A Multi-Center, Double-Masked Phase 3 Evaluation of the Safety and Efficacy of LNZ101 for the Treatment of Presbyopia
Phase: PHASE3
Conditions: Presbyopia, Near Vision, Refractive Error, Eye Diseases
Sponsor: LENZ Therapeutics, Inc

Clinical Trial Protocol 22-150-0018 
Protocol 
Title: 
A Multi-Center, Double-Masked Phase 3 Evaluation 
of the Safety and Efficacy of LNZ101 for the 
Treatment of Presbyopia 
Protocol Number: 
22-150-0018 
Study Phase: 
Phase 3 
LNZ101 
 
Investigational 
Product Name: 
Ophthalmic Solution 
LNZ100 
 Ophthalmic Solution 
IND/IDE/PMA Number: 
120,609 
Indication: 
Presbyopia 
Investigators: 
TBD 
Sponsor: 
Contract 
Research 
Organization: 
IRB/IEC: 
LENZ Therapeutics, Inc. 
 
Ora, Inc. 
300 Brickstone Square, 3rd Floor 
Andover, MA 01810 
Alpha IRB 
1001 Avenida Pico, Suite C, #497 
San Clemente, CA 92673 
949-542-3882 www.alphairb.com
Confidentiality Statement 
This protocol contains confidential, proprietary information of Ora, Inc. and/or LENZ 
Therapeutics, Inc. Further dissemination, distribution or copying of this protocol or its contents 
is strictly prohibited.
Date 
Original Protocol: 
Version 1.0 (17 Nov 2022) 
Amendment 1 
Version 2.0 (30 Jan 2023) 
Amendment 2 
Version 3.0 (02 May 2023) 
Amendment 3 
Version 4.0 (16 Jun 2023) 
Amendment 4 
Version 5.0 (31 Jul 2023) 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 1 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 2 of 70

1.0 
SYNOPSIS 
Protocol Title: 
A Multi-Center, Double-Masked Phase 3 Evaluation of 
the Safety and Efficacy of LNZ101 for the Treatment of 
Presbyopia 
Protocol Number: 
22-150-0018
Investigational Products: 
LNZ101 
 
ophthalmic solution 
LNZ100 
 ophthalmic solution 
Vehicle ophthalmic solution 
Study Phase: 
Phase 3 
Primary Objective: 
To evaluate the safety and efficacy of LNZ101/LNZ100 
compared with vehicle for the treatment of Presbyopia. 
Secondary Objective: 
Not applicable 
Overall Study Design: 
Structure: 
A multi-center, double-masked, randomized, vehicle- 
controlled, safety and efficacy study 
Duration: 
Approximately 6 weeks 
Controls: 
Screening Control: 
 
Randomized Control Treatment:
Vehicle ophthalmic solution 
Dosage/Dose Regimen/ 
Instillation/Application/Use: 
Enrolled subjects will be randomized to receive 
LNZ101, LNZ100, or vehicle
. 
 
 
 Subjects will dose for 6 
weeks. 
Summary of Visit 
Schedule: 
•
Visit 1 (Day -60 to -4): Screening;
•
Visit 2 (Day 1):
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 3 of 70

• 
 
 
 
 
 
 
Measures Taken to Reduce Bias: 
Randomization will be used to avoid bias in the 
assignment of subjects to treatment and to enhance the 
validity of statistical comparisons across treatment 
groups. Double-masked treatment will be used to reduce 
potential of bias during data collection and evaluation of 
clinical endpoints. 
 
 
 
 
 
 
Number of Subjects: 
Approximately 222 subjects will be enrolled at Visit 2. 
 
 
 
 
 
 
 
 
Condition/Disease: 
Healthy adult subjects ages 45 to 75 years who have 
presbyopia 
Inclusion Criteria: 
Subjects must:  
1. Be able and willing to provide written informed 
consent and sign a Health Information Portability and 
Accountability Act (HIPAA) form prior to any study 
procedure being performed; 
2. Be able and willing to follow all instructions and 
attend all study visits; 
3. Be 45-75 years of age of either sex and any race or 
ethnicity at Visit 1; 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 4 of 70

 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exclusion Criteria: 
1. Subject must not be a female of childbearing potential 
who is currently pregnant, nursing, or planning a 
pregnancy; 
2. Subject must not have known contraindications or 
sensitivity to the use of any of the study medications 
or their components;  
3. Neither eye can have an active ocular infection at 
Visit 1 or at Visit 2 (bacterial, viral, or fungal), 
positive history of an ocular herpetic infection, 
preauricular lymphadenopathy, or ongoing, active 
ocular inflammation (e.g., moderate to severe 
blepharitis, allergic conjunctivitis, peripheral 
ulcerative keratitis, scleritis, uveitis);  
4. Neither eye can have moderate or severe dry eye 
 
 
   
1 Punctal plugs are acceptable if they have been in place for a minimum of 90 days prior to visit 1.  
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 5 of 70

5. Neither eye can have clinically significant abnormal 
lens findings (e.g., cataract) including early lens 
changes and/or any evidence of a media opacity 
during dilated slit-lamp biomicroscopy and fundus 
exam documented within 3 months of Visit 1 or at 
Visit 1; 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 6 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 7 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Formulations: 
LNZ101 
 
ophthalmic solution 
LNZ100 
 ophthalmic solution 
Brimonidine 
ophthalmic solution 
Evaluation Criteria: 
2 Any blood sugar in an otherwise normal, non fasting blood chemistry panel that is greater than 
150mg/dl would be considered abnormal and indicative of a diabetic or prediabetic state and is 
exclusionary. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 8 of 70

Efficacy Measures and Endpoints: 
Primary Efficacy Endpoint: 
• 
Percentage of subjects who achieve a 3-line (15- 
letter) or greater improvement from baseline in 
the measurement of monocular BCDVA at 40 
cm and no loss in BCDVA ≥ 5 letters (ETDRS 
chart at 4 m)
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 9 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 10 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 11 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 12 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Measures: 
• 
Adverse events (AE) (reported, elicited, and 
observed) 
• 
Pregnancy test 
 
• 
Monocular and binocular BCDVA (normal and 
low-luminance) 
• 
Slit lamp biomicroscopy 
• 
IOP 
• 
Dilated fundus exam 
 
• 
Conjunctival redness 
Other: 
• 
Dark Adapted Pupillometry 
• 
Patient-reported outcome (PRO) questionnaire 
• 
Drop instillation assessment 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 13 of 70

General Statistical Methods and Types of Analyses Analysis Sets: 
Full Analysis Set (FAS) – The FAS will include all randomized subjects. No subjects will be 
excluded from the FAS due to protocol violations/deviations. Subjects in the FAS will be 
analyzed as randomized. 
Per Protocol (PP) Set – The PP set will include subjects in the FAS who do not have significant 
protocol deviations that affect the primary endpoint analysis. Protocol deviations will be 
assessed prior to database lock and unmasking. Subjects in the PP set will be analyzed as 
treated. 
Safety Set – The Safety set will include all subjects who have received at least one dose of the 
study drug. Subjects in the Safety set will be analyzed as treated. 
Unit of Analysis: 
The study eye will be used for all monocular efficacy analyses. The qualified fellow eye will 
be used in additional binocular analyses as specified. Both eyes will be displayed and analyzed 
for all ophthalmic safety variables. 
 
 
 
General Considerations: 
In general, quantitative/continuous data will be summarized using descriptive statistics 
(number of subjects [n], mean, standard deviation [SD], median, minimum, and maximum). 
Qualitative/categorical data will be summarized using frequencies and percentages. Statistical 
testing, unless otherwise indicated, will be performed at a 2-sided 0.05 significance level. 
For all variables, baseline is defined as the last measurement taken prior to the administration 
of first dose of study drug at Visit 2. Change from baseline will be calculated as follow-up 
measure minus baseline measure. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 14 of 70

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sample Size 
A sample size of 222 subjects (74 per arm) yields >99% power to establish superiority of 
LNZ101/LNZ100 to vehicle in the proportion of study eyes demonstrating a ≥ 3-line (15-letter) 
improvement or greater from baseline in BCDVA at 40 cm and no loss in BDVA ≥ 1 line (5 
letters) at 4 
 
 
Primary Efficacy Analyses 
The primary efficacy endpoint in this study is the percentage of study eyes with a ≥ 3-line (15-
letter) improvement in BCDVA at 40 cm from baseline and no loss in best distance corrected 
visual acuity ≥ 1 line (5-letter) at 4 m 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 15 of 70

Descriptive statistics will be presented by treatment group. Testing of the primary endpoint 
will be completed using logistic regression with treatment as the fixed effect and baseline 
BCDVA at 40 cm as a covariate. The adjusted odds ratios and marginal proportions and 
differences in proportions along with corresponding two-sided 95% confidence intervals (CIs) 
and p-values will be presented. 
Treatment comparison will also be made using Pearson’s chi-squared test or Fisher’s exact test 
if any of the expected cell counts are less than five as a sensitivity analysis to the primary 
model above. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Analysis 
All safety data will be analyzed using the Safety set. Safety of LNZ101 and LNZ100 will be 
assessed by the review of all safety parameters. 
Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory Activities 
(MedDRA) terms and be presented in a data listing. Treatment emergent AEs (TEAEs), those 
that occur after the first dose of study drug, will be summarized by treatment group using 
frequency and percent for each system organ class (SOC) and preferred term (PT) within each 
SOC. Similar summaries will also be presented for expected and unexpected TEAEs, treatment 
emergent SAEs, TEAEs related to the study drug, and TEAEs by severity. When reporting the 
incidence of AEs, a subject will only be counted once if they ever experience an event within 
the SOC and ever experience the individual PT within each treatment group. Ocular and non- 
ocular events will be summarized separately. 
Actual results and changes from baseline results in monocular and binocular BCDVA (normal 
and low-luminance), slit lamp biomicroscopy, IOP, dilated fundus examination, and 
conjunctival redness will be summarized descriptively at each visit by treatment group. 
Full details of the safety analyses will be specified in the formal SAP. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 16 of 70

Summary of Known and Potential Risks and Benefits to Human Subjects 
Approved pharmacologic treatment for presbyopia is limited. Pilocarpine ophthalmic solution 
1.25% is the only approved pharmacologic treatment for presbyopia in adults to date. There are 
currently no marketed Aceclidine-Brimonidine combination products. A 2% concentration of 
Aceclidine was approved in several European countries in 1969 for the treatment of glaucoma, 
and Aceclidine has been used in humans at concentrations of up to 4%. Possible AEs 
associated with Aceclidine include redness or brow ache (Romano 1970, Randazzo et al. 
2005). Fewer adverse effects have been reported with Aceclidine (no angle closure, fewer 
subjects reporting pain on instillation, greater comfort with long-term use, and no 
tachyphylaxis) compared to other miotics, like pilocarpine (Francois and Goes 1977; Romano 
1970). 
Brimonidine was approved in the U.S. for human use in 1996 for the lowering of intraocular 
pressure in patients with open-angle glaucoma or ocular hypertension. It is commercially 
available in the U.S. at up to 0.2% concentration. Dosing at this concentration has been shown 
to be generally safe and effective. Adverse ocular effects of Brimonidine include possible 
discomfort, irritation, blurred vision, and light sensitivity. 
In addition, vitreous floaters have also been reported. 
The concentrations proposed for use in this study 
 
are substantially lower than the concentrations in common clinical use for both of these active 
ingredients. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 17 of 70

TABLE OF CONTENTS 
1.0 SYNOPSIS ..................................................................................................................3 
TABLE OF CONTENTS ...................................................................................................18 
LIST OF ABBREVIATIONS ............................................................................................21 
2.0 INTRODUCTION .....................................................................................................23 
3.0 STUDY OBJECTIVES .............................................................................................23 
3.1 Primary Objective ..................................................................................................23 
4.0 CLINICAL HYPOTHESES ......................................................................................23 
5.0 OVERALL STUDY DESIGN ..................................................................................24 
6.0 STUDY POPULATION ...........................................................................................24 
6.1 Inclusion Criteria ....................................................................................................24 
6.2 Exclusion Criteria ...................................................................................................25 
6.3 Cohort Assignment .................................................................................................28 
6.4 Withdrawal Criteria ................................................................................................28 
7.0 STUDY PARAMETERS ..........................................................................................29 
7.1 Efficacy Endpoints Primary Efficacy Endpoint: ....................................................29 
7.2 Safety Endpoints ....................................................................................................32 
8.0 STUDY MATERIALS .............................................................................................33 
8.1 Study Treatments ....................................................................................................33 
8.1.1 Investigational Product .....................................................................................33 
8.1.2 Instructions for Use and Administration ..........................................................33 
 
9.0 STUDY METHODS AND PROCEDURES .............................................................34 
9.1 Subject Entry Procedures .......................................................................................34 
9.1.1 Overview ..........................................................................................................34 
9.1.2 Informed Consent .............................................................................................34 
 
 
 
 
9.2 Concurrent Therapies and Medical History ...........................................................35 
9.2.1 Prohibited Medications/Treatments ..................................................................35 
9.2.2 Escape Medications ..........................................................................................36 
9.2.3 Special Diet or Activities .................................................................................36 
9.3 Examination Procedures .........................................................................................36 
9.3.1 Procedures to be Performed at the Study Visit with Regard to Study 
Objective ..........................................................................................................36 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 18 of 70

 
 
 
 
 
9.4 Schedule Of Visits, Measurements and Dosing .....................................................41 
9.4.1 Scheduled Visit ................................................................................................41 
9.4.2 Unscheduled Visits ...........................................................................................41 
9.4.3 Early Termination ............................................................................................42 
9.5 Compliance with Protocol ......................................................................................42 
9.6 Subject Disposition .................................................................................................42 
9.6.1 Screened Subjects .............................................................................................42 
9.6.2 Screen failed Subjects ......................................................................................42 
9.6.3 Randomized Subjects .......................................................................................42 
9.6.4 Discontinued Subjects ......................................................................................42 
9.6.5 Completed Subjects ..........................................................................................42 
9.6.6 Withdrawn Subjects .........................................................................................42 
9.7 Study Termination ..................................................................................................42 
9.8 Study Duration .......................................................................................................43 
9.9 Monitoring and Quality Assurance ........................................................................43 
10.0 ADVERSE EVENTS ................................................................................................43 
10.1 Adverse Event ........................................................................................................43 
10.1.1 Severity ............................................................................................................44 
10.1.2 Relationship to Investigational Product ............................................................44 
10.1.3 Expectedness ....................................................................................................44 
10.2 Serious Adverse Events ..........................................................................................45 
10.3 Procedures for Reporting Adverse Events .............................................................46 
10.3.1 Reporting a Suspected Unexpected Adverse Reaction .....................................46 
10.3.2 Reporting a Serious Adverse Event ..................................................................46 
10.4 Procedures for Unmasking (if applicable) ..............................................................46 
10.5 Type and Duration of the Follow-up of Subjects after Adverse Events .................47 
11.0 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES .....................47 
11.1 General Considerations ..........................................................................................47 
11.2 Hypotheses .............................................................................................................47 
11.3 Analysis Sets ..........................................................................................................48 
11.4 Unit of Analysis .....................................................................................................48 
11.5 Efficacy Endpoints .................................................................................................49 
11.5.1 Primary Efficacy Endpoint: ..............................................................................49 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 19 of 70

 
 
11.6 Safety Endpoints ....................................................................................................52 
11.7 Sample Size ............................................................................................................52 
11.8 Demographic and Baseline Characteristics ............................................................52 
11.9 Efficacy Analysis ...................................................................................................53 
11.9.1 Primary Efficacy Analyses ...............................................................................53 
 
 
11.10 Safety Analysis .....................................................................................................53 
11.11 Interim Analysis ....................................................................................................54 
11.12 Missing Data .........................................................................................................54 
11.13 Adjustment for Multiplicity ..................................................................................54 
12.0 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ....................................55 
12.1 Protection of Human Subjects ................................................................................55 
12.1.1 Subject Informed Consent ................................................................................55 
12.1.2 IRB Approval ...................................................................................................55 
12.2 Ethical Conduct of the Study .................................................................................55 
12.3 Subject Confidentiality ...........................................................................................56 
12.4 Documentation .......................................................................................................56 
12.4.1 Retention of Documentation .............................................................................56 
12.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ..........................................................................................56 
12.5.1 Labeling/Packaging ..........................................................................................56 
12.5.2 Storage of Investigational Product ...................................................................57 
12.5.3 Accountability of Investigational Product ........................................................57 
12.5.4 Return or Disposal of Investigational Product .................................................57 
12.6 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ..................................................................................................................57 
12.7 Handling of Biological Specimens .........................................................................57 
12.8 Publications ............................................................................................................58 
 
 
 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 20 of 70

LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ADHD 
Attention-deficit/hyperactivity disorder 
AE 
Adverse event 
BID 
Twice daily 
BCDVA 
Best-corrected distance visual acuity 
cd/m2 
Candela per square meter 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
eCRF 
Electronic case report form 
D 
Diopter 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
 
 
 
 
IOP 
Intraocular pressure 
IP 
Investigational product 
IRB 
Institutional review board 
IUD 
Intrauterine device 
HIPAA 
Health Information Portability and Accountability Act 
LASEK 
Laser-assisted epithelial keratomileusis 
LASIK 
Laser-assisted in-situ keratomileusis 
logMAR 
Logarithm of the minimum angle of resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHG 
Millimeters of mercury 
NSAID 
Non-steroidal anti-inflammatory drug 
OTC 
Over-the-counter 
PP 
Per protocol 
PRK 
Photorefractive keratectomy 
PT 
Preferred term 
RGP 
Rigid gas permeable 
SAE 
Serious adverse event 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 21 of 70

 
Abbreviation 
Definition 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
VA 
Visual acuity 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 22 of 70

2.0 INTRODUCTION 
Presbyopia is defined by a loss in the ability of the eye to adjust its focal length so that 
objects at different distances produce focused images on the retina. As the eye ages, the 
lens of the eye becomes less able to change shape. Hardening of the lens, along with 
weakening of the ciliary muscles, plays a major role in the pathogenesis of presbyopia 
and leads to symptoms such as blurred vision, eye strain and headache after reading or 
computer use (Truscott 2009; Helmholtz 1855; Ostrin and Glasser 2007; Scarcelli 2011). 
Presbyopia affects most people over 45 years of age and continues to worsen until 
approximately 65 years of age. Based on data from 228 countries, it was estimated that in 
2005, presbyopia affected more than 1 billion people worldwide. Presbyopia is projected 
to increase to 1.78 billion people by 2050. More than half of the people with this 
condition do not have adequate treatment options, which results in some level of 
disability when performing tasks that require near visual acuity (Holden 2008). 
Current treatments available for presbyopia include the use of reading glasses, contact 
lenses, or refractive surgery (including laser) or intraocular lens (IOL) surgery. 
Pharmaceutical therapies have been explored but, thus far, continue to be limited in 
treating presbyopia without being associated with undesirable adverse effects (Gilmartin 
1995). Pilocarpine ophthalmic solution 1.25% is the only approved pharmacologic 
treatment for presbyopia in adults to date. 
Both Aceclidine and Brimonidine have been used extensively in humans for ophthalmic 
indications. Aceclidine is a parasympathomimetic miotic agent that is approved for 
lowering IOP in Europe. In 1969, a 2% solution (dosed four times a day) of Aceclidine 
was approved in several European countries for the treatment of glaucoma. Furthermore, 
Aceclidine has been used at concentrations of up to 4% in humans. Brimonidine is an 
alpha adrenergic drug that was approved for human use in the US in 1996. Brimonidine 
has a dual mechanism of action by reducing aqueous humor production and increasing 
uveoscleral outflow. Brimonidine at concentrations of up to 0.2% typically dosed twice 
daily has been shown to be generally safe and effective. Notably, the concentrations of 
Aceclidine and Brimonidine in LNZ-101 formulation in this study 
 
are substantially lower than the concentrations of these agents that 
are in clinical use. 
3.0 STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of the study is to evaluate the safety and efficacy of 
LNZ101/LNZ100 compared with vehicle for the treatment of Presbyopia. 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 23 of 70

5.0 OVERALL STUDY DESIGN 
This is a
 randomized, double-masked, multi-center, vehicle-controlled study 
evaluating the safety and efficacy of LNZ101/LNZ100 compared to vehicle in 
approximately 222 subjects with presbyopia. 
Visit 1 (Screening, Day -60 to -4): Subjects will be screened through ophthalmic 
assessments using best corrected distance visual acuity (BCDVA) tests.
 
 
 
Visit 2 (Randomization, Day 1): Visit 1 ophthalmic assessments will be repeated at 
Visit 2 per the Schedule of Visits and Measurements. Following the pre-treatment, 
baseline assessments, qualified subjects will be randomized 
 to one of 
the following study arms: 
• LNZ101
 
ophthalmic solution 
• LNZ100 
ophthalmic solution 
• Vehicle ophthalmic solution 
 Primary efficacy and safety 
assessments will be performed. 
 
 
 
 
 
 
 
 
 
6.0 STUDY POPULATION 
Approximately 222 healthy adult subjects from 45 to 75 years of age (inclusive) with 
presbyopia who do not have any conditions, in the investigator’s opinion, that may put the 
subject at increased risk, confound study data, or interfere significantly with the subject’s 
study participation. 
6.1  
Inclusion Criteria 
Subjects must: 
1. Be able and willing to provide written informed consent and sign a Health 
Information Portability and Accountability Act (HIPAA) form prior to any 
study procedure being performed; 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 24 of 70

2. Be able and willing to follow all instructions and attend all study visits;
3. Be 45-75 years of age of either sex and any race or ethnicity at Visit 1;
6.2 
Exclusion Criteria 
1. Subject must not be a female of childbearing potential who is currently pregnant,
nursing, or planning a pregnancy;
2. Subject must not have known contraindications or sensitivity to the use of any of
the study medications or their components;
3. Neither eye can have an active ocular infection at Visit 1 or at Visit 2 (bacterial,
viral, or fungal), positive history of an ocular herpetic infection, preauricular
lymphadenopathy, or ongoing, active ocular inflammation (e.g., moderate to
severe blepharitis, allergic conjunctivitis, peripheral ulcerative keratitis, scleritis,
uveitis);
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 25 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 26 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 27 of 70

6.4 
Withdrawal Criteria 
Subjects will be withdrawn from the study if any of the following criteria are met: 
• Be a female of childbearing potential who is currently pregnant, nursing, or 
planning a pregnancy; tests positive to a pregnancy test; or refuses to use an 
adequate method of contraception for the duration of the study; 
• Have an active ocular infection (bacterial, viral, or fungal), active ocular 
inflammation (e.g. moderate to severe blepharitis, allergic conjunctivitis, 
peripheral ulcerative keratitis, scleritis, uveitis) in either eye. 
• Subjects may also be withdrawn from the study for the following reasons: 
• Adverse event (AE) 
• Lost to follow-up 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 28 of 70

• Withdrawal of consent by subject 
• Investigator’s discretion 
• Death 
• Subject not adequately following required study procedures 
• Study terminated by the Sponsor 
• Other 
Subject withdrawals will be documented on the subject’s source document. 
7.0 STUDY PARAMETERS 
7.1 
Efficacy Endpoints  
Primary Efficacy Endpoint: 
• Percentage of subjects who achieve a 3-line (15-letter) or greater improvement 
from baseline in the measurement of monocular BCDVA at 40 cm and no loss in 
BCDVA ≥ 5 letters (ETDRS chart at 4 m)
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 29 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 30 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 31 of 70

Criteria for Efficacy 
Changes in BCDVA at 40 cm distance will be calculated as the difference, in logMAR 
units, between the post-treatment monocular (study eye) minus the pre-treatment baseline 
monocular (study eye) at Visit 2. A 3-line improvement or greater in BCDVA at 40 cm is 
considered clinically meaningful. 
7.2 
Safety Endpoints 
• Adverse events (AE) (reported, elicited, and observed) 
• Pregnancy test 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 32 of 70

• Monocular and binocular BCDVA (normal and low-luminance) 
• Slit lamp biomicroscopy 
• IOP 
• Dilated fundus exam 
 
• Conjunctival redness 
8.0 STUDY MATERIALS 
8.1 
Study Treatments 
8.1.1 
Investigational Product 
The study treatments are as follows: 
• LNZ101
 ophthalmic solution 
• LNZ100 
 ophthalmic solution 
• Vehicle ophthalmic solution 
The two active ingredients 
have been formulated and will 
be provided in a sterile container. 
Vehicle ophthalmic solution will be provided in a sterile container. 
8.1.2 
Instructions for Use and Administration 
In order to maintain masking to the study drug administrator and study subject, the 
LNZ101, LNZ100, and vehicle treatments will be prepared in sterile containers having an 
identical appearance. The sterile containers will be identical in size and color and have 
identical clinical labels (except for the subject number and Visit number). 
 
  
 
A new clinical kit will be assigned to each subject 
. 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 33 of 70

9.0 STUDY METHODS AND PROCEDURES 
9.1 
Subject Entry Procedures 
9.1.1 
Overview 
Subjects as defined by the criteria in Section 6.1 and Section 6.2 will be considered for 
entry into this study. 
9.1.2 
Informed Consent 
Prior to a subject’s participation in the trial (e.g. changes in a subject’s medical treatment 
and/or study related procedures), the study will be discussed with each subject, and 
subjects wishing to participate must give written informed consent (and/or assent) using 
an informed consent form (ICF). The ICF must be the most recent version that has 
received approval/favorable review by a properly constituted IRB. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 34 of 70

9.2 
Concurrent Therapies and Medical History 
The use of any concurrent medication, prescription, or over-the counter taken within 30 
days of Visit 1, is to be recorded on the subject’s source document and corresponding 
electronic case report form (eCRF) along with the reason the medication was taken. 
All significant current and prior ocular medical and surgical history is to be recorded on 
the subject’s source document and corresponding eCRF. All current and prior significant 
general medical and surgical history is to be recorded on the subject’s source document 
and corresponding eCRF. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
9.2.1 
Prohibited Medications/Treatments 
 
 Soft contact lenses must be removed at least 7 days prior to study Visit 1 
and during the study, and rigid gas permeable (RGP) contact lenses must be removed at 
least 14 days prior to study Visit 1 and during the study. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 35 of 70

9.2.2 
Escape Medications 
Not applicable. 
9.2.3 
Special Diet or Activities 
Not applicable. 
9.3 
Examination Procedures 
9.3.1 
Procedures to be Performed at the Study Visit with Regard to Study 
Objective 
The following procedures should be conducted at each study visit in the following order. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 36 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 37 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 38 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 39 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 40 of 70

9.4 
Schedule Of Visits, Measurements and Dosing 
9.4.1 
Scheduled Visit 
Refer to Appendix 1: Schedule of Visits and Measurements for a schedule of 
measurements at each visit. 
9.4.2 
Unscheduled Visits 
In the case of an AE, an Unscheduled Visit may be performed by the Investigator. 
The Investigator may perform additional assessments, if needed. All additional 
assessments will be documented in the subject’s source document. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 41 of 70

9.4.3 
Early Termination 
Participants who prematurely discontinue from the study after administration of the study 
drug will be encouraged to complete an early termination (ET) visit. 
9.5 
Compliance with Protocol 
This study will be conducted in compliance with the protocol, the ethical principles that 
have their origin in the Declaration of Helsinki, the International Conference on 
Harmonization (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) 
(CPMP/ICH/135/95), and applicable regulatory requirement(s), such as Food and Drug 
Administration (FDA) GCP Regulations and Code of Federal Regulations (CFR) Title 
21, parts 11, 50, 54, 56 and 312, as appropriate. 
9.6 
Subject Disposition 
9.6.1 
Screened Subjects 
Subject who has completed the Informed Consent process and if eligible to proceed with 
additional assessments to ensure candidacy at Visit 1 (Screening Visit). 
9.6.2 
Screen failed Subjects 
Screened subject who does not meet the inclusion/exclusion criteria at any time prior to 
randomization at Visit 2. 
9.6.3 
Randomized Subjects 
Subject who has signed the ICF, been issued a unique 6-digit subject number and has 
been randomized to receive investigational product at Visit 2. Once randomized, the 
subject is enrolled in the study. 
9.6.4 
Discontinued Subjects 
Randomized subject who discontinues participation in the trial prior to the last study 
procedure 
 
Prior to discontinuing a subject, every effort should be made to obtain as much follow-up 
data as possible, and to retrieve all study materials. Adverse events (AEs) will be 
followed as described in Section 10. 
9.6.5 
Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
9.6.6 
Withdrawn Subjects 
A subject may be withdrawn for meeting any of the withdrawal criteria as described in 
Section 6.3. 
Prior to discontinuing a subject, every effort should be made to obtain as much follow-up 
data as possible, and to retrieve all study materials. Adverse events (AEs) will be 
followed as described in Section 10.0. 
9.7 
Study Termination 
The study may be terminated at any time by the investigator, the sponsor, and/or Ora with 
appropriate notification. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 42 of 70

9.8 
Study Duration 
This study is
 a total duration of approximately 9 weeks. 
9.9 
Monitoring and Quality Assurance 
During the course of the study an Ora monitor, or designee, will make routine site visits 
to review protocol compliance, assess IP accountability, and ensure the study is being 
conducted according to the pertinent regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject 
confidentiality. Further details of the study monitoring will be outlined in a monitoring 
plan. 
Regulatory authorities of domestic and foreign agencies, and Ora, Inc. quality assurance 
and/or its designees, and the study sponsor may carry out on-site inspections and/or 
audits that may include source data checks. Therefore, direct access to the original source 
data will be required for inspections and/or audits. All inspections and audits will be 
carried out giving consideration to data protection as well as subject confidentiality to the 
extent that local, state, and federal laws apply. 
10.0 ADVERSE EVENTS 
10.1 
Adverse Event 
Adverse events will be monitored throughout the study. At each visit, the Investigator, or 
designee, will query for adverse events by asking subjects general, non-directed questions 
such as: 
“How have you been feeling since the last visit?” 
 
 
“Have there been any changes in how you are feeling since you came in today”? 
 
 
Directed questioning and examinations will be done as appropriate. 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered IP-related. An AE can be any unfavorable and 
unintended sign (e.g. an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an IP, without any judgment about causality. An AE can arise 
from any use of the IP (e.g. off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including an 
overdose. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination, or other 
diagnostic procedures will be recorded in the subject’s source document and eCRF. Any 
clinically relevant deterioration in clinical finding is considered an AE and must be 
recorded. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 43 of 70

Documentation regarding the AE should be made as to the nature, date of onset, end date, 
severity, relationship to IP, expectedness, action(s) taken, seriousness, and outcome of 
any sign or symptom observed by the physician or reported by the patient upon indirect 
questioning. 
All AEs will be collected from the time a subject signs the ICF through the subject’s 
study exit visit. 
10.1.1 
Severity 
The severity of an AE is defined as a qualitative assessment of the degree of intensity of 
an AE as determined by the investigator or reported to him/her by the patient/subject. The 
assessment of severity is made irrespective of relationship to IP or seriousness of the 
event and should be evaluated according to the following scale: 
• Mild: Event is noticeable to the subject, but is easily tolerated and does not 
interfere with the subject’s daily activities. 
• Moderate: Event is bothersome, possibly requiring additional therapy, and may 
interfere with the subject’s daily activities. 
• Severe: Event is intolerable, necessitates additional therapy or alteration of 
therapy, and interferes with the subject’s daily activities. 
10.1.2 
Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the investigator using 
these explanations: 
• Suspected: A reasonable possibility exists that the IP caused the AE. 
• Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
“Suspected adverse reaction” means any AE for which there is a reasonable possibility 
that the IP caused the AE. “Reasonable possibility” means there is evidence to suggest a 
causal relationship between the IP and the AE. Types of evidence that would suggest a 
causal relationship between the IP and the AE include: a single occurrence of an event 
that is uncommon and known to be strongly associated with IP exposure (e.g. 
angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of an 
event that is not commonly associated with IP exposure, but is otherwise uncommon in 
the population exposed to the IP (e.g. tendon rupture); an aggregate analysis of specific 
events observed in a clinical trial (such as known consequences of the underlying disease 
or condition under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur more 
frequently in the IP-treatment group than in a concurrent or historical control group. 
10.1.3 
Expectedness 
The expectedness of an AE should be determined based upon existing safety information 
about the IP using these explanations: 
• Unexpected: an AE that is not listed in the Investigator’s Brochure (IB) or is 
not listed at the specificity or severity that has been observed. 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 44 of 70

• Expected: an AE that is listed in the IB at the specificity and severity that has 
been observed. 
• Not applicable: an AE unrelated to the IP. 
AEs that are mentioned in the IB as occurring with a class of products or as anticipated 
from the pharmacological (or other) properties of the product but are not specifically 
mentioned as occurring with the particular product under investigation are to be 
considered unexpected. 
The investigator should initially classify the expectedness of an AE. The medical monitor 
will review and determine the expectedness of any serious adverse event (SAE) following 
the investigator’s assessment. The final classification of an AE is subject to the sponsor’s 
determination. 
10.2 
Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator or sponsor, it results 
in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
Note: An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an AE that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even 
if < 24 hours). For chronic or long-term inpatients, inpatient admission includes 
transfer within the hospital to an acute/intensive care inpatient unit. Inpatient 
hospitalization does not include: emergency room visits; outpatient/same- 
day/ambulatory procedures; observation/short stay units; rehabilitation facilities; 
hospice facilities; nursing homes; or clinical research/Phase 1 units. 
Note: The term “prolongation of existing hospitalization” refers to any extension 
of an inpatient hospitalization beyond the stay anticipated or required for the 
reason for the initial admission as determined by the investigator or treating 
physician. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
Note: An SAE specifically related to visual threat would be interpreted as any 
potential impairment or damage to the subject’s eyes (e.g. intra-ocular 
hemorrhage, retinal detachment, central corneal ulcer, or damage to the optic 
nerve). 
• A congenital anomaly/birth defect. 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 45 of 70

Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
10.3 
Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to Ora, the study sponsor, and the IRB as 
required by the IRB, federal, state, or local regulations and governing health authorities 
and recorded on the appropriate subject source document and eCRF. 
10.3.1 
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the study 
sponsor, and the IRB as required by the IRB, federal, state, or local regulations and 
governing health authorities. 
10.3.2 
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the IP, must be 
immediately reported by the investigator to Ora and the sponsor within 24 hours of 
becoming aware of the event. All information relevant to the SAE must be recorded on 
the appropriate source document, SAE Report Form, and eCRF. The investigator is 
obligated to pursue and obtain information requested by Ora and/or the sponsor in 
addition to the information reported on the source document, SAE Report Form, and 
eCRF. All subjects experiencing a SAE must be followed-up with and the outcome 
reported. 
In the event of a SAE, the investigator must notify Ora and the sponsor immediately; 
obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of the 
subject; provide Ora and the study sponsor with a complete case history, which includes a 
statement as to whether the event was or was not suspected to be related to the use of the 
IP; and inform the IRB of the AE within their guidelines for reporting SAEs. 
10.4 
Procedures for Unmasking (if applicable) 
When medically necessary, the investigator may need to determine what treatment 
has been assigned to a subject. When possible (i.e. in non-emergent situations), Ora 
and/or the study sponsor should be notified before unmasking the IP. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 46 of 70

10.5 
Type and Duration of the Follow-up of Subjects after Adverse Events 
The investigator will follow unresolved AEs to resolution, until the subject is lost to 
follow-up or until the AE is otherwise explained. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the investigator 
should make 3 reasonable attempts to contact the subject via telephone, post, or certified 
mail. All follow-up will be documented in the subject’s source document. Non-serious 
AEs identified on the last scheduled contact must be recorded on the source document 
with the status noted. 
If the investigator becomes aware of any new information regarding a SAE (i.e. 
resolution, change in condition, or new treatment), a new SAE Report Form must be 
completed and faxed/emailed to Ora and/or the study sponsor within 24 hours. The 
original SAE Report Form is not to be altered. The SAE Report Form should describe 
whether the event has resolved or continues and how the event was treated. 
11.0 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
11.1 
General Considerations 
In general, quantitative/continuous data will be summarized using descriptive statistics 
(number of subjects [n], mean, standard deviation [SD], median, minimum, and 
maximum). Qualitative/categorical data will be summarized using frequencies and 
percentages. Statistical testing, unless otherwise indicated, will be performed at a 2-sided 
0.05 significance level. 
For all variables, baseline is defined as the last measurement taken prior to the 
administration of first dose of study drug at Visit 2. Change from baseline will be 
calculated as follow-up measure minus baseline measure. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 47 of 70

11.3 
Analysis Sets 
Full Analysis Set (FAS) – The FAS will include all randomized subjects. No subjects will 
be excluded from the FAS due to protocol violations/deviations. Subjects in the FAS will 
be analyzed as randomized. 
Per Protocol (PP) Set – The PP set will include subjects in the FAS who do not have 
significant protocol deviations that affect the primary endpoint analysis. Protocol 
deviations will be assessed prior to database lock and unmasking. Subjects in the PP set 
will be analyzed as treated. 
Safety Set – The Safety set will include all subjects who have received at least one dose of 
the study drug. Subjects in the Safety set will be analyzed as treated. 
11.4 
Unit of Analysis 
The study eye will be used for all monocular efficacy analyses. The qualified fellow eye 
will be used in additional binocular analyses as specified. Both eyes will be displayed and 
analyzed for all ophthalmic safety variables. 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 48 of 70

11.5 
Efficacy Endpoints 
11.5.1 
Primary Efficacy Endpoint: 
• Percentage of subjects who achieve a 3-line (15-letter) or greater improvement 
from baseline in the measurement of monocular BCDVA at 40 cm and no loss in 
BCDVA ≥ 5 letters (ETDRS chart at 4 m)
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 49 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 50 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 51 of 70

11.6 
Safety Endpoints 
The safety endpoints are: 
• Adverse events (AE) (reported, elicited, and observed) 
• Pregnancy test 
 
• Monocular and binocular BCDVA (normal and low-luminance) 
• Slit lamp biomicroscopy 
• IOP 
• Dilated fundus exam 
 
• Conjunctival redness 
11.7 
Sample Size 
A sample size of 222 subjects (74 per arm) yields >99% power to establish superiority of 
LNZ101/LNZ100 to vehicle in the proportion of study eyes demonstrating a ≥ 3-line (15- 
letter) improvement or greater from baseline in BCDVA at 40 cm and no loss in BDVA ≥ 
1 line (5 letters) at 4 m
 
 
11.8 
Demographic and Baseline Characteristics 
Subject demographics including age, gender, race, ethnicity, and iris color will be 
presented using continuous/categorical summary statistics as appropriate. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 52 of 70

11.9 
Efficacy Analysis 
11.9.1 
Primary Efficacy Analyses 
The primary efficacy endpoint in this study is the percentage of study eyes with a ≥ 3-line 
(15-letter) improvement in BCDVA at 40 cm from baseline and no loss in best distance 
corrected visual acuity ≥ 1 line (5-letter) at 4 m 
 
 
 
Descriptive statistics will be presented by treatment group. Testing of the primary 
endpoint will be completed using logistic regression with treatment as the fixed effect and 
baseline BCDVA at 40 cm as a covariate. The adjusted odds ratios and marginal 
proportions and differences in proportions along with corresponding two-sided 95% 
confidence intervals (CIs) and p-values will be presented. 
Treatment comparisons will also be made using Pearson’s chi-squared test or Fisher’s 
exact test if any of the expected cell counts are less than five as a sensitivity analysis to 
the primary model above. 
Analyses will be repeated using the FAS with missing data imputed as failures and FAS 
and PP sets with observed data. Tipping point analysis may be performed. 
11.10 Safety Analysis 
All safety data will be analyzed using the Safety set. Safety of LNZ101/LNZ100 will be 
assessed by the review of all safety parameters. 
 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 53 of 70

Verbatim descriptions of AEs will be mapped to Medical Dictionary for Regulatory 
Activities (MedDRA) terms and be presented in a data listing. Treatment emergent Aes 
(TEAEs), those that occur after the first dose of study drug, will be summarized by 
treatment group using frequency and percent for each system organ class (SOC) and 
preferred term (PT) within each SOC. Similar summaries will also be presented for 
expected and unexpected TEAEs, treatment emergent SAEs, TEAEs related to the study 
drug, and TEAEs by severity. When reporting the incidence of Aes, a subject will only be 
counted once if they ever experience an event within the SOC and ever experience the 
individual PT within each treatment group. . Ocular and non-ocular events will be 
summarized separately. 
Actual results and changes from baseline results in monocular and binocular BCDVA 
(normal and low-luminance), slit lamp biomicroscopy, IOP, dilated fundus examination, 
and conjunctival redness, will be summarized descriptively at each visit by treatment 
group. 
Full details of the safety analyses will be specified in the formal SAP. 
11.11 Interim Analysis 
No interim analysis is planned for this study. 
11.12 Missing Data 
The primary analysis will use the Full Analysis Set (FAS) with intercurrent events 
11.13 Adjustment for Multiplicity 
There is no adjustment necessary for the primary endpoint because only one time point is 
being considered for the primary analysis. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 54 of 70

12.0 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current GCPs, including 
the ICH Guidelines, and will, in general, be consistent with the Declaration of Helsinki. 
In addition, all applicable local, state, and federal requirements relevant to the use of Ips 
in the countries involved will be adhered to. 
12.1 
Protection of Human Subjects 
12.1.1 
Subject Informed Consent 
Informed consent must take place before any study-specific procedures are initiated. 
Signed and dated written informed consent must be obtained from each subject and/or 
from the subject’s parent or legal guardian prior to enrollment into the study. 
All ICFs must be approved for use by the sponsor and receive approval/favorable opinion 
from an IRB prior to their use. If the ICF requires revision (e.g. due to a protocol 
amendment or significant new safety information), it is the investigator’s responsibility to 
ensure that the amended informed consent is reviewed and approved by Ora prior to 
submission to the governing IRB and that it is read, signed, and dated by all subjects 
subsequently enrolled in the study as well as those currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed consent), then the 
procedures to be followed must be determined by Ora and/or the sponsor and provided in 
writing by Ora and/or the sponsor prior to the consent process. 
12.1.2 
IRB Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 CFR Part 
56.103). The investigator must obtain appropriate IRB approval before initiating the study 
and re-approval at least annually. 
Only an IRB-approved version of the ICF will be used. 
12.2 
Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated with 
the Declaration of Helsinki. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 55 of 70

12.3 
Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions as to 
ensure that the confidentiality of the data is in accordance with local, state, and federal 
laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the IRB 
approving this study, the FDA, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted 
direct access to the study subject’s original medical and study records for verification of 
the data and/or clinical trial procedures. Access to this information will be permitted to 
the aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the IP may ultimately be marketed in, but the 
subject’s identity will not be disclosed in these documents. 
12.4 
Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic charts, 
the investigator’s subject files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms. The investigator’s copy of the eCRFs serves as 
the investigator’s record of a subject’s study-related data. 
12.4.1 
Retention of Documentation 
All study-related correspondence, patient records, consent forms, records of the 
distribution and use of all Ips, and copies of case report forms should be maintained on 
file for at least 2 years after the last approval of a marketing application in an ICH region 
and until there are no pending or contemplated marketing applications in an ICH region; 
or until at least two years have elapsed since the formal discontinuation of clinical 
development of the IP. These documents will be retained for a longer period if required 
by the applicable regulatory requirements or by an agreement with the sponsor. It is the 
responsibility of the sponsor to inform the investigator/institution as to when these 
documents no longer need to be retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping study records, custody must be transferred to a person who will 
accept the responsibility. The sponsor must be notified in writing of the name and address 
of the new custodian. 
12.5 
Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product 
12.5.1 
Labeling/Packaging 
Investigational drug will be packaged and labeled into clinical kits, following the 
randomization list generated prior to the start of the study. Each clinical kit will be 
uniquely identified by a 5-digit kit number. 
 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 56 of 70

The primary packaging of the LNZ101, LNZ100, and Vehicle Ophthalmic Solution will 
be blow-fill-seal ampoules.
 
 
 
Clinical label texts for the primary packaging and secondary packaging (clinical kits) 
meet applicable regulatory requirements and include the statement “Caution: New Drug- 
Limited by Federal Law to Investigational Use. 
12.5.2 
Storage of Investigational Product 
Investigational drug must be stored in a secure area of the investigative site, accessible 
only to Investigator or designees
 The investigational product will 
be administered only to subjects entered into the clinical study, in accordance with the 
conditions specified in this protocol. All investigational drugs will be returned to 
inventory after use. 
12.5.3 
Accountability of Investigational Product 
The investigational product is to only be administered by a trained study technician 
delegated by the principal Investigator,) and is to only be used in accordance with this 
protocol. The investigational product must only be distributed to subjects properly 
qualified under this protocol to receive investigational product. 
The Investigator must keep an accurate accounting of the investigational product received 
from the supplier. This includes the amount of investigational product administered to 
subjects and the amount returned or disposed upon the completion of the study. A 
detailed inventory must be completed for the investigational product. 
12.5.4 
Return or Disposal of Investigational Product 
All IPs will be returned to the sponsor or their designee or destroyed. The return or 
disposal of IP will be specified in writing. Any remaining IP will be collected from 
subjects before study exit. 
12.6 
Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) 
The investigator is responsible for ensuring that study data is completely and accurately 
recorded on each subject’s source document, eCRF, and all study-related material. All 
study data should also be attributable, legible, contemporaneous, and original. Recorded 
datum should only be corrected in a manner that does not obliterate, destroy, or render 
illegible the previous entry (e.g. by drawing a single line through the incorrect entry and 
writing the revision next to the corrected data). An individual who has corrected a data 
entry should make clear who made the correction and when by adding to the correction 
his/her initials as well as the date of the correction. 
12.7 
Handling of Biological Specimens 
Not applicable. 
 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 57 of 70

12.8 
Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript. Ora 
and the study sponsor will have the final decision regarding the manuscript and 
publication. 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 58 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 59 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 60 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 61 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 62 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 63 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 64 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 65 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 66 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 67 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609
Proprietary & Confidential
Page 68 of 70

LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023)
LNZ101/LNZ100 Ophthalmic Solution 
IND # 120609
Proprietary & Confidential 
Page 69 of 70

Proprietary & Confidential 
Page 70 of 70 
LENZ Therapeutics, Inc. 
Protocol 22-150-0018 ver 5.0 (31 Jul 2023 )
LNZ101/LNZ100 Ophthalmic Solution
IND # 120609