Grade 1 – Mild 
Asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated 
Grade 2 – Moderate 
Minimal, local or noninvasive intervention indicated; limited 
age-appropriate instrumental ADL 
Grade 3 – Severe
Medically significant but not life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-
care ADL 
Grade 4 – Life-threatening 
Life-threatening consequences; urgent intervention indicated 
Grade 5 – Fatal
Death 
ADL = activities of daily living; NCI CTCAE = National Cancer Institute Common Terminology Criteria for 
Adverse Events. 
8.2 
Documenting Adverse Events 
8.2.1 
Timeframe for Collection 
AEs and SAEs will be collected from Screening (with the aflibercept run-in, prior to aflibercept 
should be collected as medical history) through the last follow-up visit at Visit 14, Week 48, or 
ET. All events prior to this will be documented as medical history. TEAEs will be collected from 
Visit 1 through Week 48, or ET. 
The Investigator must follow up on all AEs through Week 48/ET. Nonserious AEs may be 
followed to resolution past the patient’s last study visit at the discretion of the Investigator and/or 
Medical Monitor if in the best interest of the patient and the assessment of safety of UBX1325. 
The Investigator must follow up on all SAEs until the events have subsided, returned to 
baseline, or, in case of permanent impairment, the condition stabilizes. 
8.2.2 
Classification of Events 
Although AEs should be based on the signs or symptoms detected during the physical 
examination and on the clinical evaluation of the patient, a specific diagnosis should be reported 
as the AE whenever feasible. In addition to the information obtained from those sources, the 
patient should be asked the following nonspecific question: “How have you been feeling since 
your last visit?” Signs and symptoms should be recorded using standard medical terminology. 
8.3 
Reporting Adverse Events 
All AEs and SAEs must be recorded on source documents and collected in the electronic data 
capture (EDC) system. Any unanticipated risks to the patients must be reported by the 
Investigator promptly to the Sponsor and IRB/IEC. 
All SAEs, whether or not deemed drug-related or expected, must be reported by the Investigator 
or qualified designee within 24 hours of first becoming aware of the event. The Investigator or 
qualified designee will enter the required information regarding the SAE into the appropriate 
module of the eCRF, which will automatically result in distribution of the information to the 
Sponsors Pharmacovigilance provider. If the eCRF system is temporarily unavailable, the event, 
including the Investigator-determined causality to Study Drug, should be reported via fax using 

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an SAE form to the appropriate Sponsor or Pharmacovigilance contact. Upon return of the 
availability of EDC system, the SAE information must be entered on the SAE eCRF. 
The Sponsor (or designee) will process and evaluate all SAEs as soon as the reports are 
received. For each SAE received, the Sponsor will make a determination as to whether the 
criteria for expedited reporting have been met. The Medical Monitor should also be contacted 
immediately for any fatal or life-threatening SAE that is considered possibly or probably related 
to Study Drug. 
The Sponsor (or designee) is responsible for reporting relevant SAEs to the relevant regulatory 
authorities and participating Investigators, in accordance with FDA regulations 21 Code of 
Federal Regulations 312.32, International Conference on Harmonisation (ICH) Guidelines, 
European Clinical Trials Directive (Directive 2001/20/European Commission, and/or local 
regulatory requirements and monitoring the safety profile of the Study Drug. To meet this 
requirement, the Sponsor (or designee) may request additional information from the sites 
including, but not limited to, hospitalization records, discharge summaries, or autopsy reports. 
Any requests for such information should be addressed in a timely manner. Additionally, any 
SAE considered by an Investigator to be possibly or probably related to the Study Drug that is 
brought to the attention of the Investigator at any time outside of the time period specified for 
SAE reporting also must be reported immediately to one of the individuals listed on the Sponsor 
contact information page. 
Reporting of SAEs by the Investigator to the IRB or IEC will be done in accordance with the 
standard operation procedures and policies of the IRB/IEC. Adequate documentation must be 
maintained showing that the IRB/IEC was properly notified. 
8.4 
Adverse Events of Special Interest 
No AEs of special interest have been identified for UBX1325. 
8.5 
Clinical Laboratory Findings 
Clinical laboratory tests will include the analytes in Table 3. Patients should be in a seated or 
supine position during blood collection. 

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Table 3 
Laboratory Parameters 
Hematology:
Hematocrit
Hemoglobin
Platelet count
RBC count
Mean
corpuscular
volume
WBC count with
differential
Serum Chemistry:
Albumin
Alkaline phosphatase
Alanine aminotransferase
Aspartate aminotransferase
Blood urea nitrogen
Calcium
Carbon dioxide
Chloride
Creatininea
Globulin
Glucose
Human chorionic gonadotropin
Lactate dehydrogenase
Phosphorus
Potassium
Sodium
Total and direct bilirubin
Total cholesterol
Total protein
CKD-EPI = Chronic Kidney Disease Epidemiology Collaboration; RBC = red blood cell; WBC = white 
blood cell 
 
Creatinine clearance will be calculated by the CKD-EPI method. 
Serum human chorionic gonadotropin is required only for females who are of childbearing potential. 
8.6 
Pregnancy 
Although not considered an SAE, cases of pregnancy exposure by parent to the Study Drug 
must be recorded, reported, and followed up as indicated for an SAE. After the patient has been 
enrolled in the study and received Study Drug by IVT injection, the Investigator must report 
immediately (within 24 hours or next business day whichever is the shorter) any drug exposure 
during pregnancy to the Sponsor using the Sponsor-supplied Pregnancy Reporting Forms, 
using the same contact method for SAE reporting. Information about exposure in pregnancy 
encompasses the entire course of pregnancy and delivery and perinatal and neonatal 
outcomes, even if there were no abnormal findings. All reports of pregnancy must be followed 
for information about the course of the pregnancy and delivery, as well as the condition of the 
newborn. When the newborn is healthy, additional follow-up is not needed. Pregnancies 
occurring up to 12 weeks after last administration of the Study Drug must be reported to the 
Investigator. 

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8.7 
Overdose or Misuse 
Although not considered an SAE, cases of overdose (e.g., a dose higher than that indicated in 
the protocol, with or without an AE) must be recorded, reported, and followed up as indicated for 
an SAE. 

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9 
STATISTICAL METHODS 
9.1 
General Considerations 
All study parameters will be listed, and a selected list of parameters will be summarized 
descriptively by dose cohort and overall. The descriptive statistics will include number of 
patients, mean, standard deviation, median, minimum, and maximum for continuous parameters 
and frequency and percent for categorical parameters. Details about the statistical analyses for 
this study will be provided in the Statistical Analysis Plan (SAP), which will be developed and 
finalized before database lock. 
9.2 
Determination of Sample Size 
The sample size is for exploratory statistical analysis purposes only. There are no formal 
confirmatory hypotheses to be tested. 
A total of approximately 46 patients will be randomized 1:1 into the UBX1325 repeat dose or 
aflibercept arm. With 23 UBX1325 repeat dose patients, a single group t-test with a 0.10 two-
sided significance level will have approximately 80% power to detect a 5-letter change from 
baseline in BCVA, assuming the standard deviation is 9 letters. 
9.3 
Analysis Populations 
9.3.1 
Full Analysis Set 
The Full Analysis Set will include all randomized patients who received study treatment, have a 
baseline and at least one post baseline BCVA assessment. The Full Analysis Set will be the 
primary population for evaluating all efficacy variables. 
9.3.2 
Safety Analysis Set 
The Safety Analysis Set will include all patients who received study treatment. The Safety 
Analysis Set will be the primary population for evaluating all safety variables and patient 
characteristics. 
9.4 
Demographics and Baseline Characteristics 
Demographics and baseline characteristics include sex, age, race, ethnicity, weight, height, and 
other parameters as appropriate. These variables will be listed and summarized using 
descriptive statistics for each study arm and overall, based on the Safety Analysis Set. 
Medical history will be summarized using MedDRA (Medical Dictionary for Regulatory Activities) 
terms. Prior medications will be tabulated using World Health Organization (WHO) Drug 
Dictionary terms. 
9.5 
Efficacy Analysis 
The Full Analysis Set will be used for all efficacy analyses. 
Change in BCVA and CST from Baseline to each visit will be analyzed by a mixed model for 
repeated measures (MMRM). The details of MMRM and the analysis methods for other efficacy 
endpoints described in Section 3 will be provided in the SAP. 

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9.6 
Safety Analysis 
The Safety Analysis Set will be used for all safety analyses. 
Ocular and systemic safety and tolerability of a repeat IVT injection of UBX1325 will be 
evaluated by treatment emergent adverse events (TEAEs). The safety variables will be 
summarized descriptively. 
AEs will be coded using the MedDRA. Patients with any AEs will be tabulated by system organ 
classification and preferred term specified in the MedDRA. AEs will also be summarized by 
relationship to treatment and maximum severity. In addition, SAEs and discontinuations due to 
AEs will be summarized. 
9.7 
Exploratory Analysis 
Additional exploratory analyses may be carried out to better inform interpretation of treatment 
effects depending on examination of the summary statistics originally planned as mentioned 
above and in the SAP. 
9.8 
Planned Interim Analysis 
Formal interim analyses may be performed at 16 and 24 weeks. The SAP will specify what 
proportion of patients with Week 16 and Week 24 data are needed for the interim analyses. 

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10 
ETHICAL CONSIDERATIONS 
10.1 
Good Clinical Practice 
This study will be conducted in compliance with the protocol approved by the IRB/IEC, and in 
accordance with ICH Good Clinical Practice (GCP) standards. Any amendments to the protocol 
or changes to the consent document will be approved by the IRB/IEC before implementation of 
that amendment. The study will be conducted in accordance with the ethical principles, which 
have their origins in the Declaration of Helsinki. 
10.2 
Ethics Review  
The study and any amendments will be reviewed by an appropriately constituted and composed 
IRB/IEC. Written IRB approval for the protocol, amendments, ICF, and Investigator(s) will be 
obtained in accordance with GCP. The IRB/IEC will be notified of SAEs in accordance with 
IRB/IEC Policy. 
10.3 
Informed Consent 
An initial sample ICF is provided for the Investigator and IRB/IEC to prepare the informed 
consent document to be used at his or her site. The site-specific informed consent document 
will be submitted for review to the central IRB and the IRB-approved informed consent 
document will be held in the site study file and in the Sponsor’s Trial Master File. 
The ICF is to be prepared in the language(s) of the potential patient population for this study. 
The languages under consideration are English and Spanish. 
Before a patient’s participation in the clinical study, the Investigator is responsible for obtaining 
written informed consent from the patient after adequate explanation of the aims, methods, 
anticipated benefits, and potential hazards of the study and before any protocol specific 
procedures are performed. 
The Investigator is also responsible for asking the patient if the patient has a primary care 
physician and if the patient agrees to have his/her primary care physician informed of the 
patient’s participation in the clinical study. If the patient agrees to such notification, the 
Investigator is to inform the patient’s primary care physician of the patient’s participation in the 
clinical study. If the patient does not have a primary care physician and the Investigator will be 
acting in that capacity, the Investigator is to document such in the patient’s medical record. The 
acquisition of informed consent and the patient’s agreement or refusal of his/her notification of 
the primary care physician, if relevant, is to be documented in the patient’s medical records, and 
the ICF is to be signed and personally dated by the patient and by the person who conducted 
the informed consent discussion. The original signed ICF is to be retained in accordance with 
institutional policy, and a copy of the signed consent form is to be provided to the patient. 
10.4 
Data Privacy 
All study-related laboratory and clinical data gathered in this protocol will be stored in a 
password-protected database. All patient information will be handled using anonymous 
identifiers. Linkage to patients’ study data is only possible after accessing a password-protected 
database. Access to the database is only available to individuals directly involved in the study. 
Patient personal health information that is accessed for this study will not be reused or disclosed 
to any other person or entity, or for other research. 

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10.5 
Financial Disclosure 
In connection with the clinical study described in the protocol, the Investigator certifies that the 
Investigator will read and answer the Clinical Investigator Financial Disclosure Form truthfully 
and to the best of Investigator’s ability. The Investigator also certifies that, if asked, the 
Investigator will have any other applicable parties (e.g., Sub-Investigators) read and answer the 
Clinical Investigator Financial Disclosure Form as a condition of their participation in the study. If 
the financial interests reported on the Clinical Investigator Financial Disclosure Form change 
during the course of the study or within 1 year after the last patient has completed the study as 
specified in the protocol, the Investigator and the other applicable parties are obligated to 
update the Sponsor of financial disclosure in accordance with the Sponsor’s standard 
procedures. 
10.6 
Biological Specimens and Data 
Biological samples are only collected for safety and will be destroyed after analysis at 
Screening, Week 24, Week 48, and at Unscheduled/ET. Samples should be sent to the 
Sponsor’s designated laboratory as detailed in the Laboratory Manual. 

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OVERSIGHT 
11.1 
Safety Assessment Committee 
A SAC will be established to support pharmacovigilance activities for the study, such as 
adjudication of AEs or possible safety signals. The SAC Charter will describe the committee’s 
structure, roles, and responsibilities. 
11.2 
Quality Control and Assurance 
11.2.1 
Monitoring and Audits 
The Investigator will permit regular study-related monitoring by the Sponsor or designee, audits, 
IRB/IEC review, and regulatory inspections by providing direct access to source data and 
documents. 
11.2.2 
Protocol Deviations 
Protocol violations/deviations will be documented in accordance with good documentation 
practice and reported to the IRB/IEC in accordance with IRB/IEC Policy. In case of a deviation 
necessary to eliminate an immediate hazard to a research participant, the deviation will be 
reported to the IRB/IEC as soon as possible. Investigational sites should make every effort to 
adhere to the processes and procedures described in this protocol. 
11.2.3 
Records 
11.2.3.1 
Data Capture and Management 
An EDC system will be designed and managed on behalf of the Sponsor by the Sponsor’s 
designated contract research organization. Clinical data will be entered by study site personnel 
within 5 business days of the patient visit or activity conduct. Monitoring of the study will be 
conducted on site by a designee of the Sponsor (clinical research associate), who will conduct 
document and source data review, as well as remote data monitoring in the intervals between 
monitoring visits. Data will be reviewed remotely by the Medical Monitor for safety oversight. 
Investigator 
All study-related information will be recorded on source documents. All required study data will 
be recorded in the eCRFs. All eCRF data must be submitted to the Sponsor throughout and at 
the end of study in a timely and accurate manner. 
If an Investigator retires, relocates, or otherwise withdraws from conducting the study, the 
Investigator must notify the Sponsor to agree upon an acceptable storage solution. 
Regulatory agencies will be notified with the appropriate documentation. 
Sponsor 
The data will be checked for completeness and correctness in real-time online. 
Data are checked as they are entered into the EDC system. Offline checks will also be run to 
assess the need for additional data review. Discrepancy reports will be generated and 
transferred to the study center for resolution by the Investigator or its designee. 

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11.2.3.2 
Records Retention 
The Investigator shall retain and preserve one copy of all data generated in the course of the 
study, specifically including, but not limited to, those defined by GCP as essential, for the 
duration of (i) 2 years after the last marketing authorization for the Study Drug has been 
approved or the Sponsor has discontinued its research with respect to such Study Drug or 
(ii) such longer period as required by applicable global regulatory requirements. At the end of 
such period, the Investigator shall notify the Sponsor, in writing, of the intent to destroy all such 
material. The Sponsor shall have 30 days to respond to the Investigator’s notice, and the 
Sponsor shall have a further opportunity to retain such materials at the Sponsor’s expense. 

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12 
PUBLICATION POLICY 
Any formal presentation or publication of data collected from this study will be considered as a 
joint publication by the Investigator(s) and the appropriate personnel at UNITY Biotechnology, 
Inc. 
Authorship of any publications resulting from this study will be mutually agreed and determined 
on the basis of the Uniform Requirement for Manuscripts submitted to Biomedical Journals 
(International Committee of Medical Journal Editors), which states the following: 
 
Authorship credit should be based on (1) substantial contributions to conception and 
design, acquisition of data, or analysis and interpretation of data; (2) drafting the article 
or critically revising it for important intellectual content; (3) final approval of the version to 
be published. Authors should meet conditions 1, 2, and 3. 
 
When a large, multicenter group has conducted the work, the group should identify the 
individuals who accept direct responsibility for the manuscript. These individuals should 
fully meet the criteria for authorship defined above. 
 
Acquisition of funding, collection of data, or general supervision of the research group, 
alone, does not justify authorship. 
 
All persons designated as authors should qualify for authorship, and all those who 
qualify should be listed. 
 
Each author should have participated sufficiently in the work to take public responsibility 
for appropriate portions of the content. (Additional information on the current guidelines 
for publications can be found at the following location: http://www.icmje.org/). 
 
All publications (e.g., manuscripts, abstracts, oral/slide presentations, or book chapters) 
based on this study must be submitted to the Sponsor, for review. The Clinical Trial 
Agreement among the institution, Investigator, and the Sponsor will detail the 
procedures for, and timing of, the Sponsor’s review of publications. 

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FINANCING AND INSURANCE 
Financial disclosure, site budget, and any insurance policies relevant to this clinical study are 
described in each Clinical Trial Agreement. 

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