A Phase 2a, Prospective, Multicenter, Randomized, Double Masked, Sham-Controlled Study to Assess the Safety, Tolerability and Evidence of Activity of a Single Intravitreal Injection of UBX1325 in Patients With Diabetic Macular Edema
Phase: PHASE2
Conditions: Diabetic Macular Edema (DME)
Sponsor: Unity Biotechnology, Inc.

Clinical Study Protocol
UBX1325-02
Protocol Amendment 4/Version 5.0
UNITY Biotechnology, Inc
Page 1 
Confidential
A Phase 2a, Prospective, Multicenter, Randomized,
Double-Masked, Sham-Controlled Study to Assess the Safety, 
Tolerability and Evidence of Activity of a Single Intravitreal 
Injection of UBX1325 in Patients with Diabetic Macular Edema
Investigational Product(s)
UBX1325
Protocol Number
UBX1325-02
Version Number
5.0
Version Date
14 February 2022
Amendment
4
IND Number
145348
Sponsor
UNITY Biotechnology, Inc.
Sponsor’s Legal 
Representative
Sharon Klier, MD, MPH
VP of Ophthalmology and Medical Director, UNITY 
Biotechnology, Inc.
285 East Grand Avenue
South San Francisco, CA 94080
Dates
Original Protocol:
12 April 2021 Version 1.0
Amendment 1
27 April 2021 Version 2.0
Amendment 2
07 July 2021 Version 3.0
Amendment 3
03 November 2021 Version 4.0
Amendment 4
14 February 2022 Version 5.0
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 bekept in confidence in
the same manner as the contents of this document.

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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
Revisions were made throughout to reflect 
double-masking, and any reference to 
single-masking has been replaced accordingly.
The study is considered double-masked because 
the patient and investigator are masked.
Exclusion Criteria 5: History of IVT, 
subconjunctival, or periocular steroids in the 
3 months prior to screening conflicts with 
Exclusion Criteria 13: History of systemic and 
intraocular steroid use for 6 months prior to 
Day 1. The use of intravitreal nonbiodegradable 
steroid implants (ex. Iluvien®, Yutiq®, 
Retisert® is prohibited.
Exclusion Criteria #5 has been removed.
[Section Number 4.6 Exclusion Criteria]
Retaining Exclusion Criteria #13 (now 
documented as #12 in this amendment) as a 
higher standard reflects the scientific rigor and 
safety precautions taken in this study 
population.
Post-dilution solutions for clinical 
administration will be held no more than 1 hour 
at room temperature prior to administration to 
the patient.
[Section Number 6.1.1 UBX1325]
The original hold times and conditions were 
inaccurate. This change was made to align with 
guidance in the Pharmacy Manual.

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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
Screening window was increased from 
28 days to 42 days
[Section 1.2 Schedule of Events Table 1] and 
[Section 5 Study Conduct] 
Linking the window acceptable for screening 
period to coincide with the optimal timing post last 
anti-VEGF injection (see item 3). The number of 
days permitted for screening is increased to avoid a 
patient falling outside the screening window due to 
when they received their last anti-VEGF treatment 
and having to rescreen.
Removal of reference to dose starting at 5 µg 
[Section 4.2.2 Dose Rationale] 
10 µg was confirmed safe per the Safety 
Assessment Committee (SAC) in UBX1325-01 
study. On 18May2021, the SAC confirmed that 
10 µg should be used in all future UBX1325 study 
enrollments.
Inclusion criteria for last anti-VEGF given 
was changed from between 3 and 5 weeks 
prior to day 1, to between 3 and 6 weeks 
prior to day 1
[Section 4.5 Inclusion Criteria] 
Matching the time from last anti-VEGF injection to 
best capture response sensitivity (i.e., long enough
from last anti-VEGF injection to avoid anti-VEGF 
induced inhibition of activity but short enough to 
avoid re-emergence of active neovascularization 
and inflammation). This increases the likelihood of 
differentiating between UBX1325 and sham treated 
patients. Furthermore, the window of 3–6 weeks 
might better capture standard visit timing for 
patients and clinic.
Revised inclusion criteria to allow patients 
with PDR DME (ETDRS-DRSS Score at 
65C [or DR severity level of 8] or less 
severe) to participate in this study
[Section 4.5 Inclusion Criteria]
Based on preclinical animal studies and impact on 
neovascularization, there is sufficient data to 
support the hypothesis that there could be a 
potential effect of UBX1325 on PDR patients.
Stratification by anti-VEGF treatment agents
[Section 6.2 Method for Assigning Patients 
to the Treatment Group]
To obtain a balance between UBX1325 and sham 
treatment arms with regards to prior anti-VEGF 
agents.
Established that a formal interim analysis 
will occur at 12 weeks
[Section 8.7 Planned Interim Analysis] 
Revised the plan for analysis to reflect a planned 
interim analysis at 12 weeks after a certain 
proportion of patients meet the 12-week timepoint 
as will be determined in the SAP. Based on
UBX1325-01 data, we believe study drug effects 
may be seen earlier at 8–12 weeks. This is also to 
ensure the safety and well-being of patients at 
12-week timepoint.

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Area of Change
Rationale
Changed rescue criteria from “worsening 
CST by 100 µm from Baseline (Day 1) per 
SD-OCT or a 10-letter decrease in BCVA 
compared to peak BCVA from Baseline 
(Day 1)” to “worsening CST by 75 µm from 
Baseline (Day 1) per SD-OCT and/or a 
10-letter decrease in BCVA compared to 
peak BCVA from Baseline (Day 1)”
[Section 5.1.10 Rescue Criteria]
To better align with the standard practices followed 
by the treating physician.

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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
Inclusion Criteria 2: clarified DRSS will be 
determined by a Central Reading Center and 
re-incorporated the requirement for having at least 
3 anti-VEGF treatments in the preceding 6 months
Inclusion Criteria 3: CST requirement was reduced 
Inclusion Criteria 5: BCVA requirement in non-
study has been removed since safety was 
established
23 mmHg requirement 
applies to Day 1
Exclusion Criteria 1: removed definition of high 
risk/active PDR as Inclusion Criteria 2 is more 
explicit
Exclusion Criteria 9: patients with glaucoma who 
are poorly controlled in the opinion of the 
investigator or on more than 3 meds (new language 
explicitly excludes patients with unstable 
glaucoma)
Exclusion Criteria 12: prior steroid use applies to 
study eye only
[Section 4.5 Inclusion Criteria] and 
[Section 4.6 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
Reordering of secondary endpoints putting BCVA 
changes at the top of the list
[Section 1 Synopsis] and [Section 3 Objectives and 
Endpoints] and [Section 8 Statistical Methods]
Change of CST enrollment requirement may 
limit the magnitude of change from baseline 
in CST, while BCVA is deemed less 
sensitive to this change.
PK sampling was removed as a study procedure 
and subsequently as an endpoint
[Section 1 Synopsis] and 
[Section 1.2 Schedule of Events Table 1] and 
[Section 5 Study Conduct]
An adequate number of PK samples were 
collected in the First-in-Human study and 
analysis confirmed there is no evidence of 
systemic exposure of UBX0601/UBX1325
Removal of Australia and New Zealand as 
participating countries [Section 1 Synopsis]
The Sponsor opted to conduct the study 
within North America only

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SUMMARY OF CHANGES: AMENDMENT 4
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
Inclusion Criteria 2: Revised the requirement for 
having at least 3 anti-VEGF treatments in the 
preceding 6 months, to having at least 2 anti-VEGF 
treatments in the preceding 6 months
Inclusion Criteria 4: Upper BCVA limit in study 
eye changed from 70 letters to 73 letters
Exclusion Criteria 20: replaced reference to permit 
non-facial basal cell carcinoma with reference to 
permit stable, superficial basal or squamous cell 
carcinoma of the skin
[Section 4.5 Inclusion Criteria] and 
[Section 4.6 Exclusion Criteria]
Eligibility criteria were revised to clarify 
requirements and/or better align with patient 
population
Extended the follow-up period from 24 weeks to 
48 weeks, subsequently, the number of visits 
increased from 9 to 12. The secondary and 
exploratory endpoints apply to Week 48
[Section 1 Synopsis] and 
[Section 1.2 Schedule of Events Table 1] and 
[Section 3 Objectives and Endpoints] and 
[Section 5 Study Conduct]
To assess the extent of durability of a single 
IVT injection of UBX1325
As of November 9, 2021, additional data became 
available supporting the ongoing safety profile of 
UBX1325
[Section 2.3.5 Benefit: Risk Assessment] 
[Section 4.2.2 Dose Rationale]
The safety summary was revised to reflect 
additional non-serious, non-drug related 
adverse events
Clarified that the pre-dose assessments, specifically 
Anterior Segment Evaluation, Posterior Segment 
Evaluation and IOP are done OU, however, only the 
study eye should be assessed post-dose
[Section 1.2 Schedule of Events Table 1] and 
[Section 5 Study Conduct]
This clarifies required pre- and post-dose 
assessments
The following data will be collected for both eyes in 
the preceding 6 months prior to screening: use of 
anti- VEGF and historical imaging and visual acuity 
assessments
[Section 5.1.3 Medical History and Concomitant 
Medication Review]
This allows us to have better access to data 
as to patient’s prior treatment history; such 
prior treatment could be a useful tool in 
assessing patients who are most likely to 
respond well to UBX1325

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Area of Change
Rationale
Clarified that patients, investigators, visual acuity 
technicians, photographers, reading center 
personnel and Sponsor are masked.
[Section 6.6 Masked and Unmasked Study Staff]
To clarify who is masked in this double-
masked study
The following changes were made to the section on 
prohibited treatments.
Removed this statement: There are no known 
contraindications to the administration of UBX1325 
injection
Revised this statement: 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).
[Section 6.8.2 Prohibited Treatments]
Safety has been established in the First-in-
Human study and prohibited medication 
statement was further clarified with specific 
examples
Added that interim analyses may be conducted at 
timepoints outside the initially specified 12 Week
[Section 8.7 Planned Interim Analysis]
To allow for assessment of data at other 
study timepoints

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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 Institutional Review
Board (IRB), Independent Ethics Committee (IEC) 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 
patientsmay be necessary, depending on the nature of the amendment. 
All personnel involved in the conduct of this study have completed Human Subjects 
Protection and GCPs training, as outlined by their governing institution. 

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SPONSOR’S APPROVAL
Title
A Phase 2a, Prospective, Multicenter, Randomized, Double-
Masked, Sham-Controlled Study to Assess the Safety, 
Tolerability and Evidence of Activity of a Single Intravitreal 
Injection of UBX1325 in Patients with Diabetic Macular Edema
Protocol Number
UBX1325-02
Version Number
5.0
Version Date
14 February 2022
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 of Ophthalmology and 
Medical Director

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INVESTIGATOR’S AGREEMENT
I have read the protocol, appendices, and accessory materials related to Study UBX1325-02 
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......................................................................3
SUMMARY OF CHANGES: AMENDMENT 3......................................................................5
SUMMARY OF CHANGES: AMENDMENT 4......................................................................6
STATEMENT OF COMPLIANCE...........................................................................................8
SPONSOR’S APPROVAL........................................................................................................9
INVESTIGATOR’S AGREEMENT .......................................................................................10
TABLE OF CONTENTS .........................................................................................................11
LIST OF TABLES ...................................................................................................................13
LIST OF FIGURES .................................................................................................................14
LIST OF ABBREVIATIONS ..................................................................................................15
1
SYNOPSIS .............................................................................................................18
1.1
Study Schematic ...............................................................................................20
1.2
Schedule of Events ...........................................................................................20
2
INTRODUCTION .................................................................................................25
2.1
Overview of DME ............................................................................................25
2.2
Standard of Care for DME ...............................................................................27
2.2.1
Target Indication and Population .........................................................29
2.3
Scientific Rationale for UBX1325 as a Treatment for DME ...........................29
2.3.1
Role of Senescence in Retinal Diseases ...............................................29
2.3.2
Disease-relevant SASP from Senescent Retinal Cells .........................31
2.3.3
Description of UBX1325 .....................................................................32
2.3.4
Supportive Nonclinical Data ................................................................34
2.3.5
Benefit: Risk Assessment .....................................................................35
3
OBJECTIVES AND ENDPOINTS .......................................................................37
4
STUDY PLAN .......................................................................................................38
4.1
Study Design ....................................................................................................38
4.2
Design Rationale ..............................................................................................38
4.2.1
Patient Population Selection ................................................................38
4.2.2
Dose Rationale .....................................................................................38
4.3
Recruitment ......................................................................................................38
4.4
Definitions........................................................................................................38
4.5
Inclusion Criteria .............................................................................................39
4.6
Exclusion Criteria ............................................................................................39
5
STUDY CONDUCT ..............................................................................................42
5.1
Study Procedures .............................................................................................42
5.1.1
Study Screening and Treatment Periods ..............................................42

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5.1.2
Informed Consent .................................................................................46
5.1.3
Medical History and Concomitant Medication Review .......................46
5.1.4
Physical Examination ...........................................................................46
5.1.5
Vital Signs and Body Weight ...............................................................47
5.1.6
Laboratory Tests ..................................................................................47
5.1.7
Pregnancy Test .....................................................................................47
5.1.8
Electrocardiography .............................................................................47
5.1.9
Ocular Evaluations (must be conducted on both eyes) ........................47
5.1.10
Rescue Criteria .....................................................................................48
5.1.11
End of Study ........................................................................................48
5.2
Discontinuation or Withdrawal ........................................................................49
5.2.1
Individual Patients ...............................................................................49
5.3
Study Termination............................................................................................49
6
STUDY INTERVENTIONS .................................................................................50
6.1
Description of Product .....................................................................................50
6.1.1
UBX1325 .............................................................................................50
6.2
Method for Assigning Patients to the Treatment Group ..................................50
6.3
Randomization Code Creation and Storage .....................................................51
6.4
Administration of UBX1325 ............................................................................51
6.5
Administration of Sham Procedure ..................................................................51
6.6
Masked and Unmasked Study Staff .................................................................51
6.7
Extent and Maintenance of Double-Masking ..................................................52
6.8
Permitted and Prohibited Concomitant Treatments .........................................52
6.8.1
Permitted Treatments ...........................................................................52
6.8.2
Prohibited Treatments ..........................................................................53
7
SAFETY MONITORING ......................................................................................54
7.1
Definitions........................................................................................................54
7.2
Documenting Adverse Events ..........................................................................56
7.2.1
Timeframe for Collection .....................................................................56
7.2.2
Classification of Events .......................................................................56
7.3
Reporting Adverse Events................................................................................57
7.4
Adverse Events of Special Interest ..................................................................57
7.5
Clinical Laboratory Findings ...........................................................................57
7.6
Pregnancy .........................................................................................................58
7.7
Overdose or Misuse .........................................................................................59
8
STATISTICAL METHODS ..................................................................................60
8.1
General Considerations ....................................................................................60
8.2
Determination of Sample Size .........................................................................60

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8.3
Analysis Populations ........................................................................................60
8.3.1
Full Analysis Set ..................................................................................60
8.3.2
Safety Analysis Set ..............................................................................60
8.3.3
PK Analysis Set ...................................................................................60
8.4
Demographics and Baseline Characteristics ....................................................60
8.5
Efficacy Analysis .............................................................................................61
8.6
Safety Analysis ................................................................................................61
8.6.1
Exploratory Analysis ...........................................................................61
8.6.2
Pharmacokinetics Analysis ..................................................................61
8.7
Planned Interim Analysis .................................................................................62
9
ETHICAL CONSIDERATIONS ...........................................................................63
9.1
Good Clinical Practice .....................................................................................63
9.2
Ethics Review ..................................................................................................63
9.3
Informed Consent .............................................................................................63
9.4
Data Privacy .....................................................................................................64
9.5
Financial Disclosure .........................................................................................64
9.6
Biological Specimens and Data .......................................................................64
10 
OVERSIGHT .........................................................................................................65
10.1
Safety Assessment Committee .........................................................................65
10.2
Quality Control and Assurance ........................................................................65
10.2.1
Monitoring and Audits .........................................................................65
10.2.2
Protocol Deviations ..............................................................................65
10.2.3
Records ................................................................................................65
11 
PUBLICATION POLICY ......................................................................................67
12 
FINANCING AND INSURANCE ........................................................................68
13
REFERENCES ......................................................................................................69
LIST OF TABLES
Table 1 
Schedule of Events .....................................................................................21
Table 2 
Grading for Adverse Events Not Covered in the NCI CTCAE .................56
Table 3 
Laboratory Parameters ...............................................................................58

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LIST OF FIGURES
Figure 1
Schematic of Phase 2a Proof-of-Concept Study ........................................20
Figure 2
Immunohistochemical Staining of p16+ Cells in Human Donors ..............30
Figure 3
Induction of Senescence and Diabetic Retinopathy-relevant Genes 
AfterGlucose Treatment .............................................................................31
Figure 4
Improved Vascular Leakage in the Diabetic Mouse ..................................33
Figure 5
Decreased Neovascularization in the OIR Mouse .....................................33

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LIST OF ABBREVIATIONS
Abbreviation
Definition
aAMD
atrophic age-related macular degeneration
AMD
age-related macular degeneration
AE
adverse event
AUC
area under the curve
AUC0-672
area under the curve from t=0 to t=672
AUC0-t
area under the curve from t=0 to t
AUC0-inf
area under the curve from t=0 to infinity
AUC%extrap
percent of the area under the curve extrapolated from AUC0-t to AUC0-inf
AR
adverse reaction
Bcl-2
B-cell lymphoma 2
BCVA
best corrected visual acuity
BRB
blood-retinal barrier
CFP
color fundus photography
CL/F
apparent total clearance of the drug from plasma after intravitrealinjection
Cmax
maximum concentration
CRA
clinical research associate
CST
central subfield thickness
CV
coefficient of variation
DLT
dose-limiting toxicity
DME
diabetic macular edema
DNA
deoxyribonucleic acid
DR
diabetic retinopathy
DRCR
Diabetic Retinopathy Clinical Research Network
DRSS
diabetic retinopathy severity scale
EC
European Commission
ECG
electrocardiogram
eCRF
electronic case report form
EDC
electronic data capture
EMR
electronic medical record
ERG
electroretinogram
ERM
epiretinal membrane
ET
early termination
ETDRS
Early Treatment Diabetic Retinopathy Study
FA
fluorescein angiography
FDA
Food and Drug Administration
FIH
first-in-human
GCP
good clinical practice
GLP
good laboratory practice
HbA1C
hemoglobin A1C

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Abbreviation
Definition
hERG
human ether-à-go-go-related gene
HRMEC
human retinal microvascular endothelial cells
IB
investigator’s brochure
ICAM-1
intercellular adhesion molecule-1
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IHC
immunohistochemistry
IL
interleukin
IND
investigational new drug (application)
IOP
intraocular pressure
IRB
institutional review board
IVT
intravitreal
LAR
legally authorized representative
LLOQ
lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
MMPs
matrix metalloproteinases
MRI
magnetic resonance imaging
MTD
maximally tolerated dose
nAMD
neovascular age-related macular degeneration
NCA
non-compartmental analyses
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
NV
neovascularization
NZW
New Zealand White
OCT
optical coherence tomography
OCT-A
optical coherence tomography angiography
OIR
oxygen-induced retinopathy
OU
both eyes
PAD
pharmacologically active dose
PDR
proliferative diabetic retinopathy
PDGF
platelet-derived growth factor
PEDF
pigment epithelium-derived growth factor
PK
pharmacokinetic
POC
proof-of-concept
PS 80
polysorbate 80
RPE
retinal pigment epithelium

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Abbreviation
Definition
SAC
safety assessment committee
SAD
single-ascending dose
SAE
serious adverse event
SAP
statistical analysis plan
SAR
suspected adverse reaction
SASP
senescence-associated secretory phenotype
SD-OCT
spectral domain optical coherence tomography
SDM
subthreshold diode micropulse laser therapy
SE
study eye 
SLE
slit lamp exam
SnCs
senescent cells
SRT
selective retinal therapy
SUSAR
suspected unexpected serious adverse reaction
T1D
Type 1 diabetes
T2D
Type 2 diabetes
T1/2
half-life
Tmax 
time at which the maximum concentration is observed
TA
triamcinolone acetonide
TGF
tumor growth factor
TNF
tumor necrosis factor
US
United States
VA
visual acuity
Vd/F
apparent volume of distribution after non-intravenous administration
VEGF
vascular endothelial growth factor
VO
vaso-obliteration
WHO
World Health Organization

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1
SYNOPSIS
Title
A Phase 2a, Prospective, Multicenter, Randomized, Double- Masked, 
Sham-Controlled Study to Assess the Safety, Tolerabilityand 
Evidence of Activity of a Single Intravitreal Injection of UBX1325 in 
Patients with Diabetic Macular Edema (DME)
Phase
Phase 2a
Study Design
This is a Phase 2a Proof-of-Concept (POC) study. The total number 
of patients will be approximately 62 patients who will be enrolled and 
randomized 1:1 into either the UBX1325 or sham study arms, in order
to assess the primary objective. All patients will be followed for 
approximately 48 weeks
The injector will be unmasked but the evaluator is masked.
Rationale
This study is intended to assess the exposure, safety, biological 
activity and durability of UBX1325, a phosphate pro-drug, and its
active parent molecule (UBX0601) following a single intravitreal
(IVT) injection of UBX1325 in patients with DME.
Target Population
This study will enroll patients 18 years of age with DME with best
corrected visual acuity (BCVA) between 73 to 20 Early Treatment
Diabetic Retinopathy Study (ETDRS) letters (equivalent to 20/40 to 
20/400 on the Snellen chart) at Screening and at Day 1.
Number of Patients
Approximately 62 patients
Length of Participation
On treatment: 1 day. Each patient will receive UBX1325 IVT
injection or sham on Day 1.
On study: Up to 54 weeks (6-week screening period + 1 dose day +
48-week follow-up period)
Intervention
injection 
(10 µg) or sham.
Primary Objective and
Primary Endpoint
Objective: Assess the local and systemic safety and tolerability
following a single IVT injection of UBX1325 compared to sham
Endpoint:
Ocular and systemic safety and tolerability of a single IVT
injection of UBX1325 evaluated by treatment emergent
adverse events (TEAEs)

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Secondary Objectives
and Corresponding
Endpoints
Objectives: Assess the biological activity following a single
UBX1325 injection in patients with DME. Also, assess efficacy
parameters and retinal structure improvement of patients following a 
single IVT injection of UBX1325 compared to sham. 
Endpoints: 
Changes in BCVA from Baseline to Weeks 12, 24 and 48
Proportion of patients who require 2 or more anti-VEGF
rescue over 12, 24 and 48 Weeks
Change in CST from Baseline to each study visit as assessed
by SD-OCT and read by a Reading Center
Change in CST area under the curve (AUC) from baseline to
each study visit
Proportion of patients without macular fluid at Weeks 12, 24
and 48 as assessed by SD-OCT
Exploratory Objectives
and Corresponding
Endpoints
Objective: Assess efficacy parameters and retinal structure
improvement of patients following a single IVT injection of
UBX1325 compared to sham.
Endpoints:
Change from Baseline in Diabetic Retinopathy Severity Scale
(DRSS) score at Weeks 24 and 48
Change in capillary perfusion from Baseline to Weeks 12, 24
and 48 as assessed by OCT-A and FA
Number of Sites
Approximately 32 sites in the US and Canada
Study Duration
Approximately 24 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. This
committee will meet on an ad hoc basis.

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1.1
Study Schematic
The study schematic is presented in Figure 1. 
Figure 1 
Schematic of Phase 2a Proof-of-Concept Study
1.2
Schedule of Events
The schedule of events (SOE) is presented in Table 1.

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Table 1 
Schedule of Events
Test/Procedure
Screening
Day -42 to
Day -1
Visit 1 
Week 0 
Day 1
Visit 2 
24 ± 4 hours
Observationa 
Day 2
Visit 3 
Week 1 
Day 8 
±1
Visit 4 
Week 2 
Day 15
±2
Visit 5 
Week 4 
Day 29
±7
Visit 6 
Week 8 
Day 57
±7
Visit 7 
Week 12
Day 85
±7
Visit 8 
Week 18
Day 127
±7
Visit 9 
Week 24
Day 169
±7
Informed
Consent
X 
  
Demographics
X
Medical/
Ophthalmic
History
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medication
History/ 
Concomitant
Medications
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical
Examination
X 
X 
Vital Signs and 
Weight
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory Tests:
Hematology and
Chemistry
X 
X 
Pregnancy Test
X
(serum)
X
(urine)c
X
(urine)c
12-Lead ECG
X
X
BCVA
X
X
X
X
X
X
X
X
X
X
Anterior Segment
Evaluation 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
Posterior 
Segment
Evaluation 
X 
Xd 
X 
X 
X 
X 
X 
X 
X 
IOP 
X 
Xd
X 
X 
X 
X 
X 
X 
X 
SD-OCTe
X
X
X
X
X
X
X
X
X
OCT-Ae
X
X
X
FAe
X
X
X
X

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Test/Procedure
Screening
Day -42 to
Day -1
Visit 1 
Week 0 
Day 1
Visit 2 
24 ± 4 hours
Observationa 
Day 2
Visit 3 
Week 1 
Day 8 
±1
Visit 4 
Week 2 
Day 15
±2
Visit 5 
Week 4 
Day 29
±7
Visit 6 
Week 8 
Day 57
±7
Visit 7 
Week 12
Day 85
±7
Visit 8 
Week 18
Day 127
±7
Visit 9 
Week 24
Day 169
±7
CFPe
X
X
X
DRSS score
X
X
X
Eligibility
Criteria
X 
X 
Study Drug
Administrationg
X 
AE assessment
X
X
X
X
X
X
X
X
X

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Table 1 
Schedule of Events (Continued)
Test/Procedure
Visit 10 
Week 32
Day 225 ± 7
Visit 11
Week 40
Day 281 ± 7
Visit 12
Week 48
Day 337 ± 7
Unscheduled Visit/ET
Medical/Ophthalmic
History
X 
X 
X 
X 
Medication
History/Concomitant
Medications
X 
X 
X 
X 
Physical Examination
X
X
Vital Signs and Weight
X
X
X
X
Laboratory Tests:
Hematology and
Chemistry
X
X 
Pregnancy Test
X
(urine)
12-Lead ECG
X
X
BCVA
X
X
X
X
Anterior Segment 
Evaluation
X 
X 
X 
X 
Posterior Segment 
Evaluation
X 
X 
X 
X 
IOP
X
X
X
X
SD-OCT
X
X
X
X
OCT-A
X
X
FA
X
Xf
CFP
X
X
DRSS score
X
X
AE assessment
X
X
X
X
AE = adverse event; BCVA = best corrected visual acuity; CFP = color fundus photography; DRSS = diabetic retinopathy severity scores;
ECG = electrocardiogram; ET = early termination; FA = fluorescein angiography; IOP = intraocular pressure; OCT-A = optical coherence tomography
angiography; SD-OCT = spectral domain optical coherence tomography; rescue treatment administered if needed
a
Procedures to be performed at the end of the ~24 hours (± 4 hours) of observation.

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b
Height should also be measured at Screening.
c
Pre-dose urine dipstick for females of childbearing potential. Urine dipstick should also be done at the last study visit, Visit 9 Week 24.
d
Procedure to be performed both pre-dose and post-dose. Post-dose procedures will be done in the study eye only by the unmasked injector,
30 minutes ± 15 minutes post dose.
e
CFP, FA, SD-OCT, and OCT-A images should be transmitted to the Central Reading Center at each applicable visit. Screening images should be 
transmitted to Central Reading Center for eligibility verification. OCT-A to be conducted at sites with the proper equipment available.
f
To be completed only if assessment has not been performed within the preceding 30 days.
g
After all other study procedures have been completed. Optional post-injection prophylactic antibiotics may be administered. Sites should follow their 
standard practice and document all medication given.

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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 diabetic macular edema (DME).
DME is a complication of diabetic retinopathy (DR) following chronic, poorly controlled 
diabetes, and is the most common form of sight-threatening retinopathy in people with 
diabetes (Tan et al., 2016, IDF 2019). Approximately one in 14 patients with diabetes has 
some degree of DME (Coney 2019).
The overall prevalence of DR in patients with diabetes using retinal images was estimated to
be 35%, with vision-threatening DR present in 12% (WHO 2015). Prevalence depends on the 
type of diabetes and the duration of the disease. For both types of diabetes, type 1 diabetes 
(T1D) and type 2 diabetes (T2D), after 25 years duration, prevalence approximates 30% 
(Browning et al., 2018).
In the US, at least 5.5 million individuals over the age of 40 are estimated to have DR in the 
absence of DME, and an additional 800,000 to 1 million patients have DME. According to 
some estimates, only 40% of them diagnosed and treated, and about 5% are diagnosed and 
observed (IDF 2019, VanderBeek et al., 2016).
Fewer than half of all US adults with diabetes adhere to guideline-recommended 
eye-screeningschedules. Patients with DR typically have no symptoms in the early stage of 
the disease and may not seek medical evaluation until DR advances and results in vision 
impairment. These delays in diagnosis and treatment may result in visual impairment that is 
permanent and irreversible (Coney 2019).
Despite advances in diagnosis and management of ocular disease in patients with diabetes,
eye complications from diabetes continue to be a leading cause of vision loss and new onset 
blindness in working-age individuals in the United States (Aiello 2005, 
Antonetti et al., 2012).
2.1
Overview of DME
The most common early clinically visible manifestations of DR include microaneurysm 
formation and intraretinal hemorrhages. Microvascular damage (e.g., retinal capillary
non-perfusion, cotton wool spots, increased numbers of hemorrhages, venous abnormalities, 
and intraretinal microvascular abnormalities) leads to increased vasopermeability, which can 
subsequently result in retinal thickening and/or exudates that may lead to loss in central visual 
acuity (VA).
When blood-retinal barrier (BRB) is further compromised, pooling of fluid within the 
retina’s central area, the macula, may ensue and cause DME. Capillary leakage causes diffuse 
edema, whereas focal or multifocal leakage from grouped microaneurysms leads to localized 
edema (IDF 2019).
The natural history of DME is characterized by a slow progression of retinal thickening until 
the center of the macula is involved, causing VA deterioration. Spontaneous resolution of 

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DME is rare and usually secondary to improvement in systemic risk factors, such as 
glycemic control, hypertension, or hypercholesterolemia. If untreated, 29% of eyes with 
DME and foveal involvement experience moderate visual loss (doubling of the visual angle) 
after 3 years.
Spontaneous visual recovery is also unusual, with improvement of at least 3 Early Treatment
Diabetic Retinopathy Study (ETDRS) lines occurring in 5% of cases (Bandello et al., 2017).
No difference in the prevalence of DME was observed when subjects were analyzed by age 
or gender; however, non-Hispanic black subjects had a greater odd of having DME compared 
with non-Hispanic white subjects (Varma et al. 2014). Systemic risk factors associated with
DME include longer duration of diabetes, high systolic blood pressure, and elevated 
hemoglobin A1C (HbA1C) levels. Other studies found that lipid and triglyceride levels, 
advanced diabetic nephropathy, and pregnancy are also associated risk factors. The sole 
ocular factor associated with DME is DR severity as increasing severity is associated with 
increasing prevalence of DME (Browning et al., 2018, Kim et al., 2019).
The macula in DME is thickened due to increased extracellular fluid derived from 
hyperpermeable retinal capillaries. Prolonged hyperglycemia in uncontrolled diabetes leads 
to reduced inner retinal oxygen tension, venous dilation, increased vascular endothelial 
growth factor (VEGF) concentration within the retina, leukocyte stasis, and dysregulated 
growth factor levels, which together are associated with increased exudation of serum out of 
the retinal vasculature and into the extracellular space. The retinal pigment epithelium (RPE) 
pump is overwhelmed by the exudation of serum and macular swelling results
(Browning et al., 2018).
While the underlying pathophysiology of DME is believed to be VEGF-mediated, there is a
growing body of evidence suggesting that inflammatory mediators and cytokines contribute 
to the vascular permeability and edema in DME (Ascaso et al., 2014,
Owen and Hartnett 2013, Browning et al., 2018). Increased inflammation, characterized by 
leukostasis, accumulation of macrophages, intercellular adhesion molecule-1 (ICAM-1), and 
prostacyclin upregulation is associated with capillary non-perfusion and breakdown of BRB 
(Browning et al., 2018). Patients with DME have elevated vitreous levels of VEGF, ICAM-1, 
interleukin (IL)-6, and monocyte chemoattractant protein-1 compared with non-diabetic 
patients (Funatsu et al., 2009).
Inflammatory cytokines such as tumor necrosis factors alpha and beta, alpha 4 integrin, nitric 
oxide, and IL-
dysfunction and increased vascular permeability through a local inflammatory response and 
higher levels of advanced glycation end products (Miljanovic et al., 2004). Many other small 
molecules and growth factors may contribute to the development of DME, although the
details of the pertinent pathways are incompletely understood (Kent et al., 2000;
Patel et al., 2006, Browning et al., 2018).

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2.2
Standard of Care for DME
Photocoagulation has been the standard of care for DME for decades. However, a substantial
group of patients are unresponsive to laser therapy and fail to improve after photocoagulation 
(Bandello et al., 2017). Some studies show that conventional photocoagulation is effective in 
reducing macular thickness in patients with DME; however, it causes visible laser scars that
may enlarge once treatment is finished. In addition, the thermal effects of photocoagulation 
cantrigger complications, including choroidal neovascularization, subretinal fibrosis, and 
visual fieldloss. Subthreshold diode micropulse laser therapy (SDM) and selective retinal 
therapy (SRT) may be valuable for treating sub-clinically significant DME that is diagnosed 
early (Park et al., 2014). However, given the risk of progression and general lack of early
detection, in addition to AEs, other treatment modalities for DME have been investigated. 
Intravitreal (IVT) administration of steroids has provided promising results for the treatment 
of DME (Sarao et al., 2014). The anti-inflammatory, angiostatic, and antipermeability 
properties of these compounds have gained interest in chronic retinal conditions such as 
DME. A complete understanding of the mechanism of action of corticosteroids has not been 
fully clarified.
However, corticosteroids have been shown to interfere with many regulatory components of 
gene expression inhibiting the expression of VEGF and key proinflammatory genes (tumor 
anti- inflammatory factors (pigment epithelium-derived growth factor [PEDF]) 
(Tsaprouni et al., 2002; Tong et al., 2006; Kim et al., 2019; Zhang et al., 2006). The 
anti-inflammatory activity of steroids is also related to the inhibition of the phospholipase A 
2 pathway, to the lower release of inflammatory cell mediators, and to the reduced leukocyte 
chemotaxis (Bandello et al. 2017). Additionally, triamcinolone acetonide (TA) seems to 
reduce the expression of matrix metalloproteinases (MMPs) and down-regulates ICAM-1 on 
choroidal endothelial cells (Mizuno et al., 2007). IVT and peribulbar injections of TA must 
be repeated every 2 to 4 months to maintain effect. Several steroid applications have been 
studied, for example, biodegradable dexamethasone extended release implant (Ozurdex®), 
fluocinolone acetonide (Iluvien®) and TA implants to prolong the intervals between
treatments (Bandello et al., 2017).
Side effects of steroids are a concern, especially considering the availability of anti-VEGF
medications that have minimal ocular side effects. The primary risks associated with IVT
administration of corticosteroids for DME are cataract progression and development of
glaucoma, which is why it is sometimes contraindicated in patients with glaucoma or ocular 
hypertension. Nonetheless, steroid treatment can be considered first line in special 
populations such as, patients who have had a recent history of cardiovascular event, pregnant 
women, patients unable to adhere to monthly treatments, or DME in eyes undergoing cataract 
surgery (Zur et al., 2019).
Surgical vitrectomy was proposed as a treatment option for DME in the early 1990s. Eyes 
with DME were observed to have lower prevalence of posterior vitreous detachment than 
eyes without DME, and it was thought that vitreomacular adhesion might promote DME. 
This was further supported by the observation that resolution of DME could occur after 

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posterior vitreous detachment and surgical induction of a vitreomacular separation might 
improve DME. With the advent of optical coherence tomography (OCT), vitreomacular 
adhesion was shown to be a risk factor for DME (Browning et al., 2018). A controversy exists 
regarding the effects of vitrectomy for DME. Some reports suggest that vitrectomy reduces 
macular thickening but does not improve VA, yet others report improved VA and decrease in 
macular thickening. Prospective, randomized clinical studies have not been conducted to 
evaluate the effect of vitrectomy on diverse DME patient population. Nonetheless, there is a 
general acceptance that vitrectomy has a role in the management of at least some cases of 
DME (Browning et al., 2018).
Studies have shown the safety and efficacy of IVT anti-VEGF treatments in patients with 
DME, some of which were the basis for Food and Drug Administration (FDA) approval of 
anti-VEGF therapies for the treatment of DME (Elman et al., 2010; Nguyen et al. 2012; 
Brown et al., 2015).The Diabetic Retinopathy Clinical Research Network (DRCR) net trial, 
Protocol T, was a 660-patient study comparing 3 IVT anti-VEGF treatments in patients with
DME, followed for 2 years of treatment. Focal/grid laser was added if DME persisted and 
was not improving at 6 months or later. Results showed that focal/grid laser was administered
as a supplement in 41%, 64%, and 52% of aflibercept, bevacizumab, and ranibizumab 
groups, respectively. From  Baseline to 2 years, mean VA letter score improved by 12.8 with 
aflibercept, 10.0 with bevacizumab, and 12.3 with ranibizumab. Treatment group differences 
varied by baseline VA (Wells et al. 2016).
A meta-analysis published by Virgili et al., 2018 concluded that anti-VEGF treatments are
effective at improving vision in patients with DME with 3 to 4 in every 10 patients likely to
experience an improvement of 3 or more lines VA at 1 year. Aflibercept may confer some
advantage over ranibizumab and bevacizumab in patients with DME at one year in visual and
anatomic terms, but it is unclear whether this applied to the long-term. Overall, the safety 
profile between the 3 anti-VEGF drugs, aflibercept, ranibizumab, or bevacizumab is similar 
(Virgili et al., 2018).
Evidence from randomized controlled trials may not apply to real-world practice, where 
patients in need of anti-VEGF treatment are often under treated and under monitored. In a 
number of studies, the full effect of anti-VEGF agents are not even experienced for up to 
12 months, and inmany patients, even after 12 months, significant retinal fluid remains. This 
suggests that other therapeutic options with more rapid and complete effect could have an 
important role in the treatment of this disease.
Despite the success achieved with anti-VEGF treatment for DME, patients’ poor compliance 
with the regimen (monthly and/or bimonthly IVT injections or a treat-and-extend regimen),
refractory cases to anti-VEGF treatment (50% of DME patients (AAO PPP for AMD 2019;
AAO PPP for DR 2017), the long-term complication of retinal fibrosis and the prolonged 
time it takes to achieve maximal response account for the unmet need that remains in DME. 
Although VEGF has been identified as a primary biomarker for the neovascular disease, other 
biomarkers are present in DR (including IL-1 , tumor necrosis factor [TNF]- , IL-6, tumor
growth factor [TGF- ], among others) and it could be argued that anti-VEGF treatment alone 
does not address the multifactorial nature of the disease.

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Analysis of electronic medical records (EMRs) from a geographically and demographically 
diverse sample of US retina specialists revealed that real-world outcomes of anti-VEGF
therapies in DME are meaningfully poorer than those shown in anti-VEGF randomized 
control trials (Ciulla et al., 2018). Overall, this EMR study demonstrated that best corrected 
visual acuity (BCVA) outcomes in DME patients treated with anti-VEGF agents in the real
world are inferior to those in randomized control trials (RCTs) by approximately 1 line of VA
at 1 year (Ciulla et al., 2018). A subsequent study by the same group confirmed that real 
world patients with DME undergo fewer anti-VEGF injections and exhibit worse 1-year VA 
gains compared with RCTs, regardless of anti-VEGF medication (Ciulla et al., 2020). This 
underscores the importance of asafe drug that has long durability of effect on DME patients.
2.2.1
Target Indication and Population 
 18 years of age with DME with BCVA of 73 to 20 ETDRS 
letters (equivalent to 20/40 to 20/400 on the Snellen chart).
2.3
Scientific Rationale for UBX1325 as a Treatment for DME
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. In preclinical 
studies, activation of the apoptotic cascade was selective for animals with a senescent cell 
burden. IVT administration of UBX1325 in diabetic animals led to improvements in retinal 
vascular leakage, providing support for the treatment of DME.
2.3.1
Role of Senescence in Retinal Diseases
The principal feature of senescence, a regulated, stress-induced, 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 the senescence-associated secretory phenotype (SASP). Although many factors of 
SASP have been identified in neovascular age-related macular degeneration (nAMD) and 
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.

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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.
Immunohistochemical (IHC) staining performed by the Sponsor of retinal sections from 
patients with DR/DME and age-related macular degeneration (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. 
Figure 2 
Immunohistochemical Staining of p16+ Cells in Human Donors 
AMD = age-related macular degeneration; 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.
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. 

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2.3.2
Disease-relevant SASP 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, 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 deoxyribonucleic acid (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. 
Figure 3 
Induction of Senescence and Diabetic Retinopathy-relevant Genes 
AfterGlucose Treatment
DR = diabetic retinopathy; SnC = senescent cells; mRNA = messenger ribonucleic acid; VEGF = vascular
endothelial growth factor; PDGF = platelet-derived growth factor; p16 = p16 cellular biomarker; p21 = p21 
cellular biomarker; NSnC = non-senescent cells. 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.

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2.3.3
Description of UBX1325
UBX1325 is a soluble, small-molecule phosphate pro-drug, which is cleaved rapidly in
tissues by ubiquitous phosphatases to yield the active parent molecule UBX0601. UBX1325 
was designed to improve the solubility of UBX0601 as an ophthalmic formulation. In this 
protocol, the phrase “Study Drug” refers to the administered phosphate form (UBX1325), not 
the active inhibitor UBX0601. In all nonclinical studies, Study Drug is administered as 
UBX1325, and converted rapidly to UBX0601, which potently inhibits subtypes within the 
B-cell lymphoma 2 (Bcl-2) family of apoptosis regulatory proteins, including Bcl-2, Bcl-xL,
and Bcl-w.
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 programmed cell 
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. In 
mouse models of retinal dysfunction, UBX1325 demonstrated inhibition of disease-relevant 
endpoints suggesting the potential for efficacy.
In a streptozotocin-induced diabetic retinopathy mouse model, IVT administration of 
UBX1325 resulted in decreased vascular leakage at all doses tested (2–200 pmol) (Figure 4). 
In a mouse model of retinal neovascularization (oxygen-induced retinopathy (OIR) model), 
an IVT administration of UBX1325 led to a decrease in the total area of neovascularization at 
all doses tested (3–100 pmol) (Figure 5). Refer to the Investigator’s Brochure (IB) for 
additional details.

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Figure 4 
Improved Vascular Leakage in the Diabetic Mouse
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.
Figure 5 
Decreased Neovascularization in the OIR Mouse
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.
2.3.3.1
Administration Regimen
On Day 1, patients will be administered a single 50 µL IVT treatment of 
of UBX1325 
or a sham procedure. The UBX1325 dose is based on the safe dose established in 
UBX1325-01, the Phase 1 SAD study (NCT04537884). 

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2.3.3.2
Justification for Dosing Strategy
The UBX1325 dose regimen planned for evaluation in this study was selected based on the 
safe dose established in the Phase 1 SAD study. 
In the Phase 1 SAD study, single IVT 
study, the dose is 10 
. 
2.3.4
Supportive Nonclinical Data
All nonclinical pharmacology, toxicology, and PK studies briefly described in this section 
were conducted by or for the Sponsor. More detailed information is provided in the current 
version of the UBX1325 Investigator’s Brochure (IB).
2.3.4.1
Pharmacology
UBX1325 (pro-drug) and UBX0601 (active parent molecule) 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 ofdisease-relevant endpoints such as neovascularization (NV) and 
vascular leakage.
2.3.4.2
Toxicology 
UBX1325 has been evaluated in Good Laboratory Practice (GLP) ocular toxicity studies in 
New Zealand White (NZW) rabbits and monkeys with observation periods of up to 2 months 
following a single IVT dose. In order to evaluate the potential for systemic toxicity, 
one-month GLP studies were conducted in which UBX1325 was given as a once weekly IV 
dose to rats and dogs. The no-observed-effect-level (NOEL) following IVT injection in 
rabbits at which there were no findings was 5 µg/eye; the no-observed-adverse-effect-level 
(NOAEL) in monkeys was 25 µg/eye. In the systemic repeat-dose toxicity studies, NOAELs 
were 0.3 mg/kg and 0.1 mg/kg for rats and dogs, respectively. The systemic levels noted at 
these NOAELs (NOAEL = 0.3 mg/kg, Cmax = 1260 ng/mL and AUClast = 649 hr·ng/mL; 
NOAEL = 0.1 mg/kg, Cmax = 568 on Day 29; AUC could not be determined) are not
anticipated to be observed following IVT dosing. 
Cardiovascular, respiratory, and neurobehavioral safety pharmacology studies following IV 
dosing of UBX1325 up to 0.3 mg/kg UBX1325 did not result in any adverse findings. Of
note, the cardiovascular study in dogs did not show any effect on QT prolongation, consistent 
with in vitro results evaluating the effect of UBX1325 and UBX0601 on the human 
ether-à-go-go- related gene (hERG) channel. In addition, UBX1325 and UBX0601 were not 
genotoxic in in vitroand in vivo studies. Further development of UBX1325 is supported by 
the available data.

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2.3.4.3
Pharmacokinetics
Ocular tissue exposures of UBX1325 and UBX0601 following a single IVT injection of 
50 ug of UBX1325 were well-characterized in rabbits following serial necropsy at 2, 24, 72, 
168, 240, and 336 hours, post-dose. UBX601 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 UBX601 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 remain at a very low level of 0.02 µg/mL. Systemic exposure to 
UBX1325/UBX0601 following intraocular dose was minimal, usually below the lower limit 
of quantification (LLOQ) in the assay (1 ng/mL), suggesting rapid clearance once UBX0601 
reaches systemic circulation.
2.3.5
Benefit: Risk Assessment
2.3.5.1
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 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 
FDA-approved oral Bcl-2 selective inhibitor for chronic lymphocytic leukemia/small 
lymphocytic lymphoma and 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 7). 
However, based on currently available exposure data from nonclinical studies following IVT 
administration (Section 2.3.4.3), 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 

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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
Objective
Endpoints
Primary
Assess the local and systemic safety
and tolerability following a 
single-dose IVT injection of
UBX1325 in patients with DME
Ocular and systemic safety and
tolerability of a single IVT injection of
UBX1325 evaluated by treatment
emergent adverse events (TEAEs)
Secondary
Assess the biological activity
following a single UBX1325 injection
in patients with DME
Assess further efficacy parameters 
and retinal structure improvement of 
patients following a single UBX1325 
injection compared to sham
Changes in BCVA from Baseline to
Weeks 12, 24 and 48  
Proportion of patients who require 2 or 
more anti-VEGF rescue over 12, 24 
and 48 Weeks
Change in CST from Baseline to each
study visit as assessed by SD-OCT and
read by a Reading Center
Change in CST area under the curve
(AUC) from baseline to each study
visit
Proportion of patients without macular
fluid at Weeks 12, 24 and 48 as
assessed by SD-OCT
Exploratory
Assess further efficacy parameters 
and retinal structure improvement of 
patients followinga single UBX1325 
injection compared to sham
Change from Baseline in Diabetic
Retinopathy Severity Scale (DRSS)
score at Weeks 24 and 48
Change in capillary perfusion from
Baseline to Weeks 12, 24 and 48 as
assessed by OCT-A and FA

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4
STUDY PLAN
4.1
Study Design
This is a Phase 2a, Proof-of-Concept (POC), prospective, multicenter, randomized, 
double-masked, sham-controlled study to assess the safety, tolerability, evidence of activity 
and durability of a single IVT injection of UBX1325 in subjects with DME. Approximately 
62 total patients will be enrolled 1:1 in the UBX1325 or sham study arms, in order to assess 
the primary objective. All patients will be followed for approximately 48 weeks.
See Section 6.6 for details on double-masking and site requirements. A schematic
representation of the study design is presented in Figure 1. 
4.2
Design Rationale 
4.2.1
Patient Population Selection
Based on the in vitro and in vivo pharmacology and toxicology data (UBX1325 Investigator 
Brochure), scientific rationale (see Section 2.3), and safety data from the UBX1325-01 
First-in- Human study, the Sponsor asserts that UBX1325 can be tested for safety and 
efficacy in DME patients. 
Patients will be those diagnosed as having DME (as defined by the AAO PPP DME 
Guidelines 2019) with BCVA in the study eye of 73 to 20 ETDRS letters (equivalent to 
20/40 to 20/400 on the Snellen chart).
4.2.2
Dose Rationale 
The planned dose is 10 µg based on favorable safety data in the Phase 1 SAD study. 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 safety profile supporting further clinical 
development; no dose-limiting toxicities in any of the dose cohorts, including the high dose 
.
ble safety data in the Phase 1 SAD study. 
4.3
Recruitment
Approximately 62 patients are planned to enroll in this study. 
4.4
Definitions
Patients officially enter the Screening Period following provision of informed consent 
directly.
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. 

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An enrolled patient is one who has been deemed eligible and has been randomized. 
4.5
Inclusion Criteria
To be included in this study, each individual must satisfy all of the following criteria:
1. Patients aged  18 years.
2. DR (PDR and NPDR) patients with DME (ETDRS-DRSS Score at 65C [or DR severity 
level of 8] or less severe as determined by a Central Reading Center), who had at least 
2 anti-VEGF intravitreal (IVT) injections (one or more of the following agents: 
aflibercept, bevacizumab or ranibizumab) in the preceding 6 months prior to Day 1, with 
the last anti-VEGF given between 3 and 6 weeks prior to Day 1. 
3. Center-
 300 µm on SD-OCT at
Screening as determined by a Central Reading Center.
4. BCVA in the study eye (most affected) of 73 to 20 ETDRS letters (equivalent to 20/40 to
20/400 on the Snellen chart) at Screening and at Day 1. If both eyes are equal, then it’s 
Investigator discretion.
5. IOP  23 mmHg in the study eye on Day 1.
6. Clear ocular media and adequate pupillary dilation to permit CFP 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.
4.6
Exclusion Criteria
If an individual meets any of the following criteria, he or she is ineligible for this study: 
1. Concurrent disease in the study eye or structural damage, other than DME, 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 of toxicity or CFP in the study eye. This includes, but is not limited to,
the following:
•
Macular edema of etiologies other than diabetes 
•
Clinically significant subretinal fibrosis
•
Subfoveal lipid
•
Cataract requiring surgery during the study period
•
RPE atrophy or tear or rips involving the macula
•
Clinically significant macular hole 
•
Clinically significant noninfectious uveitis 
•
Vitreomacular traction
•
Clinically significant epiretinal membrane (ERM)

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•
Aphakia 
•
Pseudophakia with anterior chamber intraocular lens (A/C IOL)
2. HbA1c  12 and/or recent signs of uncontrolled diabetes
3. Any ocular/intraocular/periocular infection or inflammation in either eye in the past 
4 weeksprior to Screening (mild blepharitis is acceptable)
4. History of vitreous hemorrhage in the study eye within 2 months prior to Screening
5. History of vitrectomy in the study eye 
6. History of intraocular, periocular, or corneal surgery in the study eye within 3 months 
prior to Screening, or anticipated need for such surgery during the study 
7. History of panretinal photocoagulation (within 3 months) or macular laser
photocoagulation (within 3 months) in the study eye prior to dosing 
8. History of corneal transplant in the study eye 
9. Patients with glaucoma who are poorly controlled in the opinion of the investigator or on 
more than 3 meds
10. Any condition, including laboratory findings and findings in the medical history or in the 
pre-study 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 
11. Presence of severe myopia (-8 diopters or greater) in the study eye 
12. History of systemic or intraocular steroid use for or in the study eye for 6 months prior to 
Day 1. The use of intravitreal nonbiodegradable steroid implants (ex. Iluvien®, Yutiq®, 
Retisert®) is prohibited 
13. Significant media opacities, including cataract, which might interfere with VA, 
assessment of toxicity, or fundus imaging
14. Intraocular surgery, including cataract surgery, in the study eye  3 months of screening
15. Known allergy to dye injected during FA
16. Known allergy to any component (phosphate buffered saline and polysorbate 80) in the 
Study Drug. Refer to the Investigator Brochure for more details.
17. Female patients who are pregnant, lactating, or of childbearing potential 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 menses for more than 1 year) and surgically sterilized females are exempt from 
these requirements.
18. 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.

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19. 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. COVID vaccinations are permitted prior to or during the 
course of the study. 
20. 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 (not including stable, superficial basal or squamous cell carcinoma of the 
skin), history of myocardial infarction within the last 6 months, or concomitant therapy. 

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5
STUDY CONDUCT
The expected duration of study participation for patients will be approximately 54 weeks, 
which includes a 6-week screening period, a single dose at Visit 1, and 48 weeks of 
follow-up. 
The study procedures are outlined below and in the SoE (Table 1).
5.1
Study Procedures
5.1.1
Study Screening and Treatment Periods
5.1.1.1
Screening Period (Day -42 to Day -1)
•
Informed Consent
•
Demographics
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Physical Examination
•
Vital Signs and Weight
•
Height
•
Laboratory Tests: Hematology and Chemistry
•
Pregnancy Test (serum)
•
12-lead ECG
•
BCVA
•
Anterior Segment Evaluation
•
Posterior Segment Evaluation
•
IOP
•
SD-OCT*
•
OCT-A (to be conducted at sites with the proper equipment available)*
•
FA*
•
CFP*
•
DRSS score*
•
Eligibility Criteria

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*SD-OCT, OCT-A (if applicable), FA and CFP will be submitted to the Central Reading 
Center for eligibility confirmation. A report for SD-OCT will be returned to the site within 
48 hours and a separate report with DRSS score will be returned to the site within 72 hours to 
support eligibility and subsequent randomization
5.1.1.2
Visit 1 
The following procedures will be done: 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Vital signs and Weight
•
Pregnancy Test (pre-dose urine dipstick)
•
BCVA
•
Anterior Segment Evaluation (conduct pre-dose OU and post-dose SE)
•
Posterior Segment Evaluation (conduct pre-dose OU and post-dose SE)
•
IOP (conduct pre-dose OU and 30 minutes ± 15 minutes post-dose SE)
•
SD-OCT (conduct pre-dose)
•
Eligibility Criteria
•
Conduct randomization
•
Study Drug Administration
•
AE Assessment
5.1.1.3
Visits 2, 10 and 11 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Vital Signs and Weight
•
BCVA
•
Anterior Segment Evaluation
•
Posterior Segment Evaluation

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•
IOP
•
SD-OCT for Visits 10 and 11 only
•
AE Assessment
5.1.1.4
Visits 3–7 
•
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 the proper equipment available) for Visit 7 only
•
FA for Visit 5 and 7 only
•
DRSS score at Visit 7 only
•
AE Assessment
5.1.1.5
Visit 8 
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Vital Signs and Weight
•
BCVA
•
SD-OCT
•
AE Assessment

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5.1.1.6
Visits 9 and 12
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Physical Examination
•
Vital Signs and Weight
•
Pregnancy Test (urine dipstick)
•
Laboratory Tests: Hematology and Chemistry
•
12-lead ECG
•
BCVA
•
Anterior Segment Evaluation
•
Posterior Segment Evaluation
•
IOP
•
SD-OCT
•
OCT-A (to be conducted at sites with the proper equipment available)
•
FA
•
CFP
•
DRSS score
•
AE Assessment
5.1.1.7
Unscheduled Visit/Early Termination
•
Medical and Ophthalmic History
•
Medication History/Concomitant Medications
•
Physical Examination
•
Vital Signs and Weight
•
Laboratory Tests: Hematology and Chemistry
•
12-lead ECG
•
BCVA

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•
Anterior Segment Evaluation
•
Posterior Segment Evaluation
•
IOP
•
SD-OCT
•
OCT-A (to be conducted at sites with the proper equipment available)
•
FA (only if assessment has not been performed within the preceding 30 days)
•
CFP
•
DRSS score
•
AE Assessment
5.1.2
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).
5.1.3
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 use of anti-VEGF for both eyes in 
the preceding 6 months prior to Screening should be documented in the concomitant 
medication log. All historical imaging and visual acuity assessments when available for both 
eyes in the preceding 6 months prior to Screening should be entered into the designated 
eCRF. Past medical history deemed by the Investigator as not clinically relevant to the 
patient’s overall health status or to his or her DME will not be captured. Relevant medical
history will be recorded in the electronic case report form (eCRF).
All medications taken will be recorded in the eCRF Concomitant Medication Log. Medical
History and Concomitant Medication Review should log should be performed at each study 
visit.
5.1.4
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. 

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Complete physical examinations will be performed by a licensed physician (or a physician’s 
assistant or nurse practitioner) at Screening, Visit 9 (Week 24), Visit 12 (Week 48) or 
Unscheduled Visits/Early Termination (ET). After Screening, symptom-directed physical 
examinations are required to be performed as clinically indicated. 
5.1.5
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. 
Vital signs and body weight assessment will be performed at all study visits.
5.1.6
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. 
5.1.7
Pregnancy Test
Serum pregnancy tests will be performed at Screening, and urine pregnancy tests will be
performed pre-dose on the dosing day (Day 1), Visit 9 (Week 24) and at the last study visit, 
Visit 12 Week 48 for all females of childbearing potential. 
5.1.8
Electrocardiography 
Evaluation will be performed at Screening for baseline reference, Visit 9 (Week 24) and at 
the last study visit, Visit 12 (Week 48).
5.1.9
Ocular Evaluations (must be conducted on both eyes)
•
BCVA: should be assessed using the ETDRS chart starting at 4 meters at Screening, on
Day 1 (pre-dose), Day 2, and at Weeks 1, 2, 4, 8, 12, 18, 24, 32 and 48, and 
Unscheduled/ET. See the Ophthalmic Manual for details.
•
Anterior Segment Evaluation: should be performed prior to pupillary dilation, or after, 
depending on the site Standard of Care. Any abnormalities of the anterior chamber, 
eyelids, conjunctivae, pupil, iris, lens and cornea should be documented at Screening, on 
Day 1 pre-dose and post-dose, on Day 2, and at Weeks 1, 2, 4, 8, 12, 24, 32 and 48 and 
Unscheduled/ET. Any anterior chamber inflammation (cells and flare), phakic status, and 
posterior lens capsule status should also be noted. For post-dose, only the study eye 
should be assessed
•
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 Day 1 pre-dose and post-dose, on Day 2, and at 

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Weeks 1, 2, 4, 8, 12, 24, 32 and 48/ET. Any vitreous inflammation (haze and cells) 
should also be noted. For post-dose, only the study eye should be assessed
•
IOP: should be measured using Goldmann applanation tonometry at Screening, on Day 1
pre-dose and 30 minutes ± 15 minutes post-dose, on Day 2, and at Weeks 1, 2, 4, 8, 12, 
24, 32 and 48 and Unscheduled/ET. Tonometry should be performed prior to pupillary 
dilation or as per site’s standard procedures. For post-dose, only the study eye should be 
assessed
•
CFP: should be obtained at Screening, Visit 9 (Week 24), Visit 12 (Week 48) and 
Unscheduled/ET.
•
FA: should be obtained at Screening (or on Day 1 pre-dose) and at Weeks 4, 12, 24 and 
48, and Unscheduled/ET (if it had not been done within 30 days prior).
•
SD-OCT: should be obtained at Screening, on Day 1 (pre-dose), and at Weeks 1, 2, 4, 8, 
12, 18, 24, 32, 40 and 48 and Unscheduled/ET.
•
OCT-A: to be conducted at sites with the proper equipment available at Screening,
Weeks 12, 24 and 48 and Unscheduled/ET.
CFP, FA, SD-OCT, and OCT-A (if done) images should be transmitted to the Central 
Reading Center at each applicable visit.
5.1.10
Rescue Criteria
If at any visit between Visit 4 (Week 2) to Visit 12 (Week 48) or Unscheduled, patients 
exhibit worsening CST by 75 µm from Baseline (Day 1) per SD-OCT and/or a 10-letter 
decrease in BCVA compared to peak BCVA from Baseline (Day 1), they can be rescued with 
standard of care. For this study, standard of care is defined as the last anti-VEGF a patient 
was administered prior to enrolling into the study. Rescued patients will continue their visit 
schedule as safety follow-up through Week 48. For any questions on rescue criteria, and prior 
to administering rescue medication, when possible, 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. 
5.1.11
End of Study
The study will be considered complete when the last patient has completed the last study
visit.

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5.2
Discontinuation or Withdrawal 
5.2.1
Individual Patients
5.2.1.1
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,
•
Lack of efficacy,
•
A serious or intolerable AE occurs,
•
The Sponsor terminates the study,
•
The Investigator suspends or terminates that site’s participation in the study, or
•
The patient requests to be discontinued from the study.
5.3
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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6
STUDY INTERVENTIONS
6.1
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, Illinois.
Sham kits will be supplied by the central lab and will be included in the bulk ancillary supply 
shipment. There will be a needleless syringe to complete the sham procedure. These will also
be accounted for as part of Study Drug accountability. 
6.1.1
UBX1325
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 prior to administration to the patient.
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.
6.2
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 

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will be obtained before any study-specific procedures are performed. Patients who have 
consented to participate in the study will be assigned a unique number. 
After the patient has been consented and completed all screening procedures confirming
eligibility, they may proceed to Day 1, where they will be randomized in a 1:1 ratio to
UBX1325 or sham arm, stratified by most recent anti-VEGF treatment that patients received 
prior to Day 1. There will be two strata: 1) aflibercept vs 2) ranibizumab or bevacizumab.
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.
6.3
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 
subject randomization. All randomization information will be stored in a secured area, 
accessible only by authorized personnel. 
6.4
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 administration of 
UBX1325 per the site’s preferred practice patterns. Such drops, if prescribed, should be 
documented in the patient’s eCRF.
6.5
Administration of Sham Procedure
Control will be a sham procedure (i.e., needleless, empty sterile syringe) touched to the 
surface of the study eye to mimic an IVT injection. 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.
6.6
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
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procedure, as well as certain post-injection assessments on Day 1 only. Specifically, the 
unmasked injector will do the anterior and posterior segment exams, IOP and AE assessment.
Other supporting activities such as study drug preparation, study drug accountability, as well 
as screening assessments as needed, will be performed by designated unmasked personnel. 
Unmasked personnel should not be involved in any other study procedures outside of Day 1. 
Subsequent visits (Day 2 and onward) should be conducted by masked staff. It is important
the randomization code is not revealed to anyone in order to maintain the integrity of the 
double-masking. 
6.7
Extent and 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).
6.8
Permitted and Prohibited Concomitant Treatments
6.8.1
Permitted Treatments
Permitted concomitant treatments in/for the study eye and non-study eye include: 
•
Topical antibiotics administered prophylactically with IVT injection and topical/systemic
antibiotics used for AE treatment.
•
Artificial tears
•
Steroid use is permitted only for the following conditions: 
Topical (e.g., for atopic dermatitis treatment), inhaled (e.g., for asthma treatment), or
locally injected (e.g., for epidural or joint injection)
Topical use of steroids in the fellow eye 
Topical use of steroids for treatment of inflammation in the study eye (e.g., uveitis).
Concomitant intravitreal therapy in the non-study eye is permitted but cannot be 
administered within 7 days of treatment with masked study drug. 

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6.8.2
Prohibited Treatments
Patients will not be permitted to received treatments for the management of DME in the 
study eye, once randomized to this study, unless it is a rescue treatment (see Section 5.1.11).
Systemic (oral, intramuscular, and intravenous) steroids are not allowed unless for an AE
treatment. All systemic steroids should be discontinued before the study drug administration.
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 study eye that, in the opinion of 
the Investigator and/or the Medical Monitor, may have an effect on the study results.
Patients should not have received brolucizumab as their most recent anti-VEGF treatment. 
Historical use of brolucizumab is not excluded. 

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7
SAFETY MONITORING
At each visit, patients will undergo ophthalmologic evaluation and assessment for signs of 
potential toxicity. Safety monitoring activities will be an ongoing activity done by the 
Sponsor. The SAC will convene on an ad hoc basis to assess the ongoing safety of the clinical
trial. 
For all patients, all acquired data may be reviewed by the SAC. This process will be detailed
in the SAC Charter.
7.1
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 
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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:
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. 

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•
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. 
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. 
7.2
Documenting Adverse Events
7.2.1
Timeframe for Collection
AEs and SAEs will be collected from the time of treatment through the last follow-up visit at
Week 48. All events prior to this will be documented as medical history. 
The Investigator must follow up on all AEs through Week 48. Non-serious AEs may be 
followed to resolution past the patient’s last study visit at the discretion of the Investigator 
and/or MedicalMonitor 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. 
7.2.2
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. 

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7.3
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 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 
(EC), 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. 
7.4
Adverse Events of Special Interest
No AEs of special interest have been identified for UBX1325 to date.
7.5
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:
Serum Chemistry:
Hematocrit
Albumin
Hemoglobin
Alkaline phosphatase
Platelet count
Alanine aminotransferase
RBC count
Aspartate aminotransferase
Mean corpuscular volume
Blood urea nitrogen
WBC count with differential
Calcium
Carbon dioxide
Chloride
Creatininea
Globulin
Glucose
HbA1c (Screening)b
Human chorionic gonadotropinc
Lactate dehydrogenase
Phosphorus
Potassium
Sodium
Total and direct bilirubin
Total cholesterol
Total protein
HbA1c = hemoglobin A1c; RBC = red blood cell; WBC = white blood cell
a
Creatinine clearance will be calculated by the Chronic Kidney Disease Epidemiology Collaboration 
(CKD-EPI) method.
b
All patients will be tested for HbA1c; fasting is not required.
c
Serum human chorionic gonadotropin is required only for females who are of childbearing potential.
7.6
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 administration of the Study Drug must be 
reported to the Investigator.

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7.7
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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8
STATISTICAL METHODS
8.1
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. No imputation of values 
for missing data will be performed. 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. 
8.2
Determination of Sample Size
Assuming the difference of change from Baseline in BCVA between UBX1325 and sham is 
8 letters, the standard deviation is 13 letters, and the drop-out rate is 5%, a sample size of 
62 subjects (31 per group) provides 80% power to detect the difference at a two-sided 
significance level of 0.15.
8.3
Analysis Populations
8.3.1
Full Analysis Set
The Full Analysis Set will include all randomized subjects who received a single IVT 
treatment of UBX1325 or sham, have a baseline CST assessment, and at least one 
post-baseline CST assessment. The Full Analysis Set will be the primary population for 
evaluating all efficacy variables.
8.3.2
Safety Analysis Set
The Safety Analysis Set will include all subjects who received a single IVT treatment of
UBX1325 or sham. The Safety Analysis Set will be the primary population for evaluating all
safety variables and subject characteristics.
8.3.3
PK Analysis Set
The PK Analysis Set will include subjects who received a single IVT treatment of UBX1325 
and have at least one evaluable PK concentration after injection. PK blood draws were done 
at a subset of sites in the United States and all patients enrolled at these sites up until the 
approval of the Protocol Amendment V4.0had their blood drawn for PK analysis.
8.4
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 dose cohort and overall, based on the Safety Analysis Set.

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Medical history will be summarized using Medical Dictionary for Regulatory Activities 
(MedDRA) terms. Prior medications will be tabulated using World Health Organization 
(WHO) Drug Dictionary terms.
8.5
Efficacy Analysis 
The Full Analysis Set will be used for all efficacy analyses.
The BCVA will be assessed using the ETDRS chart starting at 4 meters at each study visit.
Change in BCVA from baseline to each visit will be analyzed by mixed model for repeated 
measures (MMRM). The details of MMRM and the analysis methodsfor other efficacy
endpoints described in Section 3 will be provided in the SAP.
8.6
Safety Analysis 
The Safety Analysis Set will be used for all safety analyses. The safety variables include the
incidence of ocular and systemic safety and tolerability and will be summarized descriptively. 
AEs will be coded using the MedDRA. Subjects 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.
8.6.1
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.
8.6.2
Pharmacokinetics Analysis
Analysis of PK parameters will be based on the PK Analysis Set. PK of UBX1325 and 
UBX0601 in plasma following IVT injection of UBX1325 will be obtained at the time points 
indicated in the Schedule of Events effective through the Protocol Amendment Version 4.0.
Mean (SD) plasma concentrations of UBX1325 and/or UBX0601 will be summarized 
graphically and PK parameters will be estimated when data allow. Individual PK parameters 
(e.g., time at which the maximum concentration is observed [Tmax], maximum concentration 
observed [Cmax], area under the plasma concentration-time curve extrapolated to the last 
observed concentration [AUC0-t], area under the plasma concentration-time curve
extrapolated to infinity [AUC0-inf], percentage of area under the plasma concentration-time 
curve extrapolated after last observed concentration [AUC%extrap], apparent total clearance of 
the drug from plasma after IVT injection [CL/F], apparent volume of distribution after 
non-intravenous administration [Vd/F], half-life [t1/2]) will be calculated using 
non-compartmental analyses (NCA) when available data supports such calculations. 
Additional PK parameters may be derived, if deemed appropriate. Descriptive statistics will 
be used to characterize the inter-patient variability of the PK parameters by cohort. 
Descriptive statistics will include patients per cohort, arithmetic mean, geometric mean, 
mean, median, standard deviation, %CV, value range (minimum and maximum), as

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appropriate. The PK analysis plan will be detailed in the SAP and more specifically, applied 
to patient samples collected at the subset of participating sites through the approval of 
Protocol Amendment Version 4.0.
8.7
Planned Interim Analysis
Formal interim analyses will be performed at 12 weeks and other possible timepoints in the 
study. The SAP will specify what proportion of patients data is needed for the interim 
analyses.

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9
ETHICAL CONSIDERATIONS
9.1
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.
9.2
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. 
9.3
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, French 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 screening procedures or any Study Drug is administered.
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.

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9.4
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.
9.5
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. Ifthe 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. 
9.6
Biological Specimens and Data
Biological samples should not be destroyed at the end of the study. Samples should be sent to 
the Sponsor’s designated laboratory as detailed in the region-specific Laboratory Manual. 
Samples may be tested for exploratory endpoints or additional further research after consent
has been obtained by patients participating at US based sites. 

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10
OVERSIGHT
10.1
Safety Assessment Committee
A SAC will be established and available ad hoc 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.
10.2
Quality Control and Assurance
10.2.1
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. 
10.2.2
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. 
10.2.3
Records
10.2.3.1
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 
[CRA]), 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. 

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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. 
10.2.3.2
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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11
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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