Conditions: Ocular Hypertension Primary Open Angle Glaucoma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 194
Healthy volunteers: no

Brief summary:
This is a phase 2, double masked, randomized, multi-center, parallel-group, 28-day study assessing the safety, tolerability and ocular hypotensive efficacy of AKB-9778 Ophthalmic Solution 4.0% administered once (AM) or twice (AM \& PM) daily when used as an adjunctive therapy to latanoprost ophthalmic solution 0.005% once daily (PM) in subjects with elevated IOP due to OAG or OHT.

Detailed description:

Arms:
arm 1: • AKB-9778 4% daily (AM) and placebo for ophthalmic solution daily (PM) plus latanoprost daily (PM) for 28 days arm 2: • AKB-9778 4% twice daily (AM \& PM) plus latanoprost daily (PM) for 28 days arm 3: • Placebo for AKB-9778 4% ophthalmic solution twice daily (AM \& PM) plus latanoprost daily (PM) for 28 days

Interventions: intervention 1: Latanoprost ophthalmic solution intervention 2: AKB-9778 4% intervention 3: Placebo
Intervention descriptions: intervention 1: Latanoprost opthalmic solution to be dosed once daily intervention 2: Razuprotafib opthalmic solution intervention 3: placebo for razuprotafib opthalmic solution

Protocol document:
Prot_SAP_000.pdf: 
Study # AKB-9778-CI-OS-2001 – Final Clinical Study Report 
Final, Version 1.0, 18-Feb-2021 
 
Page 16-1 
16.0 APPENDICES 
16.1 
Study Information 
16.1.1 
Protocol and Protocol Amendments 
The original protocol (Version 0, dated 25-Feb-2020) was amended twice. Amendment 
#1 (Version 1.0, dated 28-Apr-2020) and Amendment #2 of the protocol (Version 2.0, 
dated 17-May-2020) were implemented before any subjects were screened for the study. 
The latest protocol (Amendment 2, Version 2.0, dated 17-May-2020) is provided in this 
Appendix.  
A summary of the changes in Amendment #1 and #2 follows: 
Amendment 
Summary of Changes 
Amendment #1 
version 1.0  
28-April-2020 
• The following modifications are made to the protocol. The synopsis and 
study schedule of events are updated to align with the changes described 
below. Additionally, minor text changes and clarifications are made 
throughout the document. 
• The changes are made to optimize the protocol design.  The changes are not 
considered to impact the safety of subjects in the study or the scientific 
integrity of the study. 
• Section 5.3 Efficacy Endpoints 
• Primary and secondary efficacy endpoints are clarified. 
• Mean diurnal IOP on Days 14 and 28 in both eyes is added as a 
secondary endpoint. 
• Section 5.4 Safety Measures 
• Safety measures are clarified. 
• Gonioscopy, visual field and cup disc ratio measurements are removed 
from safety endpoints.  
• Section 6.1 Overall Study Design and Plan 
• Timing of visits is clarified 
• Study design is modified to require that subjects must be on stable dose 
of topical prostaglandin eyedrops for at least 2 weeks prior to screening 
(Visit 1). 
• A minimum four-week washout is now required following completion of 
Visit 1. 
• Clarification is added that stratification will occur based on IOP mean 
diurnal IOP in the study eye. 
• An interim analysis for futility when 50% of subjects have completed 28 
days of treatment is now added 
• Blood sampling for exploratory genetic analyses is removed 
• Section 7.2 Subject Eligibility and Study Eye Determination 
• This section is added to provide clarity on selection of study eye. 
• Section 7.3 Inclusion Criteria 
• Inclusion criterion is added to state that subjects must be on stable 
regimen of topical prostaglandins for a minimum of 2 weeks prior to the 
Screening Visit 
• Screening visit IOP criterion is modified to require IOP of ≥18 mmHg 
and ≤27 mm Hg in one eye (study eye) or both eyes at screening. 


Study # AKB-9778-CI-OS-2001 – Final Clinical Study Report 
Final, Version 1.0, 18-Feb-2021 
 
Page 16-2 
• Ability to properly self-administer eye drops (or have a caregiver that 
can suitably administer eye drops) is added as an inclusion criterion. 
• Section 7.4 Exclusion Criteria 
• Additional examples of clinically significant ocular disease that should 
be excluded are added to Exclusion Criterion #1. 
• Evidence of peripheral anterior synechiae ≥ 180 degrees by gonioscopy 
within 6 months prior to Screening is added to exclusion criterion # 3.  
• Exclusion Criterion #4 is clarified to state that IOP ≥ 36 mmHg at 
Screening, Qualification Visit #1 or at any assessment on Qualification 
Visit # 2 is exclusionary.  
• Exclusion Criterion #7 is modified to state that known hypersensitivity to 
any topical prostaglandin eyedrop is exclusionary.   
• Exclusion Criterion # 8 is modified to state that that SLT within the past 
6 months is exclusionary and additional minimally invasive glaucoma 
surgery is added as exclusionary.  
• Exclusion Criterion # 9 is modified to add that limbal relaxing incision in 
either eye within 12 months prior to screening is exclusionary. 
• Exclusion Criterion # 10 is added to state any intravitreal injection within 
30 days prior to screening or anticipated intravitreal injection during the 
course of the study is exclusionary.  
• Exclusion Criterion # 13 is modified to state that bulbar conjunctival 
hyperemia scores of ≥ 3 on the hyperemia scale is exclusionary at any 
visit during Screening, Qual # 1 and Qual #2 visits. 
• Exclusion Criterion #15 is modified to clarify prohibited ocular 
medications. 
• Exclusion Criterion #16 is modified to state that corneal thickness of less 
than 480um in either eye is exclusionary. 
• Exclusion Criterion # 19 is modified to state that tubal ligation is not 
considered surgical sterilization. 
• Section 8.2 Dispensing Procedures 
• Text describing kit dispensation is simplified and clarified. 
• Section 8.6 Study Medication and Latanoprost Administration. 
• Eye drop instillation technique assessment is removed from Screen Visit 
#1 and a statement is added that on the days of study visits, subjects 
should not wear contacts until the visit is completed. 
• Section 8.7 Concomitant Mediations 
• Text is clarified to state preservative artificial tears are allowed, 
latanoprost is provided by the Sponsor, and Rho kinase inhibitors are 
added as prohibited medications. 
• Section 8.8.1 Prior Therapy and Washout 
• Text is modified to state that eligible subjects must be on a stable dose of 
topical prostaglandin eye drops (for at least 2 weeks) prior to Screening 
and that after completion of the screening visits subjects must undergo a 
minimum 4 week washout period. 
• Section 9.2.2 Ophthalmic Assessments 
• Assessments are now listed in suggested order of conduct, the 
conjunctival grading scale is updated to the Efron scale and hyperemia 
AE reporting guidance is updated to state an increase of 2 or more grades 
on the hyperemia scale when compared to the lowest score recorded at 
any previous time point should be recorded as an AE in addition to if a 


Study # AKB-9778-CI-OS-2001 – Final Clinical Study Report 
Final, Version 1.0, 18-Feb-2021 
 
Page 16-3 
subject complains of an AE regardless of grade on the hyperemia scale. 
• Section 9.2.3 Laboratory Evaluations. 
• Pregnancy guidance is clarified and blood sampling for genetic analysis 
is removed. 
• Section 10. 0 Schedule of Activities 
• This section is modified to provide clarification on timing and conduct of 
assessments. 
• Section 10.1 Visit Windows and Study Days 
• This section is modified to provide clarity that IOP and hyperemia 
assessments at 8:00, 10:00, 12:00 and 16:00 hours must be conducted at 
a minimum of the protocol prescribed 2- or 4- hour interval. 
• A section is added to state that study days will be numbered relative to 
the first day of dosing and to define the start of study. 
• Section 10.2 Visit 1 (Screening Visit) 
• This section is updated to remove the eye drop instillation technique 
evaluation, update the order of assessments to reflect conduct of 
assessments, IOP eligibility criteria at this visit is clarified and the 
washout period is updated from optional to required. 
• (Former) Section 10.2.1 Evaluation of Eye Drop Instillation Performance 
• This section is removed; a formal assessment of eye drop instillation 
technique is deemed not necessary as eligible subjects will have prior 
experience with dosing topical eye drops via the requirement to have a 
history of stable treatment with prostaglandin eyedrops.  Per Investigator 
discretion, an instillation assessment can be conducted but is no longer 
required per protocol.  
• Section 10.2.2 Visit 2  
• Text describing the optional washout period is removed as the washout is 
now required. Timing of the visit is corrected to state that the visit will 
occur no later than 42 days after the screening visit. 
• IOP eligibility criteria at this visit is clarified 
• Sections 10.2.3 -10.2.15 
• These sections are updated to include statements that that IOP and 
hyperemia assessments at 8:00, 10:00, 12:00 and 16:00 hours must be 
conducted at a minimum of the protocol prescribed 2- or 4- hour interval. 
• Study medication dispensing instructions are clarified. 
• Section 11.1.1 Adverse Events 
• Guidance for reporting hyperemia is updated to align with changes to 
Section 9.2.2 Ophthalmic Assessments. 
• Guidance for reporting abnormal labs as adverse events (AEs) is 
removed as no clinical laboratory assessments are conducted in this 
study. 
• Section 12.5.2. Interim Analysis 
• This section is updated to describe the planned interim analysis for 
futility. 
• Section 12.5.5 Analysis of Efficacy 
• Primary and secondary efficacy endpoints are clarified. 
• Mean diurnal IOP on Days 14 and 28 in both eyes is added as a 
secondary endpoint. 
• Section 12.6 Procedure for Accounting for Missing, Unused or Spurious 
data. 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
 
 
Aerpio — Company Confidential 
Page 1 of 89 
 
 
 
 
AKB-9778-CI-OS-2001 
Phase 2 Multi-Center, Double-Masked, Randomized, 28-Day Study to Assess the Efficacy, 
Safety and Tolerability of Single or Twice Daily Doses of AKB-9778 Ophthalmic Solution as an 
Adjunct to Latanoprost in Patients with Ocular Hypertension (OHT) or Open Angle Glaucoma 
(OAG) 
Original Protocol (Version 0) February 25, 2020 
Amendment #1 (Version 1.0) April 28, 2020 
Amendment #2 (Version 2.0) May 17, 2020 
 
 
 
• 
aer1210 
pharmaceuticals 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
 
 
Aerpio — Company Confidential 
Page 2 of 89 
1.0 
STUDY CONTACTS 
 
For study related and administrative questions, please contact: 
Barbara Withers, PhD 
Vice President, Clinical Operations 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 256-3592 
Email:  bwithers@aerpio.com 
 
For study medication and latanoprost related questions, please contact: 
Christopher Ernst 
Vice President of CMC and Quality Assurance 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Office Telephone:  (513) 985-1922 
Mobile Telephone:  (513) 806-4718 
Email:  cernst@aerpio.com 
 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
 
 
Aerpio — Company Confidential 
Page 3 of 89 
For clinical and subject related issues or questions, please contact: 
 
MEDICAL MONITOR 
Kevin Peters, MD 
Chief Scientific Officer, Chief Medical 
Officer and Senior Vice President,  
Research and Development 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Office Telephone:  (513) 985-1934 
Mobile Telephone:  (513) 544-8868 
 
 
 
 
 
Mitchell Brigell, PhD 
Vice President, Clinical Development 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 432-7790 
Email:  mbrigell@aerpio.com  
 
 
Barbara Withers, PhD 
Vice President, Clinical Operations 
Aerpio Pharmaceuticals, Inc. 
9987 Carver Road, Suite 420 
Cincinnati, OH  45242 
Mobile Telephone:  (513) 256-3592 
Email:  bwithers@aerpio.com 
 
 


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Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
 
 
Aerpio — Company Confidential 
Page 5 of 89 
1.2 
Investigator Agreement 
I confirm that I have read and that I understand this protocol, and other product information 
provided by the Sponsor. I agree to conduct this study in accordance with the requirements of 
this protocol and also protect the rights, safety, privacy, and well-being of study subjects in 
accordance with the following: 
• The ethical principles that have their origin in the Declaration of Helsinki. 
• International Council for Harmonisation Guidance for Industry, Good Clinical Practice 
E6R(2). 
• All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations. 
• Regulatory requirements for reporting serious adverse events defined in this protocol. 
• Terms outlined in the Clinical Trial Agreement. 
 
Signature of Investigator 
Date 
Investigator Name (print or type) 
Investigator’s Title 
Name of Facility 
Location of Facility (City, State) 
 
 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
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Page 6 of 89 
 
2.0 
SYNOPSIS 
Sponsor:  
Aerpio Pharmaceuticals, Inc. 
Investigational Product: AKB-9778 Ophthalmic Solution 
Protocol Number: AKB-9778-CI-OS-2001 
Study Title: 
Phase 2 Multi-Center, Double-Masked, Randomized, 28-Day Study to Assess the Efficacy, Safety and Tolerability of 
Single or Twice Daily Doses of AKB-9778 Ophthalmic Solution as an Adjunct to Latanoprost in Patients with Ocular 
Hypertension (OHT) or Open Angle Glaucoma (OAG) 
Phase of Development: 2 
Objectives: 
Primary: 
• 
To evaluate the ocular hypotensive effects of AKB-9778 Ophthalmic Solution 4.0% administered once or twice 
daily for 28 days when used as an adjunctive therapy to latanoprost ophthalmic solution 0.005% in subjects with 
OAG or OHT 
 
Secondary: 
• 
To evaluate the safety and tolerability of AKB-9778 Ophthalmic Solution 4.0% administered once or twice daily 
for 28 days when used as an adjunctive therapy to latanoprost ophthalmic solution 0.005% in subjects with OAG 
or OHT 
Endpoints: 
All efficacy analyses will be conducted in study eye and both eyes (average of study eye and eligible fellow eye) 
 
Primary Efficacy Endpoint: 
• 
Mean change from baseline in diurnal intraocular pressure (IOP) on Day 28 (study eye) 
 
Secondary Efficacy Measures: 
• 
Mean change from baseline in diurnal IOP on Day 14 (study eye) 
• 
Mean change from baseline in diurnal IOP on Days 14 and 28 (both eyes) 
• 
Mean diurnal IOP on Days 14 and 28 (both eyes) 
• 
Mean observed IOP at each time point on Days 14 and 28 
• 
Mean change from diurnally adjusted baseline IOP at each time point on Days 14 and 28 
• 
Mean percent change from diurnally adjusted baseline IOP at each time point on Days 14 and 28 
• 
Mean percent change from baseline in diurnal IOP on Days 14 and 28 
• 
Percentages of subjects achieving pre-specified mean, mean change, and percent mean change in diurnal IOP 
levels 
 
Safety Measures:  
• 
AEs  
• 
Hyperemia assessments (study eye and worse eye) 
• 
Pachymetry 
• 
Visual acuity 
• 
Biomicroscopic examinations (i.e., lids, conjunctiva, cornea, anterior chamber, iris and lens) 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
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• 
Dilated ophthalmoscopy 
Study Design: 
This is a phase 2, double masked, randomized, multi-center, parallel-group, 28-day study assessing the safety, 
tolerability and ocular hypotensive efficacy of AKB-9778 Ophthalmic Solution 4.0% administered once (AM) or twice 
(AM & PM) daily when used as an adjunctive therapy to latanoprost ophthalmic solution 0.005% once daily (PM) in 
subjects with elevated IOP due to OAG or OHT.  Eligible subjects are required to have a diagnosis of either OAG or 
OHT in each eye and are on stable dose of topical prostaglandin eye drops (for at least 2 weeks prior to screening). 
Subjects eligible to be enrolled in this study must meet all inclusion criteria and none of the exclusion criteria. Subjects 
who agree to participate in this study and are randomized in the study will attend a total of 6 study visits: a Screening 
Visit, Qualification Visit #1, Qualification Visit #2/Day -1 (Baseline), and visits on Days 7, 14 and 28. After 
completion of the Screening Visit, subjects will undergo a minimum 4-week washout period from IOP lowering 
treatment prior to attending Qualification Visit #1. Subjects will receive an eye examination including IOP 
measurements at Qualification Visits #1 and #2/Day -1.  If deemed eligible, subjects will be enrolled at Qualification 
Visit #2/Day -1 and assigned to 1 of 3 treatment arms (AKB-9778 QD + Latanoprost; AKB-9778 BID + Latanoprost; 
or Latanoprost monotherapy) in a 1:1:1 ratio according to a computer-generated randomization list. Subject 
randomization will be stratified by mean diurnal IOP on Day -1 (< 26 mmHg vs ≥ 26 mmHg) in the study eye. During 
the treatment period, randomized subjects will self-administer study medication (AKB-9778 4.0% or placebo for AKB-
9778) daily in the AM and PM and will also administer 0.005% latanoprost ophthalmic solution daily in the PM. Daily 
AM dose administration of study medication should occur between 7:00 and 10:00 hours and PM dose administration 
should occur between 19:00 and 22:00 hours. Latanoprost PM dose administration will occur at least 5 minutes before 
administration of the PM dose of study medication. Subjects will begin dosing with the AM dose of study medication 
on the morning of Day 1 and conclude dosing after administration of the AM dose of study medication on Day 28 
(there is no PM dose on Day 28). At visits conducted on Days 14 and 28, subjects will self-administer the AM dose of 
study medication at the site after the 8:00 hour ophthalmic assessments have been completed. During the treatment 
period, subjects will be seen in the clinic on Days 7, 14 and 28; safety assessments will be conducted on all days and 
efficacy measurements (IOP) will be conducted on Days 14 and 28 at the following time points: 08:00, 10:00, 12:00 
and 16:00 hours. Following completion of the Day 28 study visit procedures, subjects will exit from the study. For 
subjects who discontinue early, every possible effort will be made to assure there is an exit visit that includes all 
required examinations for the Day 28 visit. 
Number of Subjects Planned: 
Approximately 195 subjects are planned to be randomized (approximately 65 per treatment group).  
Number of Sites Planned: 
Approximately 25 sites across the USA are planned.   
Duration of Treatment: 28 days 
Duration of Participation: 
The Screening, Washout, Qualification Visits and Treatment periods will require subject participation for up to 
approximately 11 weeks.  


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
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Eligibility Criteria: 
Inclusion Criteria 
Subjects must meet all of the following criteria at screening and qualification visits to enter into the study. For a subject 
to be included in the study, at least one eye (the same eye) must meet ALL ophthalmic inclusion and no exclusion 
criteria through the screening period (Screening, Qualification #1 and Qualification #2 [Day -1] visits).  
1. Males and non-pregnant, non breast-feeding females 
2. Aged ≥ 18 years  
3. Diagnosis of OAG or OHT in each eye (OAG in one eye and OHT in the fellow eye is acceptable) 
4. Must be receiving treatment with a stable regimen of topical prostaglandin eyedrop for a minimum of 2 weeks 
prior to the Screening Visit; may be taking one additional IOP lowering eyedrop (for the purposes of this inclusion 
criterion, a combination product is counted as a single eyedrop) 
5. IOP of ≥ 18 mmHg and ≤ 27 mmHg in one eye (study eye) or both eyes at the Screening Visit    
6. Unmedicated (post-washout) IOP at 2 qualification visits 2-7 days apart meeting the following criterion.  At the 
first qualification visit, if tested at or before 10:00 hour, have IOP ≥ 24 mmHg in study eye or both eyes and < 36 
mmHg in both eyes or if tested after 10:00 hour, have IOP ≥ 22 mmHg in study eye or both eyes and < 36 in both 
eyes. At the second qualification visit, IOP ≥ 24 mmHg in study eye or both eyes and < 36 mmHg in both eyes at 
08:00 hour and IOP ≥ 22 mmHg in study eye or both eyes and < 36 mmHg in both eyes at 10:00, 12:00 and 16:00 
hours.   
7. Visual Acuity (VA) of +0.5 logMAR (20/63 Snellen) or better in each eye  
8. Must be willing and able to communicate and participate for the duration of the study 
9. Ability to properly self-administer eye drops (or have a caregiver that can suitably administer eye drops) 
10. Must provide written informed consent 
Exclusion Criteria 
Subjects meeting any of the following criteria during screening or qualification evaluations will be excluded from entry 
into the study: 
Ophthalmic: 
1. Clinically significant ocular disease (e.g., corneal edema, uveitis, severe keratoconjunctivitis sicca, diabetic 
macular edema, proliferative diabetic retinopathy, or neovascular age-related macular degeneration) which might 
interfere with interpretation of the study efficacy endpoints or with safety assessments  
2. Pseudoexfoliation or pigment dispersion component glaucoma  
3. History of angle closure glaucoma, or narrow angles (i.e., Shaffer Grade 2 or less; extreme narrow angle with 
complete or partial closure), or with evidence of peripheral anterior synechiae (PAS) ≥ 180 degrees by gonioscopy 
within 6 months prior to Screening visit in either eye. Note: Previous laser peripheral iridotomy is NOT acceptable 
4. Intraocular pressure ≥ 36 mmHg in either eye at the Screening Visit, Qualification Visit #1, or at any assessment 
on Qualification Visit #2/Day-1 (individuals who are excluded for this criterion are not allowed to attempt 
requalification) 
5. Cup/disc ratio of > 0.8 in either eye 
6. Severe visual field defect in either eye as assessed by the investigator, or significant defect (sensitivity of ≤ 10dB) 
within 10 degrees of fixation in either eye  


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7. Known hypersensitivity to any component of the investigational formulations or to any topical prostaglandin 
eyedrop 
8. Selective laser trabeculoplasty (SLT) within the past 6 months or any history of argon laser trabeculoplasty (ALT) 
or minimally invasive glaucoma surgery (MIGS) in either eye 
9. Any history of radial keratotomy, corneal cross linking, photorefractive keratectomy (PRK), Laser-assisted in-situ 
keratomileusis (LASIK), or limbal relaxing incision (LRI) in either eye within 12 months prior to screening 
10. Any intravitreal injection within 30 days prior to screening or anticipated intravitreal injection during the course of 
the study 
11. Ocular trauma in either eye within the 6 months prior to screening, or ocular surgery or non-refractive laser 
treatment within the 3 months prior to screening 
12. Recent (within 90 days prior to screening) or current evidence of ocular infection or inflammation in either eye. 
Current evidence of clinically significant blepharitis, conjunctivitis, keratitis, or a history of herpes simplex or 
zoster keratitis in either eye at screening 
13. Bulbar conjunctival hyperemia ≥3 (moderate) on the hyperemia scale (Section 9.2.2) in either eye at Screening, 
Qualification Visit #1, or at any assessment on Qualification Visit #2/Day -1 
14. History of recurrent uveitis in either eye 
15. Use of ocular medication in either eye of any kind within 30 days of screening and throughout the study, with the 
exception of a) ocular hypotensive medications (which must be washed out according to the provided schedule), b) 
lid scrubs or warm compresses (which may be used prior to, but not after, screening), c) preservative or 
preservative-free lubricating drops (excluding gels or ointments) for dry eye (which may be used throughout the 
study at maximum frequency of QID), or d) non-steroid allergy drops (note: must not contain a vasoconstrictor) 
16. Mean central corneal thickness less than 480μm or greater than 600μm at screening in either eye 
17. Any abnormality preventing reliable applanation tonometry of either eye (e.g., keratoconus, corneal scarring) 
Systemic:  
18. Women who are pregnant or breast-feeding or intending to become pregnant during the study 
19. Women of child-bearing potential who are not on an acceptable method of birth control (e.g., 1 highly effective 
method [less than 1% failure rate] of contraception, or a combination of 2 effective methods of contraception). An 
adult woman is considered to be of childbearing potential unless she is one year post-menopausal or three months 
post-surgical sterilization (excluding tubal ligation). All females of childbearing potential must have a negative 
urine pregnancy test result at the Screening Visit and Qualification Visit #2. 
20. History of any clinically significant disease or disorder which, in the opinion of the Investigator, may put the 
subject at risk because of participation in the study, influence the subject’s ability to participate in the study, or 
interfere with interpretation of the subject’s study results. Subjects with stable baseline medical conditions on 
established medication may be included as per the judgement of the Investigator; e.g., well controlled 
hypertension, type 2 diabetes, or mild, stable asthma not requiring treatment with inhaled corticosteroids.  
21. Systemic medication that could have a substantial effect on IOP within 30 days prior to screening, or anticipated 
during the study, including any corticosteroid-containing drug regardless of route of administration. 
22. Use of an investigational medication or device within 30 days or 5-half-lives of the investigational medication, 
whichever is longer, preceding Day 1, or ongoing or scheduled participation in another investigational study 
during the present study through the last visit  
23. Previous treatment with AKB-9778 
24. Subjects who are study site employees, or immediate family members of a study site or sponsor employee 


Protocol No. AKB-9778-CI-OS-2001 
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25. Failure to satisfy the Investigator of fitness to participate for any other reason  
Investigational Products (IP), Dose and Treatment Regimens: 
Study Medication 
• 
AKB-9778: AKB-9778 Ophthalmic Solution 4.0% 
• 
Placebo for AKB-9778 Ophthalmic Solution: placebo vehicle to match active formulation of AKB-9778 
Latanoprost 
• 
Latanoprost: latanoprost ophthalmic solution 0.005% (XALATAN® Pfizer) 
 
AKB-9778 QD + Latanoprost 
• 
AKB-9778 QD (AM) and placebo for AKB-9778 ophthalmic solution QD (PM) plus latanoprost QD (PM) for 
28 days 
AKB-9778 BID + Latanoprost  
• 
AKB-9778 BID (AM & PM) plus latanoprost QD (PM) for 28 days 
Latanoprost Monotherapy 
• 
Placebo for AKB-9778 ophthalmic solution BID (AM & PM) plus latanoprost QD (PM) for 28 days 
Subjects will self-administer study medication (AM & PM) and latanoprost (PM) to each eye by the topical ocular 
route using dropper bottle(s) to deliver eye drops.  Daily AM dose administrations should occur between 7:00 and 
10:00 hours and PM dose administrations should occur between 19:00 and 22:00 hours. Latanoprost PM dose 
administration will occur at least 5 minutes before administration of the PM dose of study medication.  
Statistical Methods: 
Primary Estimand 
The primary comparisons in this trial will be between two doses of AKB-9778 (QD and BID) + Latanoprost  vs 
Latanoprost monotherapy at the Day 28 Visit in the ITT population with intercurrent events handled as described in the 
following estimand.   
• 
Population: subjects with Open-Angle Glaucoma or Ocular Hypertension defined through enrolment criteria 
• 
Endpoint: 
- 
Mean diurnal (averaged over 08:00, 10:00, 12:00, and 16:00 hour time points) change from baseline IOP 
(mm Hg) at the Day 28 Visit in the study eye 
• 
Intercurrent event: 
- 
Discontinuation of study medication and non-optimal compliance will be ignored [treatment policy 
strategy]. 
- 
Withdrawal due to lack of efficacy or adverse event: missing data will be imputed employing Multiple 
Imputation (MI) assuming missing not at random using: 
▪     Control-based Markov Chain Monte Carlo (MCMC) methodology [hypothetical strategy]. 
- 
Missing data without withdrawal or withdrawal due to reasons other than lack of efficacy or adverse 
event: missing data will be imputed employing Multiple Imputation (MI) assuming missing at random 


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using randomized treatment-based Markov Chain Monte Carlo (MCMC) methodology [hypothetical 
strategy]. 
• 
Population-level summary: 
- 
The difference in the mean diurnal change from baseline IOP at the Day 28 Visit, between study eyes 
treated with each dose of AKB-9778 (QD and BID) + Latanoprost and study eyes treated with 
Latanoprost monotherapy 
Sensitivity analyses will be performed on observed data only and where worst time consistent observation within a 
subject is carried forward for withdrawal due to lack of efficacy or adverse event and last time consistent observation 
within a subject is carried forward for other missing data. 
The primary analysis of the primary efficacy outcome will employ a linear model with Day 28 mean diurnal change 
from baseline IOP as the response, baseline IOP (mean diurnal IOP on Day-1) as a covariate, and treatment as a main 
effect factor, using the intent to treat population with multiple imputation techniques used to impute missing data.  
The least squares mean differences (test – control) between AKB-9778 + Latanoprost and Latanoprost monotherapy 
will be presented as well as 2-sided p-values and 95% confidence intervals. Inference will be made on the p-value < 
0.05.  
Sixty-five (65) subjects per arm completing 28 days of treatment yields 80% power to conclude statistical superiority 
of AKB-9778 (QD or BID) + Latanoprost  to Latanoprost monotherapy assuming a two-sided alpha = 0.05, a true 
difference in mean diurnal change from baseline IOP of 1.5 mmHg,  a common standard deviation of 3.5 mmHg at 
each time point, and a correlation of 0.60 among time points within a subject’s study eye (leading to an SD of the 
mean diurnal IOP of 3.0 mmHg).  
An interim analysis for futility is planned to be performed when 50% of randomized subjects have completed 28 days 
of therapy. 
 
 
 


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TABLE OF CONTENTS 
 
1.0 
STUDY CONTACTS .......................................................................................................2 
1.1 
Protocol Approval ........................................................................................................4 
1.2 
Investigator Agreement ................................................................................................5 
2.0 
SYNOPSIS ........................................................................................................................6 
3.0 
ABBREVIATIONS ........................................................................................................16 
4.0 
BACKGROUND INFORMATION .............................................................................18 
4.1 
Rationale ....................................................................................................................18 
4.2 
Summary of Non-Clinical Experience .......................................................................19 
4.2.1 Preclinical Pharmacology ....................................................................................20 
4.2.2 Absorption, distribution, metabolism and excretion (ADME) ............................20 
4.2.3 Toxicology ...........................................................................................................21 
4.3 
Summary of Clinical Experience ...............................................................................23 
4.3.1 AKB-9778 SC Injection .......................................................................................23 
4.3.2 AKB-9778 Ophthalmic Solution .........................................................................24 
4.4 
Risks and Benefits to Human Subjects ......................................................................25 
4.4.1 Potential Benefits and Risks of AKB-9778 .........................................................25 
4.4.2 Latanoprost Safety Information ...........................................................................26 
5.0 
STUDY OBJECTIVES AND ENDPOINTS ................................................................26 
5.1 
Primary Objectives .....................................................................................................26 
5.2 
Secondary Objectives .................................................................................................27 
5.3 
Efficacy Endpoints .....................................................................................................27 
5.4 
Safety Measures .........................................................................................................27 
6.0 
INVESTIGATIONAL PLAN .......................................................................................28 
6.1 
Overall Study Design and Plan ..................................................................................28 
6.2 
Rationale for Study Design ........................................................................................29 
6.3 
Rationale for AKB-9778 Dose Selection and Frequency ..........................................30 
7.0 
STUDY POPULATION SELECTION ........................................................................30 
7.1 
General Criteria ..........................................................................................................30 
7.2 
Subject Eligibility and Study Eye Determination ......................................................31 
7.3 
Inclusion Criteria........................................................................................................31 
7.4 
Exclusion Criteria ......................................................................................................32 
7.5 
Withdrawal of Subjects ..............................................................................................34 
7.6 
Waivers ......................................................................................................................34 
7.7 
Replacement of Subjects ............................................................................................34 
8.0 
STUDY PRODUCT AND TREATMENT OF SUBJECTS .......................................35 
8.1 
Study Medication, Latanoprost, Supplies and Storage ..............................................35 
8.1.1 Masked Study Medication: AKB-9778 Ophthalmic Solution and Matching 
Placebo .....................................................................................................35 
8.1.2 Storage and Handling of AKB-9778 and Placebo for AKB-9778 .......................35 


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8.1.3 Latanoprost ..........................................................................................................36 
8.1.4 Storage and Handling of Latanoprost ..................................................................36 
8.2 
Dispensing Procedures ...............................................................................................36 
8.3 
Treatment of Subjects ................................................................................................37 
8.3.1 Treatment Group Assignments ............................................................................37 
8.3.2 Randomization and Allocation to Treatment Group ............................................37 
8.4 
Masking......................................................................................................................38 
8.5 
Unmasking .................................................................................................................38 
8.6 
Study Medication and Latanoprost Administration ...................................................38 
8.7 
Concomitant Medication ............................................................................................39 
8.8 
Restrictions ................................................................................................................40 
8.8.1 Prior Therapy and Washout .................................................................................40 
8.8.2 Fluid and Food Intake ..........................................................................................40 
8.8.3 Subject Activity Restrictions ...............................................................................41 
8.9 
Treatment Compliance ...............................................................................................41 
8.10 
Product Accountability and Destruction ....................................................................41 
9.0 
STUDY PROCEDURES ................................................................................................42 
9.1 
Administrative Procedures .........................................................................................42 
9.1.1 Informed Consent .................................................................................................42 
9.1.2 Documentation of Screen Failures .......................................................................42 
9.1.3 Contraception and Pregnancy Avoidance Measures ............................................43 
9.2 
Study Procedures and Evaluations .............................................................................44 
9.2.1 Clinical Evaluations .............................................................................................44 
9.2.2 Ophthalmic Assessments (listed in order of assessment) ....................................44 
9.2.3 Laboratory Evaluations ........................................................................................46 
10.0 
SCHEDULE OF ACTIVITIES ....................................................................................46 
10.1 
Visit Windows and Study Days .................................................................................46 
10.2 
Visit 1 (Screening Visit) ............................................................................................47 
10.2.1 Washout ...............................................................................................................48 
10.2.2 Visit 2 (Qualifying Visit #1, For IOP measurement at any hour) ........................48 
10.2.3 Visit 3.0 (Qualifying Visit #2 [Day -1] for IOP measurement at 08:00 hours) ...49 
10.2.4 Visit 3.1 (Qualifying Visit #2/Day -1, for IOP measurement at 10:00 hours) .....50 
10.2.5 Visit 3.2 (Qualifying Visit #2/Day -1, for IOP measurement at 12:00 hours) .....51 
10.2.6 Visit 3.3 (Qualifying Visit #2/Day -1, for IOP measurement at 16:00 hours) .....52 
10.2.7 Visit 4 (Day 7, for IOP measurement at any hour) ..............................................53 
10.2.8 Visit 5.0 (Day 14, for IOP measurement at 8:00 hours) ......................................53 
10.2.9 Visit 5.1 (Day 14, for IOP measurement at 10:00 hours) ....................................54 
10.2.10 
Visit 5.2 (Day 14, for IOP measurement at 12:00 hours) ........................55 
10.2.11 
Visit 5.3 (Day 14, for IOP measurement at 16:00 hours) ........................55 
10.2.12 
Visit 6.0 (Day 28, for IOP measurement at 08:00 hours) ........................55 
10.2.13 
Visit 6.1 (Day 28, for IOP measurement at 10:00 hours) ........................56 
10.2.14 
Visit 6.2 (Day 28, for IOP measurement at 12:00 hours) ........................57 
10.2.15 
Visit 6.3 (Day 28, for IOP measurement at 16:00 hours) ........................57 
10.3 
Unscheduled Visits ....................................................................................................58 


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10.4 
Early Termination Visits ............................................................................................58 
11.0 
ADVERSE EVENTS .....................................................................................................58 
11.1 
Definitions..................................................................................................................58 
11.1.1 Adverse Events (AEs) ..........................................................................................58 
11.1.2 Serious Adverse Events (SAEs) ...........................................................................59 
11.1.3 Severity ................................................................................................................60 
11.2 
Eliciting Adverse Event Information .........................................................................60 
11.3 
Reporting....................................................................................................................60 
11.3.1 Reporting Period ..................................................................................................61 
11.3.2 Reporting AEs ......................................................................................................61 
11.3.3 Reporting SAEs ...................................................................................................61 
11.3.4 Relationship to Study Medication ........................................................................62 
11.3.5 Follow-Up of Unresolved Events ........................................................................62 
11.4 
Exposure In Utero ......................................................................................................63 
12.0 
STATISTICAL METHODS .........................................................................................63 
12.1 
Primary Hypotheses ...................................................................................................63 
12.2 
Multiplicity Adjustment .............................................................................................64 
12.3 
Sample Size Considerations .......................................................................................64 
12.4 
Analysis Populations ..................................................................................................64 
12.5 
Statistical Methods to be Employed ..........................................................................65 
12.5.1 General Considerations ........................................................................................65 
12.5.2 Interim Analyses ..................................................................................................65 
12.5.3 Analysis of Baseline Data ....................................................................................66 
12.5.4 Subject Disposition ..............................................................................................66 
12.5.5 Analysis of Efficacy .............................................................................................66 
12.5.6 Analysis of Safety ................................................................................................69 
12.6 
Procedure for Accounting for Missing, Unused, or Spurious Data ...........................69 
12.7 
Procedure for Reporting Deviations from the Statistical Plan ...................................69 
12.8 
Data Listings ..............................................................................................................69 
13.0 
DATA HANDLING AND RECORD KEEPING ........................................................70 
13.1 
Case Report Forms (CRFs) ........................................................................................70 
13.2 
Record Retention .......................................................................................................70 
14.0 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) ........................71 
14.1 
Study Site Monitoring Visits .....................................................................................71 
14.2 
Protocol Deviations ....................................................................................................71 
15.0 
TRIAL DISCONTINUATION/INVESTIGATIVE SITE TERMINATION ...........71 
15.1 
Criteria for Premature Termination or Suspension of the Study ...............................71 
15.2 
Criteria for Premature Termination or Suspension of Investigational Site ................72 
15.3 
Procedures for Premature Termination or Suspension of the Study or Investigational 
Site(s) ...................................................................................................................72 
16.0 
ETHICS ..........................................................................................................................72 
16.1 
Ethical Conduct of the Study .....................................................................................72 
16.2 
Institutional Review Board (IRB) ..............................................................................72 
16.3 
Subject Information and Consent...............................................................................73 


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16.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP ........73 
16.5 
Subject Confidentiality ..............................................................................................73 
17.0 
PUBLICATION OF STUDY RESULTS .....................................................................74 
18.0 
REFERENCES ...............................................................................................................75 
APPENDIX 1 
SCHEDULE OF VISITS AND PROCEDURES .................................78 
APPENDIX 2 
MARKETED PRODUCT: XALATAN® (LATANOPROST 
OPHTHALMIC SOLUTION) 0.005% ........................................................................80 
 
 
 


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3.0 
ABBREVIATIONS 
Abbreviation 
Definition 
AEs 
Adverse events 
AH 
Aqueous humor 
ALT 
Argon laser trabeculoplasty 
Angpt 
Angiopoietin 
Angpt1 or 2 
Angiopoietin1 or 2 
AUC 
Area under the curve 
AUClast 
Area under the concentration-time curve from time 0 to last 
quantifiable concentration  
BID 
Twice daily 
BLQ 
Below limit of quantitation 
BOCF 
Baseline observation carried forward 
Cmax 
Maximum plasma drug concentration 
CO 
Conventional outflow 
CRF 
Case report form 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EGF 
Epidermal Growth Factor 
eNOS 
Endothelial nitric oxide synthase 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practices 
HPTPβ 
Human protein tyrosine phosphatase β 
HPβCD 
Hydroxypropyl-beta-cyclodextrin 
ICH 
International Council for Harmonisation 
IP 
Investigational product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat Population 
IVT 
Intravitreal injection 
IWRS 
Interactive Web-based response system 
LASIK 
Laser-assisted in-situ keratomileusis 
LOCF 
Last observation carried forward 
logMAR 
Logarithm of the minimum angle resolvable 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIGS 
Minimally Invasive Glaucoma Surgery 
MITT 
Modified Intention-To-Treat 
NOAEL 
No observed adverse-effect level 
OAG 
Open angle glaucoma 
OHT 
Ocular hypertension 


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Abbreviation 
Definition 
OTC 
Over-the-counter 
OU 
Both eyes 
PI 
Principal Investigator 
PK 
Pharmacokinetics  
PP 
Per-protocol 
PRK 
Photorefractive keratectomy 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
QD 
Once daily 
QID 
Four times daily 
Rac1 
Ras-related C3 botulinum toxin substrate 1 
Rap1 
Ras-proximate 1 
SAEs 
Serious Adverse Events 
SC 
Subcutaneous  
SITA 
Swedish interactive threshold algorithm 
SLT 
Selective laser trabeculoplasty 
SNPs 
Single-nucleotide polymorphisms 
SOC 
System Organ Class 
T½ 
Terminal half-life 
TEAEs 
Treatment-emergent adverse events 
TID 
Three times daily 
Tie 2 
Tyrosine kinase with immunoglobulin-like and EGF-like domains 2 
TM 
Trabecular meshwork 
USP 
United States Pharmacopeia 
VA 
Visual Acuity 
VE-PTP 
Vascular endothelial protein tyrosine phosphatase 
w/v 
Weight/volume 
 
 


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4.0 
BACKGROUND INFORMATION 
Open angle glaucoma (OAG) is a leading cause of blindness affecting approximately 44.7 
million people worldwide with an estimated prevalence in the United States of 2.7 million in 
2011, which is expected to increase to 7.3 million by 2050 (Tham et al., 2014; Vajaranant et al. 
2012; Vajaranant et al., 2012b).  OAG is characterized by optic nerve and neuroretina anomalies 
and progressive visual field defects. Elevated intraocular pressure (IOP)/Ocular hypertension 
(OHT) is the primary modifiable risk factor and reducing IOP is the only clinical approach 
shown to slow/prevent vision loss (Gordon et al., 2002; Heijl et al., 2002; Kass et al., 2002; 
Leske et al., 2007). Despite the availability of effective IOP lowering drugs, many patients 
require multiple agents to control IOP that together often fail to achieve a “target” IOP (Aptel et 
al., 2015).   
Aerpio Pharmaceuticals, Inc. (Aerpio) is developing AKB-9778 Ophthalmic Solution as a 
treatment for OAG. AKB-9778 is a novel small molecule which selectively inhibits VE-PTP 
(vascular endothelial-protein tyrosine phosphatase), otherwise known as HPTPβ (human protein 
tyrosine phosphatase β), and enhances Tie2 (tyrosine kinase with immunoglobulin-like and 
Epidermal Growth Factor (EGF)-like domains 2) activation and signaling. Recent findings 
suggest that Angiopoietin (Angpt)/Tie2 pathway activation may have therapeutic benefit in 
patients with OAG and OHT by directly targeting the conventional outflow (CO) pathway. 
The CO pathway, consisting of the trabecular meshwork (TM) and a specialized vessel called 
Schlemm’s canal, controls IOP under normal physiology and has been identified as the site of 
increased resistance to aqueous humor (AH) outflow in OAG (Grant, 1951; Grant, 1963; Stamer 
and Acott, 2012). Importantly, a vast majority of topical ocular OAG therapies do not target CO, 
but rather reduce IOP by either decreasing the formation of AH or facilitating unconventional 
outflow pathways. The failure of current therapies to modify CO has been hypothesized to 
contribute to continued deterioration of the CO pathway and progressive increases in IOP over 
time (Braunger et al., 2015; Stamer, 2012). Relative to current therapies, developing agents that 
target CO pathology directly may have improved efficacy either alone or in combination with 
approved glaucoma agents, and may prevent progression of OAG that often occurs despite 
current therapy. 
4.1 
Rationale 
Schlemm’s canal develops postnatally from the intrascleral venous plexus but has a “hybrid” 
phenotype characterized by expression of lymphatic endothelial as well as blood endothelial 
markers (Aspelund et al., 2014; Hamanaka et al., 1992; Kizhatil et al., 2014; Park et al., 2014; 
Truong et al., 2014).  Tie2, the receptor for the Angpt family of secreted proteins, is a receptor 
tyrosine kinase expressed on both blood and lymph endothelial cells and is required for 
development of both vascular systems (Augustin et al., 2009; Morisada et al., 2005; Peters et al., 
2004; Saharinen et al., 2017; Tammela et al., 2005). Tie2 is constitutively expressed and 
activated in the normal adult blood vasculature, consistent with the established role of the Tie2 
pathway in maintenance of endothelial function and vascular stability (Wong et al., 1997). 
Recently, two independent groups have shown that Tie2 is expressed and activated in Schlemm’s 
canal endothelial cells during development and in the mature vessel (Bernier-Latmani and 


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Petrova, 2017; Kim et al., 2017; Thomson et al., 2014).  Disruption of the Tie2 pathway in mice, 
by conditional knockout of Tie2 or both Tie2 ligands (Angpt1 and Angpt2) early in postnatal 
development (postnatal day 1), results in failure of the formation of Schlemm’s canal, associated 
with increased IOP with retinal and optic nerve pathology resembling human congenital 
glaucoma (Kim et al., 2017; Thomson et al., 2014).  Tie2 pathway disruption later in postnatal 
development (8 weeks) results in degeneration of Schlemm’s canal with development of 
increased IOP and retinal and optic pathology reminiscent of OAG (Kim et al., 2017).  Tie2 is 
most highly expressed in mature inner wall endothelium of Schlemm’s canal and disruption of 
the Tie2 pathway results in increased apoptosis and reduced formation of giant vacuoles 
consistent with compromised CO. Supporting these preclinical findings, Tie2 loss of function 
variants were identified in 10 of 189 unrelated primary congenital glaucoma families, and single-
nucleotide polymorphisms (SNPs) in Angpt1, the Tie2 activating ligand, were significantly 
associated with the risk of OAG (Bailey et al., 2017; Choquet et al., 2017; Kabra et al., 2017; 
Souma et al., 2016). The preclinical findings, along with human genetic evidence, suggest that 
activation of the Angpt/Tie2 pathway in Schlemm’s canal could provide a novel CO-targeted 
OAG therapy. 
VE-PTP is a receptor tyrosine phosphatase that is co-expressed with Tie2 in vascular endothelial 
cells that functions as a pivotal negative regulator of Tie2 activation (Shen et al., 2014). AKB-
9778 is a potent and selective small molecule inhibitor of the catalytic activity of VE-PTP.  
Pharmacologic inhibition of VE-PTP with AKB-9778 restores Tie2 activation independent of the 
presence or absence of Tie2 ligands Angpt1 and Angpt2.  Consistent with a role for VE-PTP in 
regulation of CO, subcutaneous (SC) administration of AKB-9778 reduced IOP in subjects with 
diabetic macular edema and nonproliferative diabetic retinopathy.  Topical ocular administration 
of AKB-9778 reduced IOP more than subcutaneous AKB-9778 administration in rabbits and 
decreased IOP in mice in association with increased Tie2 activation in Schlemm’s canal 
endothelium and increased outflow facility. Data in normotensive dogs indicate that topical 
ocular administration of AKB-9778 immediately following topical ocular dosing of 0.005% 
latanoprost is well tolerated and has an additive IOP-lowering effect relative to latanoprost alone.  
Moreover, in a recently completed Phase 1b study, topical ocular administration of AKB-9778 
once a day for 7 days was well tolerated (minimal to mild conjunctival hyperemia only) and 
significantly reduced IOP in a cohort of OHT/OAG patients on standard of care prostaglandin 
therapy.  Taken together, these data support development of AKB-9778 Ophthalmic Solution as 
a novel CO targeted treatment for OAG/OHT and provide strong rationale for the current study 
with AKB-9778 as an adjunct to latanoprost. 
4.2 
Summary of Non-Clinical Experience 
Please see the AKB-9778 Ophthalmic Solution Investigator Brochure for additional discussion 
and information for the following section. 
The nonclinical experience for AKB-9778 Ophthalmic Solution is supported by a comprehensive 
set of in vitro and systemic pharmacology and nonclinical studies completed during the 
development of the AKB-9778 SC Injection program, including evaluation in multiple 
retinopathy models, safety pharmacology studies, pharmacokinetic (PK) and metabolism studies, 
toxicology studies in rats, dogs, and monkeys, embryo-fetal development studies in rats and 


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rabbits, and genotoxicity studies. Some of these studies are briefly summarized in the sections 
below, as well as the nonclinical studies for topical ocular administration of AKB-9778. 
4.2.1 
Preclinical Pharmacology 
AKB-9778 is a highly optimized small molecule inhibitor of the VE-PTP catalytic phosphatase 
domain that restores Tie2 activation and downstream signaling. Supporting a role in regulation of 
IOP, VE-PTP inhibition triggers signaling pathways downstream of Tie2 that have been 
implicated in modulation of CO facility including endothelial nitric oxide synthase (eNOS) 
activation and Rho pathway inhibition via Ras-related C3 botulinum toxin substrate 1 (Rac1)/ 
Ras-proximate 1 (Rap1) activation (Frye et al., 2015; Shen et al., 2014).  In ocular normotensive 
mice, topical ocular administration of AKB-9778 activated Tie2 in Schlemm’s canal 
endothelium after a single dose and reduced IOP via increased outflow facility after three days of 
once a day dosing. 
In normotensive female New Zealand White rabbits (n = 5/group) administered bilateral topical 
ocular doses (30 μL to both eyes) of 1.5% weight/volume (w/v) AKB-9778 in 15% w/v 
hydroxypropyl-beta-cyclodextrin (HPβCD) + 2% w/v dextrose or 4.0% w/v AKB-9778 in 15% 
w/v HPβCD + 1% w/v dextrose either once daily (QD) or BID, or vehicle control (15% w/v 
HPβCD) twice daily (BID), or subcutaneous administration of 10 mg/kg AKB-9778 BID for 
seven consecutive days, IOP was measured daily at baseline prior to dosing, on each day of 
dosing, and 24 hours after the last dose. Results showed that AKB-9778 Ophthalmic Solution 
4.0% w/v topically administered either QD or BID reduced IOP, whereas the 1.5% w/v BID 
topical dose and the 10 mg/kg SC dose were not as effective. IOP reductions persisted through 
the last assessment 24 hours after the end of dosing.  
Preliminary data from a dog IOP-lowering efficacy study indicates that topical ocular 
administration of 4.0% w/v AKB-9778 in a 15% w/v HPβCD + 1% w/v mannitol formulation 
also lowers IOP in normotensive dogs. Further, administration of AKB-9778 immediately 
following topical ocular dosing of 0.005% latanoprost was well tolerated and had an additive 
IOP-lowering effect relative to latanoprost alone. 
Safety Pharmacology 
All in vitro and in vivo safety pharmacology assessments were conducted for AKB-9778 SC 
Injection program. In vitro assessments demonstrated very limited interactions with AKB-9778; 
and in vivo safety pharmacology assessments demonstrated no respiratory or neurobehavioral 
effects in rat and a minimal decrease in blood pressure in dog and no effects on QT interval 
following SC dosing. 
4.2.2 
Absorption, distribution, metabolism and excretion (ADME) 
In a 3-day PK study conducted in New Zealand White rabbits, topical ocular instillation of 4.0% 
w/v AKB-9778 in 15% w/v HPβCD + 1% w/v mannitol three times daily (TID) to both eyes 
(7.2 mg total daily dose) resulted in dose normalized AKB-9778 concentrations in aqueous 
humor approximately 2-fold higher than achieved with SC BID doses (33 mg total daily dose). 
By contrast, relative to topical ocular administration, systemic exposure following subcutaneous 


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administration of the same AKB-9778 formulation had a ~44-fold greater maximum plasma drug 
concentration (Cmax) and 29-fold greater area under the concentration-time curve from time 0 to 
last quantifiable concentration (AUClast), based on dose normalized values. In dogs, following 
bilateral topical ocular instillation of 30μL of 4.0% w/v AKB-9778 in 15% w/v HPβCD + 1% 
w/v mannitol QD (2.4 mg/day), BID (4.8 mg/day), or four times daily (QID, 9.6 mg/day) for 3 
days, plasma half-life (T½) was 0.5 hours and mean plasma Cmax and AUC values were generally 
similar across groups, suggesting rapid elimination of AKB-9778 between the BID and QID 
inter-day dosing intervals. There was no evidence for accumulation between the QD, BID, and 
QID dosing regimens.  
In the Good Laboratory Practices (GLP) 28-day rabbit and dog toxicity studies, quantifiable 
systemic exposure of AKB-9778 in plasma was observed following bilateral topical ocular 
administration of 30 μL of 4% w/v AKB-9778 in 15% w/v HPβCD + 1% w/v mannitol to each 
eye QD (2.4 mg/day), BID (4.8 mg/day), and QID (9.6 mg/day) in males and females on Day 1 
and during the last week of dosing (Day 23 for rabbit; Day 26 for dog).  There were no consistent 
sex-related differences in systemic exposure; however, the data exhibited a high degree of inter-
animal variability. In most cases, an initial peak at ≤ 0.25 hours postdose was observed in the 
mean concentration-time profiles across all dosing regimens and days; however, a second peak in 
some cases constituted Cmax. Systemic exposure to AKB-9778 was similar (Cmax and AUC 
approximately within 2-fold) following BID and QID dosing regimens on Day 1 and Days 23 
and 26 for rabbits and dogs, respectively. Exposure was generally similar across all three dosing 
regimens with no evidence of accumulation. 
4.2.3 
Toxicology 
Topical Ocular (AKB-9778 Ophthalmic Solution) 
The topical ocular instillation of 4.0% w/v AKB-9778 in 10% w/v to 15% w/v HPβCD-based 
solution formulations has been well tolerated in rabbits and dogs in non-GLP toleration and GLP 
toxicity studies.  
In the 28-day GLP toxicity studies, New Zealand White rabbits and Beagle dogs were 
administered a 30 μL bilateral ocular instillation of 4.0% w/v AKB-9778 in 15% w/v HPβCD + 
1% w/v mannitol (1.2 mg/eye) QD (2.4 mg/day), BID (4.8 mg/day), and QID (9.6 mg/day) for 
28 days. In both species, there were no adverse vehicle- or test article-related effects on body 
weight, food consumption, clinical pathology, ophthalmologic or IOP parameters, 
electroretinography, or post-mortem organ weight or macroscopic histological findings. Test 
article-related clinical observations involved only the eyes and surrounding skin areas for both 
rabbit and dog. 
In rabbit, AKB-9778-related effects were primarily limited to clinical observations that included 
red conjunctiva (palpebral conjunctiva), red skin of the periorbital region, and red eyeballs 
(bulbar conjunctiva).  Palpebral conjunctiva and periorbital skin redness were observed in all 
drug-treated animals the last 2 weeks of dosing. Periorbital redness was also observed in saline 
and vehicle control animals the last week of dosing but at a lesser incidence. Red eyeballs (red 
bulbar conjunctiva) were observed only in the test article-treated rabbits at the end of the dosing 
period on Days 28 and 29. In dog, similar results were noted where AKB-9778-related effects 


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were also limited to clinical observations including clear discharge, red eyeballs (bulbar 
conjunctiva), and red conjunctiva (palpebral conjunctiva). Red eyeballs were observed in all but 
one drug-treated animal, in 2/10 vehicle control, and in 2/10 saline control animals beginning the 
second week of dosing. Palpebral conjunctiva redness was observed in all drug-treated dogs 
during most of the dosing phase, with the earliest onset in dogs treated at 9.6 mg/day. These non-
adverse findings in dog and rabbit resolved quickly during the recovery phase. Dose-dependent 
clear ocular discharge was observed in dog at all dose levels, including the vehicle control, but 
with the greatest incidence following QID dosing, with persistence in the QID group throughout 
the recovery phase.  
There were no microscopic histopathological findings in the 28-day dog toxicity study. In rabbit, 
marked diffuse unilateral corneal epithelial atrophy was observed in 1 male following QID 
dosing.  While corneal epithelial atrophy is not a reported background finding in this rabbit 
strain, the single incidence and unilateral distribution suggest that this is unlikely to be a test 
article-related effect.  It would be unexpected for a direct test article effect to result in marked 
severity in only a single eye when both eyes were treated identically.  However, a test article-
related effect could not be ruled out due to its occurrence in the high-dose group; therefore, this 
finding was considered to have an uncertain relationship to the administration of the test article. 
The no observed adverse-effect level (NOAEL) in the 28-day rabbit and dog toxicity studies was 
considered to be the highest dose administered in each study at 9.6 mg/day (2.4 mg QID). In 
rabbits, this dose was associated with mean combined-sex Cmax and estimated AUC0-24 values of 
20.7 ng/mL and 132 ng·hr/mL, respectively; and, in dogs, of 51.7 ng/mL and 243 ng·hr/mL, 
respectively. These exposures numerically describe the margin to human exposure since the 
measured human exposure following topical ocular administration of 40 mg/mL AKB-9778 QD 
and BID was below the limit of quantitation (BLQ = <1 ng/mL). 
Systemic (AKB-9778 Injection) 
In the in vivo GLP general, genetic, and reproductive toxicity studies for AKB-9778 Injection, 
AKB-9778 was formulated as a solution in 10% w/v HPβCD + 1.7% w/v dextrose and 
demonstrated an excellent safety profile and was well tolerated by SC administration in up to 6 
months (182 days) dosing in rats and up to 9 months (273 days) dosing in dogs and monkeys. 
The primary target tissues for AKB-9778 were identified as injection site and liver in rat, dog 
and monkey; skin/subcutis (vascular) in dog and monkey; and gastrointestinal (GI; vascular) in 
dog. The NOAEL exposures measured in rat, dog, and monkey were, respectively, 4-, 25-, and 
33-fold the AUC value associated with a human dose of 15 mg SC BID.  
No liver findings or unusual or unexpected dermal findings have been observed in clinical 
studies with SC administration of AKB-9778. 
AKB-9778 is not considered to be mutagenic or clastogenic based on the negative findings in the 
pivotal battery of genotoxicity studies. 
Definitive systemic embryo-fetal development toxicity studies in rat and rabbit with SC 
administration showed no evidence of external fetal teratogenic effects or of skeletal or visceral 


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malformations; and a definitive systemic fertility study in male and female rats demonstrated no 
findings on fertility or reproductive outcome.  
4.3 
Summary of Clinical Experience 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
A robust clinical program has been conducted with a subcutaneous formulation of AKB-9778 
(AKB-9778 SC injection) and a phase 1 study evaluating topical ocular administration of AKB-
9778 Ophthalmic Solution in healthy volunteers and subjects with OAG/OHT has recently been 
completed.  Clinical experience is summarized below. IOP reduction effects observed in studies 
conducted with AKB-9778 are consistent with preclinical and genetic evidence for the 
importance of Tie2 function on the CO pathway and support evaluation of Tie2 activation by 
AKB-9778 as a potential approach for IOP reduction in subjects with OAG or OHT. 
4.3.1 
AKB-9778 SC Injection 
AKB-9778 SC injection 20 mg/mL has been evaluated under an ongoing clinical development 
program in the United States for diabetic eye disease, including diabetic retinopathy and diabetic 
macular edema. A total of 478 human subjects have been randomized in completed clinical trials 
evaluating AKB-9778 SC administration (in the abdomen). Data from the two largest clinical 
trials conducted with this formulation are summarized as follows.  
Study AKB-9778-CI-2003, was a Phase 2, double-masked, parallel-group trial in which 144 
subjects with diabetic retinopathy complicated by center-involved diabetic macular edema were 
randomized to one of 3 treatment groups: AKB-9778 (15 mg) SC BID monotherapy; AKB-9778 
SC BID plus monthly Lucentis® (0.3 mg) intravitreal injection (IVT); and monthly Lucentis® 
IVT monotherapy. Ophthalmic assessment at baseline, during and at the end of the 3-month 
treatment period, included IOP measurement by applanation tonometry in both the study eye and 
the fellow eye. Pretreatment baseline IOP assessment showed both the study eye and fellow eyes 
of each treatment group to be normotensive and well balanced between treatment groups. Both 
active AKB-9778 treatment arms achieved statistically significant reductions in IOP in both the 
study eye and the fellow eye compared to baseline. In the subgroup of subjects with baseline IOP 
> 16 mm Hg, a greater IOP reduction was achieved. 
Study AKB-9778-CI-5001, was a Phase 2, double-masked, placebo-controlled, parallel-group 
trial in which 167 subjects with moderate to severe non-proliferative diabetic retinopathy were 
randomized to receive once or twice daily AKB-9778 SC (15 mg) for 12 months. Positive effects 
on IOP reduction were observed in this study and were similar to those observed in the AKB-
9778-CI-2003 study.  
AKB-9778 SC injection has shown no evidence of significant safety issues to date. A transient, 
generally asymptomatic reduction in blood pressure is observed reflecting the vasodilatory 
pharmacodynamic effect of Tie-2 activation. Vasovagal events (presyncope/syncope) have been 
observed following the first dose of AKB-9778 at doses >22 mg. A vasovagal event was 
observed after the first dose in 1/144 (0.7%) subjects in the Phase 2 AKB-9778-CI-2003 study. 


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This subject did not experience any such events during the subsequent 3 months of dosing. No 
other vasovagal events were observed in this study. In both studies there was a significant 
correlation between baseline blood pressure (BP) and change in BP. Specifically, subjects with 
higher BP had greater reductions in BP. To date there has been no evidence of adverse effects on 
clinical chemistry assessments, including liver function tests, and no evidence of unusual dermal 
findings. 
4.3.2 
AKB-9778 Ophthalmic Solution 
A Phase 1b study evaluating AKB-9778 ophthalmic solution has been recently completed. Study 
AKB-9778-CI-OS-1001 was a randomized, double-masked study designed to assess increasing 
concentrations of AKB-9778 dosed topically as eye drops (5mg/mL QD, 15 mg/mL QD, 40 
mg/mL QD and 40 mg/mL BID) conducted initially in 4 sequential cohorts of 12 healthy (ocular 
normotensive subjects), randomized 3:1 to receive AKB-9778 or placebo, for 7 days. The 
primary outcome of the study was ocular safety and tolerability with change in IOP as a 
pharmacodynamic outcome. Conjunctival hyperemia grade and IOP were assessed prior to 
dosing and at 2-, 4- and 8-hours post-dose on Day 1 and Day 7. Topical ocular administration of 
AKB-9778 was well tolerated over 7 days at all dose levels. Compared to placebo, there was a 
dose dependent increase in minimal to mild conjunctival hyperemia with AKB-9778, which was 
transient and generally considered non-adverse. There was also a time and dose dependent 
reduction in IOP that, in the highest QD dose cohort (40mg/mL) peaked at 4 hours post-dose 
(- 1.47 mmHg; p = 0.041)/-10.64%; p = 0.027) and was sustained through eight hours on day 7, 
returning to baseline levels at 24 hours post-dose.  There was a trend towards larger IOP 
decreases with BID dosing in Cohort 4, but hyperemia was similar to Cohort 3 with QD dosing. 
The results of the bioanalysis of approximately 100 plasma samples from the subjects 
administered the highest dose (40 mg/mL) indicated almost no systemic exposure (all samples 
(except 1 sample) were reported as below limit of quantitation (BLQ) using a bioanalytical 
method with a lower limit of quantification of 1 ng/mL).  As a result, no systemic AEs are 
anticipated for the topical ophthalmic dosing of AKB-9778. 
No significant safety issues were identified in Cohorts 1-4.  Overall, there was 1 AE in the 
5 mg/mL (upper airway cough syndrome), 15 mg/mL (scratch), and placebo (blood pressure 
increased) treatment groups and 7 AEs in 3 subjects in the 40 mg/mL QD treatment group (2 
events of dysgeusia in 2 subjects; 2 events of conjunctival hyperemia in 2 subjects; 2 events of 
headache in 1 subject and 1 event of upper airway cough syndrome in 1 subject). All AEs were 
mild and all resolved by the end of the study. There were no significant changes in vital signs, 
body system assessment, clinical labs or visual acuity. In the formal assessments of hyperemia 
score, minimal to mild conjunctival hyperemia was observed in subjects receiving AKB-9778. 
The hyperemia was transient and uniformly resolved to minimal or none by 4-8 hrs post-dose. 
Based on favorable tolerability and pharmacodynamic findings in these ocular normotensive 
subjects, a fifth cohort of subjects with OHT/POAG on standard of care prostaglandin therapy 
was added to assess the safety, tolerability and pilot efficacy of once-daily AKB-9778 
(40 mg/mL) as an adjunctive therapy. Briefly, 43 subjects were recruited with OHT/POAG and 
baseline IOP measurements ≥ 17 and ≤ 27 mmHg while treated with once-daily prostaglandin 
therapy. Subjects were randomized 3:1 to receive either AKB-9778 (32 subjects) or placebo (11 


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subjects), administered in the morning for 7 days, while continuing their evening prostaglandin 
therapy. Conjunctival hyperemia and IOP were assessed in the same manner as described for 
Cohorts 1-4 (see above).  Subjects in Cohort 5 randomized to the active treatment group 
exhibited statistically significant decreases in IOP at all post-AKB-9778 administration time 
points on both Days 1 and 7 compared with Day -1 baseline values when they were being treated 
with prostaglandin alone (see Figure 1; Diurnal = mean IOP of 2, 4 and 8 hour time points; ** p 
< 0.05, *** p < 0.001).  On Day 7, the diurnal mean reduction was -1.58 mmHg (p < 0.001) 
compared to 0.06 mmHg for placebo (p = 0.462). 
 
 
Figure 1: 
 Mean IOP in the Cohort 5 AKB-9778 treated subjects (N = 32) at all time points 
with diurnal mean on Days -1, 1 and 7 (left panel) and mean change from baseline at all time points 
with diurnal mean change from baseline on Days 1 and 7 (right panel). Legend: green circle, Day-1; 
blue square, Day 1; red triangle, Day 7. 
 
Topical ocular administration of AKB-9778 was well tolerated over seven days of dosing in 
Cohort 5. In the active treatment group treated with AKB-9778 plus prostaglandin, 21.9% of 
subjects experienced hyperemia compared with 9.1% of subjects in the prostaglandin 
monotherapy treatment group. In all cases, this hyperemia was minimal-to-mild in severity, 
transient in duration and generally considered non-adverse. There were no other ocular AEs and 
no systemic AEs reported during the seven days of dosing in Cohort 5. 
4.4 
Risks and Benefits to Human Subjects 
4.4.1 
Potential Benefits and Risks of AKB-9778 
Please see the AKB-9778 Investigator Brochure for additional discussion and information for 
the following section. 
Potential benefits: In this study, subjects are unlikely to benefit from the short-term 
administration of the AKB-9778 Ophthalmic Solution.  However, the results of this study may 
lead to continued development of AKB-9778 Ophthalmic Solution as a novel CO-targeted 
treatment for OAG/OHT. 
Potential risks:  No serious risks have been identified in nonclinical toxicology studies of 
AKB-9778 Ophthalmic Solution of up to 28 days duration or in extensive nonclinical toxicology 
and clinical studies of AKB-9778 Subcutaneous Injection.  
Mean IOP 
21 
20 
ciiE 19 
J: ., 
E : 
18 
.5. C: 
a. "' 
0 ., 17 
-
E 
16 
15 
Pre-dose 2 hr 
4 hr 
6 hr 
8 hr 
! 
---
Day -1 
---
Day 1 
I ... Day 7 
Diurnal 
p<0.01 
P<0.001 
0 
IOP Change From Baseline 
(Day -1) 
Pre-dose 2 hr 
4 hr 
6 hr 
8 hr Diurnal 
---
Day 1 
...,._ Day 7 


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Potential risks based on the nonclinical topical ocular dosing of AKB-9778 include conjunctival 
hyperemia and local ocular irritation. Potential risks identified in AKB-9778 Subcutaneous 
Injection nonclinical studies include hemodynamic findings (blood pressure reduction), liver 
findings and dermal vascular findings. To date, similar findings relating to the liver and dermal 
vasculature have not been observed in clinical trials.  
Based upon the observed clinical safety data from the subcutaneous program, the following risks 
have been identified: hemodynamic effects (transient reductions in blood pressure and 
compensatory increases in heart rate), adverse events related to local tolerability, and allergic 
reaction.  
The identified non-ocular risks are mitigated by the expected much lower systemic exposure 
following administration of AKB-9778 Ophthalmic Solution compared to AKB-9778 
Subcutaneous Injection and are not expected to represent significant risks for the topical ocular 
formulation. 
To date, topical ocular dosing of AKB-9778 for up to 7 days has been very well tolerated. Mild 
transient hyperemia was observed, increasing in incidence with increasing dose of AKB-9778 
and mild transient dysgeusia has been observed in some subjects at the highest dose tested 
(40 mg/mL). There were no clinically significant changes in vital signs including blood pressure 
and heart rate consistent with much lower systemic exposure of AKB-9778 Ophthalmic Solution 
compared to AKB-9778 Subcutaneous Injection. 
There is no known antidote for AKB-9778. In cases of suspected overdose, subjects should be 
treated per standard medical practice based on the Investigator’s judgment. Dose delays may be 
implemented as necessary. Subjects will be withdrawn from the study if persistent or 
unacceptable treatment-related toxicity is observed. 
4.4.2 
Latanoprost Safety Information 
The following information is from the Highlights of Prescribing Information of the XALATAN® 
(latanoprost ophthalmic solution)0.005% Package Insert.  For additional information, please 
refer to the full prescribing information [XALATAN Package Insert, 4/2017] (See Appendix 2). 
Most common adverse reactions (≥4%) from clinical trials are blurred vision, burning and 
stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the 
iris, punctate keratitis, and upper respiratory tract infection/nasopharyngitis/influenza. 
5.0 
STUDY OBJECTIVES AND ENDPOINTS 
5.1 
Primary Objectives 
The primary objective of this study is: 
• To evaluate the ocular hypotensive effects of AKB-9778 Ophthalmic Solution 4.0% 
administered once or twice daily for 28 days when used as an adjunctive therapy to 
latanoprost ophthalmic solution 0.005% in subjects with OAG or OHT 


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5.2 
Secondary Objectives 
The secondary objective of this study is: 
• To evaluate the safety and tolerability of AKB-9778 Ophthalmic Solution 4.0% 
administered once or twice daily for 28 days when used as an adjunctive therapy to 
latanoprost ophthalmic solution 0.005% in subjects with OAG or OHT 
5.3 
Efficacy Endpoints 
All efficacy analyses will be conducted in study eye and both eyes (average of study eye 
and fellow eye). 
Primary Efficacy Endpoint:  
• Mean change from baseline in diurnal IOP on Day 28 (study eye) 
Secondary Efficacy Measures 
• Mean change from baseline in diurnal IOP on Day 14 (study eye)  
• Mean change from baseline in diurnal IOP on Days 14 and 28 (both eyes) 
• Mean diurnal IOP on Days 14 and 28 (both eyes) 
• Mean observed IOP at each time point on Days 14 and 28 
• Mean change from diurnally adjusted baseline IOP at each time point on Days 14 and 28 
• Mean percent change from diurnally adjusted baseline IOP at each time point on Days 14 
and 28 
• Mean percent change from baseline in diurnal IOP on Days 14 and 28 
• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in diurnal IOP levels 
5.4 
Safety Measures 
Safety measures include:  
• Adverse events (AEs) 
• Ophthalmic examination findings including: 
o Bulbar conjunctival hyperemia assessments (study eye and worse eye) 
o Pachymetry  


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o Visual acuity 
o Biomicroscopic examinations (i.e., lids, conjunctiva, cornea, anterior chamber, iris 
and lens) 
o Dilated ophthalmoscopy 
6.0 
INVESTIGATIONAL PLAN 
6.1 
Overall Study Design and Plan 
This is a phase 2, double masked, randomized, multi-center, parallel-group, 28-day study to 
evaluate the safety, tolerability and ocular hypotensive efficacy of AKB-9778 Ophthalmic 
Solution 4.0% administered once (AM) or twice (AM & PM) daily when used as an adjunctive 
therapy to latanoprost ophthalmic solution 0.005% once daily (PM) in subjects with elevated IOP 
due to OAG or OHT.  
Subjects will participate in the study for up to approximately 11 weeks (Screening Visit, 
Washout period for 4-6 weeks, 2 Qualification Visits (2-7 days apart) and Treatment period for 
28 days).   
The study will be conducted at approximately 25 sites in the USA. 
Approximately 195 subjects will be randomized in this study and will be assigned in a 1:1:1 ratio 
to one of the following treatment groups: 
AKB-9778 QD + Latanoprost 
• AKB-9778 ophthalmic solution 4.0% QD (AM) and placebo for AKB-9778 
ophthalmic solution QD (PM) plus latanoprost ophthalmic solution 0.005% QD 
(PM) for 28 days 
 
AKB-9778 BID + Latanoprost  
• AKB-9778 ophthalmic solution 4.0% BID (AM & PM) plus latanoprost 
ophthalmic solution 0.005% QD (PM) for 28 days 
 
Latanoprost Monotherapy 
• Placebo for AKB-9778 ophthalmic solution BID (AM & PM) plus latanoprost 
ophthalmic solution 0.005% QD (PM) for 28 days 
During the treatment period, subjects will self-administer study medication (AKB-9778 
ophthalmic solution 4.0% or Placebo for AKB-9778) daily in the AM and PM and will also 
administer latanoprost daily in the PM.  Subjects will dose into each eye by the topical ocular 
route using dropper bottles to deliver eye drops. Daily AM dose administration of study 
medication should occur between 7:00 and 10:00 hours and PM dose administration should 
occur between 19:00 and 22:00 hours. Latanoprost PM dose administration will occur at least 5 
minutes before administration of the PM dose of study medication. Subjects will begin dosing 


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with the AM dose of study medication on the morning of Day 1 and conclude dosing after 
administration of the AM dose of study medication on Day 28; there is no PM dose 
administration on Day 28.  At study visits conducted on Days 14 and 28, subjects will administer 
the AM dose of medication at the site after the 8:00 ophthalmic assessments have been 
completed.  The Investigator, all study-site personnel, all Sponsor personnel (except for select 
personnel responsible for randomization scheme development and not involved with core study 
conduct), and subjects will be masked to treatment assignment during the entirety of the study.  
Subjects who agree to participate in this study and are randomized in the study will attend a total 
of 6 study visits: a Screening Visit, Qualification Visit #1, Qualification Visit #2/Day -1 
(Baseline), and visits on  Days 7, 14 and 28. Eligible subjects must be on a stable dose of topical 
prostaglandin eye drops (eg, bimatoprost [Lumigan®], latanoprost [Xalatan®], tafluprost 
[Zioptan®] and travoprost [Travatan Z®]) for at least 2 weeks prior to screening. After 
completion of the Screening Visit, subjects will undergo a minimum 4-week washout period 
from IOP lowering treatment prior to attending Qualification Visit #1. Among multiple 
procedures, subjects will receive an eye examination including IOP measurements at 
Qualification Visits #1 and #2/Day -1 and, if deemed eligible, will be enrolled at Qualification 
Visit #2/Day -1 and assigned treatment group according to a computer-generated randomization 
list. Randomization will take place using IWRS methodology and will stratify subjects by mean 
diurnal IOP (IOP averaged over 08:00, 10:00, 12:00, and 16:00 hour time points) on 
Qualification Vist#2/Day -1 (< 26 mmHg vs ≥ 26 mmHg) in the study eye.  
During the treatment period, subjects will be seen in the clinic on Days 7, 14 and 28; ocular 
safety assessments will be conducted on all days and efficacy measurements (IOP) will be 
conducted on Days 14 and 28 at the following time points: 08:00, 10:00, 12:00 and 16:00 hours. 
Following completion of the Day 28 study visit procedures, subjects will exit from the study. For 
subjects who discontinue early, every possible effort will be made to assure there is an exit visit 
that includes all required examinations listed for the Day 28 visit. Following completion of the 
study, subjects will return to the care of their ophthalmologist.  
At each study visit during the treatment period, multiple ocular safety assessments will be 
conducted including some or all of the following: adverse events, visual acuity, hyperemia 
assessment, objective findings of biomicroscopic examinations (i.e., lids, conjunctiva, cornea, 
anterior chamber, iris and lens), cup-disc ratio measurements, and dilated ophthalmoscopic 
examination. 
An interim analysis for futility is planned to be performed when 50% of randomized subjects 
have completed 28 days of therapy. 
6.2 
Rationale for Study Design  
This Phase 2 study is being conducted to assess the safety and ocular hypotensive efficacy of 
adding AKB-9778 QD or BID to latanoprost QD therapy for 28 days. In order to best evaluate 
the contributions of AKB-9778 to the ocular hypotensive efficacy of latanoprost, a parallel 
group, double-masked, three-arm study design was selected.  The information to be gained from 
this study is considered critical in the development of AKB-9778 as an IOP lowering medication. 
Results from this study will assist in design of subsequent clinical studies. 


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6.3 
Rationale for AKB-9778 Dose Selection and Frequency 
The AKB-9778 dose selected for this study is based on the recently completed Phase 1b study, 
AKB-9778-CI-OS-1001. The treatment period and dosing frequency is selected on the basis of 
nonclinical safety studies with AKB-9778 and regulatory requirements for demonstration of 
ocular hypotensive efficacy. 
In pre-clinical studies, a dose of 30 µL of a 40 mg/mL AKB-9778 formulation in 15% HPβCD in 
both eyes for 7 days demonstrated a consistent diurnal reduction in IOP in a normotensive rabbit 
model without exhibiting any systemic or significant local ophthalmic tolerability issues.  In 
addition, no systemic or serious local ocular findings were observed in 28-day GLP repeat-dose 
toxicity studies in rabbit and dog following bilateral topical ocular administration of 30 μL of 
40 mg/mL AKB-9778 in 15% HPβCD + 1% mannitol solution QD, BID, or QID for 28 
consecutive days. Preliminary data in dog following a 35 μL topical ocular dose of a 40 mg/mL 
AKB-9778 formulation in 15% HPβCD in both eyes of normotensive dogs for 5 days also 
suggest diurnal reduction in IOP with only mild hyperemia. Further, administration of AKB-
9778 immediately following topical ocular administration of latanoprost in dog appears to 
augment the IOP-lowering effect of latanoprost with a slight increase in the hyperemia observed 
with latanoprost alone and no other observed ocular changes. The 40 mg/mL AKB-9778 
formulation used in the rabbit and dog studies represents the highest formulation strength of 
AKB-9778 Ophthalmic Solution to be used in the clinical trial and was assessed for safety in the 
28-day toxicology studies at a high-dose QID dosing regimen, twice the highest daily dosing 
regimen (BID) to be used in clinical study. The dosing regimen in the clinical trial will be QD or 
BID at 4.0% w/v AKB–9778. The maximum total daily dose used in the repeat-dose toxicity 
study in rabbits and dogs (9.6 mg/day) is 2-fold the proposed highest dose in the clinical trial. 
The measured exposures in rabbit and dog at a total daily dose of 9.6 mg/day are estimated to be, 
respectively, at least 20- and 50-fold the measured human exposure (<1 ng/mL) following topical 
ocular administration of 4.8 mg/day (40 mg/mL AKB-9778 BID) in the Phase 1 study. The dose 
levels for the proposed study are selected to allow evaluation of tolerability and efficacy of 
AKB-9778 Ophthalmic Solution and are not expected to result in systemic adverse effects.   
In the Phase 1b clinical trial, AKB-9778 Ophthalmic Solution (40 mg/mL) both QD and BID 
dosing were well tolerated in ocular normotensive volunteers with a dose dependent increase in 
IOP reduction.  In OHT/OAG patients on standard of care prostaglandin therapy, QD dosing was 
well tolerated and resulted in significant IOP reduction.  Thus, based on the available preclinical 
and clinical data, both QD and BID dosing of AKB-9778 Ophthalmic Solution (40 mg/mL 
[4.0%]) will be studied. 
 
7.0 
STUDY POPULATION SELECTION 
7.1 
General Criteria 
Subjects will be recruited by the Investigative Sites.   


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To be eligible for this study, a subject must provide valid informed consent and must meet all of 
criteria outlined below.  No study procedures (including Screening tests) may be performed until 
after the informed consent has been legally signed. 
A Screening number will be allocated to each subject at the Screening visit.  If the subject 
qualifies for participation in the study, (s)he will be assigned a subject number.  If during the 
course of the screening tests and procedures, a subject does not meet the eligibility criteria or 
does not continue in the study, the subject will be considered a Screening failure (not a 
withdrawal). 
7.2 
Subject Eligibility and Study Eye Determination 
For a subject to be included in the study, at least one eye (the same eye) must meet ALL 
ophthalmic inclusion and no exclusion criteria through the screening period (Screening, 
Qualification 1 and Qualification 2 [Day -1] visits). If both eyes are eligible at Screening, and 
Qualification Visits #1 and #2, then the study eye will be the eye with the higher diurnal IOP on 
Qualification Visit #2/Day -1.  If both eyes have the same IOP at 08:00 hours on Qualification 
Visit #2, then the right eye will be the study eye.  
7.3 
Inclusion Criteria 
Subjects must meet all of the following criteria at screening and qualification visits to enter into 
the study. 
1. Males and non-pregnant, non-breast feeding females 
2. Aged ≥ 18 years  
3. Diagnosis of OAG or OHT in each eye (OAG in one eye and OHT in the fellow eye is 
acceptable) 
4. Must be treated with a stable regimen of topical prostaglandin eyedrop for a minimum of 2 
weeks prior to the Screening visit; may be taking one additional IOP lowering eyedrop (for 
the purposes of this inclusion criterion, a combination product is counted as a single 
eyedrop) 
5. IOP of ≥ 18 mmHg and ≤ 27 mmHg in one eye (study eye) or both eyes at the Screening 
Visit.  
6. Unmedicated (post-washout) IOP at 2 qualification visits 2-7 days apart meeting the 
following criterion.  At the first qualification visit, if tested at or before 10:00 hour, have 
IOP ≥ 24 mmHg in study eye or both eyes and < 36 mmHg in both eyes or if tested after 
10:00 hour, have IOP ≥ 22 mmHg in study eye or both eyes and < 36 in both eyes. At the 
second qualification visit, IOP ≥ 24 mmHg in study eye or both eyes and < 36 mmHg in 
both eyes at 08:00 hour and IOP ≥ 22 mmHg in study eye or both eyes and < 36 mmHg in 
both eyes at 10:00, 12:00 and 16:00 hours.   
7. Visual Acuity (VA) of +0.5 logarithm of the minimum angle resolvable (logMAR) (20/63 
Snellen) or better in each eye  
8. Must be willing and able to communicate and participate for the duration of the study 


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9. Ability to properly self-administer eye drops (or have a caregiver that can suitably 
administer eye drops) 
10. Must provide written informed consent 
7.4 
Exclusion Criteria 
Subjects meeting any of the following criteria during screening or qualification evaluations will 
be excluded from entry into the study: 
Ophthalmic: 
1. Clinically significant ocular disease (e.g., corneal edema, uveitis, severe 
keratoconjunctivitis sicca, diabetic macular edema, proliferative diabetic retinopathy, or 
neovascular age-related macular degeneration) which might interfere with interpretation of 
the study efficacy endpoints or with safety assessments  
2. Pseudoexfoliation or pigment dispersion component glaucoma 
3. History of angle closure glaucoma, or narrow angles (i.e., Shaffer Grade 2 or less; extreme 
narrow angle with complete or partial closure), or with evidence of peripheral anterior 
synechiae (PAS) ≥ 180 degrees by gonioscopy within 6 months prior to Screening visit in 
either eye. Note: Previous laser peripheral iridotomy is NOT acceptable 
4. Intraocular pressure ≥ 36 mmHg in either eye at the Screening Visit, Qualification Visit 
#1, or at any assessment on Qualification Visit #2/Day-1 (individuals who are excluded for 
this criterion are not allowed to attempt requalification) 
5. Cup/disc ratio of > 0.8 in either eye 
6. Severe visual field defect in either eye as assessed by the investigator, or significant defect 
(sensitivity of ≤ 10dB) within 10 degrees of fixation in either eye   
7. Known hypersensitivity to any component of the investigational formulations or to any 
topical prostaglandin eyedrop 
8. Selective laser trabeculoplasty (SLT) within the past 6 months or any history of argon laser 
trabeculoplasty (ALT) or minimally invasive glaucoma surgery (MIGS) in either eye 
9. Any history of radial keratotomy, corneal cross linking, photorefractive keratectomy 
(PRK), Laser-assisted in-situ keratomileusis (LASIK), or limbal relaxing incision (LRI) in 
either eye within 12 months prior to screening  
10. Any intravitreal injection within 30 days prior to screening or anticipated intravitreal 
injection during the course of the study 
11. Ocular trauma in either eye within the 6 months prior to screening, or ocular surgery or 
non-refractive laser treatment within the 3 months prior to screening 
12. Recent (within 90 days prior to screening) or current evidence of ocular infection or 
inflammation in either eye. Current evidence of clinically significant blepharitis, 
conjunctivitis, keratitis, or a history of herpes simplex or zoster keratitis in either eye at 
screening 


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13. Bulbar conjunctival hyperemia ≥3 (moderate) on the hyperemia scale (Section 9.2.2) in 
either eye at Screening, Qualification Visit #1 or at any assessment on Qualification Visit 
#2 (Baseline Visit) 
14. History of recurrent uveitis in either eye 
15. Use of ocular medication in either eye of any kind within 30 days of screening and 
throughout the study, with the exception of a) ocular hypotensive medications (which must 
be washed out according to the provided schedule), b) lid scrubs or warm compresses 
(which may be used prior to, but not after, screening), c) preservative or preservative-free 
lubricating drops (excluding gels or ointments) for dry eye (which may be used throughout 
the study at maximum frequency of QID), or d) non-steroid allergy drops (note: must not 
contain a vasoconstrictor)  
16. Mean central corneal thickness less than 480μm or greater than 600μm at screening in 
either eye 
17. Any abnormality preventing reliable applanation tonometry of either eye (e.g., 
keratoconus, corneal scarring) 
Systemic: 
18. Women who are pregnant or breast-feeding or intending to become pregnant during the 
study 
19. Women of child-bearing potential who are not on an acceptable method of birth control 
(e.g., 1 highly effective method [less than 1% failure rate] of contraception, or a 
combination of 2 effective methods of contraception). An adult woman is considered to be 
of childbearing potential unless she is one year post-menopausal or three months post-
surgical sterilization (excluding tubal ligation). All females of childbearing potential must 
have a negative urine pregnancy test result at the Screening Visit and Qualification Visit 
#2. 
20. History of any clinically significant disease or disorder which, in the opinion of the 
Investigator, may put the subject at risk because of participation in the study, influence the 
subject’s ability to participate in the study, or interfere with interpretation of the subject’s 
study results. Subjects with stable baseline medical conditions on established medication 
may be included as per the judgement of the Investigator; e.g., well controlled 
hypertension, type 2 diabetes, or mild, stable asthma not requiring treatment with inhaled 
corticosteroids.  
21. Systemic medication that could have a substantial effect on IOP within 30 days prior to 
screening, or anticipated during the study, including any corticosteroid-containing drug 
regardless of route of administration 
22. Use of an investigational medication or device within 30 days or 5-half-lives of the 
investigational medication, whichever is longer, preceding Day 1, or ongoing or scheduled 
participation in another investigational study during the present study through the last visit  
23. Previous treatment with AKB-9778 


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24. Subjects who are study site employees, or immediate family members of a study site or 
sponsor employee 
25. Failure to satisfy the Investigator of fitness to participate for any other reason 
7.5 
Withdrawal of Subjects 
All subjects have the right to withdraw from this study at any time.  In addition, it is the right of 
the Investigator to remove subjects from the study as a result of new symptoms, adverse 
reactions, protocol violation or for any other reason. Subjects will be discontinued from the study 
under any of the following circumstances: 
• IOP in either eye ≥ 36 at any timepoint during the study 
• Occurrence of intolerable AE, as assessed by the Investigator or designee 
• Withdrawal of consent 
• If, in the opinion of the Investigator, it is in the best interest of the subject 
• Non-compliance with study requirements and restrictions 
• Use of a concomitant medication that, in the opinion of the PI or designee, could 
interfere with the study procedures or data integrity or compromise the safety of the 
subject 
• Termination of the study 
Should a subject withdraw after administration of AKB-9778, or should the Investigator decide 
to withdraw the subject, all efforts will be made to complete and report the protocol-stipulated 
observations up to the time of withdrawal as thoroughly as possible.  A final evaluation at the 
time of the subject’s withdrawal should be made and an explanation given of why the subject is 
withdrawing or being withdrawn from the study.   
Subjects who discontinue prior to completion of all planned study assessments, should undergo 
the Day 28 assessments at time of discontinuation. 
The Investigator must document the primary reason for discontinuation of a study subject on the 
appropriate case report form (CRF). If the reason for withdrawal is a clinical AE, monitoring will 
continue until the AE resolves or the Investigator assesses the AE as chronic or stabilized. 
7.6 
Waivers 
No waivers will be granted in the study. 
7.7 
Replacement of Subjects  
No randomized subjects will be replaced.  


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8.0 
STUDY PRODUCT AND TREATMENT OF SUBJECTS 
8.1 
Study Medication, Latanoprost, Supplies and Storage 
The Investigator or designated study personnel will be responsible for study medication supply 
accountability and dispensing study medication to subjects.  
8.1.1 
Masked Study Medication: AKB-9778 Ophthalmic Solution and Matching 
Placebo 
AKB-9778 Ophthalmic Solution and matching placebo will be provided as masked, sterile, pre-
filled, single use dosing bottles packaged in kit boxes containing a one-week supply of study 
medication (seven “AM” dose bottles and seven “PM” dose bottles). Each dosing bottle is 
contained in a sealed foil pouch. Pouches contain a single dosing bottle to be used for binocular 
dose administration in the morning are labelled “AM” and pouches which contain a single dosing 
bottle to be used for binocular dose administration in the evening are labelled “PM”. Kits will be 
shipped by the Sponsor or its designated supplier/distributors to the Investigative site. 
AKB-9778 
AKB-9778 Ophthalmic Solution will be supplied as a clear, colorless to slightly yellow, 
buffered, isotonic, sterile unpreserved solution, essentially free of particulates, of AKB-9778 
(4.0% as the sodium salt) in a 5mM phosphate buffered vehicle (sodium phosphate, monobasic, 
monohydrate USP and sodium phosphate, dibasic anhydrous USP) containing 15% HPβCD, 
United States Pharmacopoeia (USP), and 1.2% mannitol, USP, and adjusted to a pH of 6.5 to 7.5 
with 1N Hydrochloric Acid and/or 1N Sodium Hydroxide.  The solution is filter sterilized and 
aseptically filled into single-use 1.0 mL LDPE sterile bottle suitable for ophthalmic delivery to 
which a sterile dropper tip is inserted (to deliver a ~30 uL drop), and then fitted with a sterile 
cap.  The completed dropper assembly is placed into a foil pouch, sealed, and labelled with the 
appropriate “AM” or “PM” designation.  
Placebo 
The placebo to match AKB-9778 Ophthalmic Solution will be supplied as a clear, colorless to 
slightly yellow, buffered, isotonic, sterile unpreserved solution, essentially free of particulates, of 
a 5mM phosphate buffered vehicle (sodium phosphate, monobasic, monohydrate USP and 
sodium phosphate, dibasic anhydrous USP) containing 15% HPβCD, USP, and 2.5% mannitol, 
USP, adjusted to a pH of 6.5 to 7.5 with 1N Hydrochloric Acid and/or 1N Sodium Hydroxide.  
The solution is filter sterilized and is packaged in the same primary container/closure system as 
outlined for AKB-9778 Ophthalmic Solution.    
8.1.2 
Storage and Handling of AKB-9778 and Placebo for AKB-9778 
At the investigational site, masked study medication kit boxes will be locked under controlled 
access and maintained at USP controlled room temperature, 20ºC - 25ºC (68ºF - 77ºF) with 
excursions between 15ºC to 30ºC (59ºF – 86ºF) permitted, which is documented by a suitable 
device. 


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The subject will be directed to store study medication in a secure location away from children at 
room temperature, 15ºC - 25ºC (59ºF - 77ºF).   
8.1.3 
Latanoprost  
Commercially available XALATAN® (latanoprost ophthalmic solution) 0.005% multi-use 
bottles (2.5 mL) will be provided by the Sponsor or its designated supplier/distributors to the 
Investigative site.  
Latanoprost ophthalmic solution 0.005% is a sterile, isotonic, buffered aqueous solution of 
latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. 
Each mL of latanoprost ophthalmic solution 0.005% contains 50 micrograms of latanoprost. 
Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are sodium 
chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, 
and water for injection. 
8.1.4 
Storage and Handling of Latanoprost 
At the investigational site, latanoprost ophthalmic solution (XALATAN) will be locked under 
controlled access and stored at refrigerated temperature (2°C to 8°C/36°F to 46°F) documented 
with a suitable device until provided to the subject. 
The subject should be instructed that, once the latanoprost product bottle is opened, the product 
may be kept at room temperature (up to 25°C/77°F) while continuing to store the bottle in the 
carton for the duration of the study. 
8.2 
Dispensing Procedures 
The Investigator will maintain drug accountability forms itemizing all latanoprost and masked 
study medication dispensed to and returned from each subject during the study.  
Randomization to treatment group and assignment of study medication kits for dispensing will 
be made using an interactive web response system (IWRS). 
On Day -1, all subjects will be dispensed a single carton of latanoprost ophthalmic solution 
sufficient for 28 days of dosing. 
On the Day -1 and the Day 14 visits, subjects will be provided with study medication which is 
packaged in study medication kit boxes. Each study medication kit box contains a one-week 
supply of study medication.  During the Day -1 and Day 14 visits, sufficient supply for 2 weeks 
of dosing plus one week of overage to allow for some flexibility in study visit scheduling are 
dispensed.   
Subjects should discard used study medication bottles after each binocular dose administration 
into a zip lock bag provided by the site.  At the Day 14 and Day 28 visits, subjects will return 
unused (unopened) study medication bottles and empty (or partial) kit boxes to the site for drug 
accountability.  Latanoprost is provided in a multiuse format and is not discarded after dosing.  


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The subject will bring the latanoprost to the Day 14 and Day 28 site visits. The returned empty 
(or partial) study medication kit boxes and returned latanoprost should be available for the 
monitor to verify during an interim monitoring visit.  
Subject dosing diaries should be returned at each study visit and subjects should be questioned 
regarding dosing compliance and whether they have questions or have experienced any problems 
related to the dosing of study medication or latanoprost.   
All unused study medication should be retained at the investigative site and must be returned to 
the Sponsor or its designee for destruction at the end of the study.  If an investigative site has 
SOPs for destruction of study medication on site; following review of the procedure, the Sponsor 
may authorize destruction of study medication at the investigative site once accountability 
procedures have been completed.  
8.3 
Treatment of Subjects 
The Treatment period will last 28 days. 
8.3.1 
Treatment Group Assignments 
Subjects meeting all eligibility criteria will be randomized 1:1:1 to one of the following 3 
treatment groups: 
 
AKB-9778 QD + Latanoprost 
• AKB-9778 Ophthalmic Solution 4.0% QD (AM) and placebo for AKB-9778 ophthalmic 
solution QD (PM) plus latanoprost ophthalmic solution 0.005% QD (PM) for 28 days 
AKB-9778 BID + Latanoprost  
• AKB-9778 Ophthalmic Solution 4.0% BID (AM & PM) plus latanoprost ophthalmic 
solution 0.005% QD (PM) for 28 days 
Latanoprost Monotherapy 
• Placebo for AKB-9778 ophthalmic solution BID (AM & PM) plus latanoprost 
ophthalmic solution 0.005% QD (PM) for 28 days 
8.3.2 
Randomization and Allocation to Treatment Group 
Approximately 195 subjects will be treated in the study. 
A randomization code for treatment allocation will be prepared by an independent biostatistician, 
who is not involved in the day-to-day conduct of the study. Using a central IWRS randomization 
system, eligible subjects will be assigned in a 1:1:1 ratio to one of the 3 treatment groups.  To 
maintain balance between treatment groups randomization will be stratified by mean diurnal IOP 
on Day -1 (< 26 mmHg vs ≥ 26 mmHg) in the study eye.  Study medication kits will be allocated 
via the IWRS system. 


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8.4 
Masking 
This study will be conducted in a double-masked manner.   
Study medication will be shipped as masked supplies.   
Commercially available latanoprost will be provided in an unmasked manner to sites.  
Treatment group assignment will be done through a central randomization system and completed 
using an IWRS.   
Treatment assignments will be masked to the Investigator, the clinical study team (Sponsor, 
personnel involved in day to day study management, Data Managers, and Statisticians), and the 
subjects prior to all subjects completing treatment. Treatment assignment(s) will be unmasked 
and made available to the Investigator and the Sponsor’s Medical Monitor only in case of 
medical emergency or occurrence of adverse events that in the opinion of the Investigator 
warrant unmasking. In the absence of medical need, the randomization code/treatment 
assignment(s) will not be available to the above study personnel until after the study is 
completed and the database is locked. 
8.5 
Unmasking 
Unmasking of the Investigator is restricted to emergency situations and should only be used 
under circumstances where knowledge of the treatment is necessary for the proper management 
of the subject.  When possible, the Investigator should first discuss the unmasking request with 
the Sponsor and or Medical Monitor prior to unmasking.  If treatment is unmasked, the subjects 
should be discontinued from the study, and the appropriate early termination visit procedures 
conducted per protocol requirements.  
8.6 
Study Medication and Latanoprost Administration 
Subjects will be responsible for self-administering study medication and latanoprost. For subjects 
deemed unable to self-administer, a caregiver can administer the study medication and 
latanoprost provided the caregiver has received documented training from the investigative site. 
On the Qualification Visit #2/Day -1 visit, subjects will be trained on study medication kits and 
instructions for dosing and diary completion for study medication and latanoprost. If necessary, 
subjects can undergo additional eye drop training during their Day -1 visit.  
During the treatment period, subjects will administer the study medication daily in the AM and 
PM to both eyes and will also administer latanoprost daily in the PM to both eyes. Daily AM 
dose administration of study medication  should occur between 7:00 and 10:00 hours and PM 
dose administration of study medication should occur between 19:00 and 22:00 hours. 
Latanoprost PM dose administration will occur at least 5 minutes before administration of the 
PM dose of study medication. Subjects will begin dosing with the AM dose of study medication 
on the morning of Day 1 and conclude dosing after administration of the AM dose of study 
medication on Day 28; there is no PM dose administration on Day 28.  At visits conducted on 
Days 14 and 28, subjects should not dose the AM dose of study medication at home and will 


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administer the AM dose of study medication at the site after the 8:00 hour assessments have been 
completed.  
At completion of the study on Day 28, the subject will return to OAG/OHT treatment per the 
care of their ophthalmologist.  
Subjects will dose study medication and latanoprost by instilling one drop of medication into 
each eye. Subjects will maintain a dosing diary noting date and time of study mediation and 
latanoprost dosing. If a subject forgets to administer a dose, that dose should be skipped, and 
noted along with the reason why in the dosing diary.  If an administered dose misses the eye, that 
dose should not be repeated and the diary properly noted to indicate the surface of the eye was 
missed.   
Contact lens wear during the study is acceptable. However, subjects must remove their contact 
lenses at least 15 minutes before instillation of masked study medication or latanoprost, and not 
place contact lenses in their eye(s) until a minimum of 15 minutes after instillation.  On days of 
study visits, subjects should not wear contacts until the study visit is completed.  
8.7 
Concomitant Medication 
Intermittent use of over-the-counter (OTC) artificial tear lubricant products is acceptable 
(including preservative and preservative-free), with a minimum of 10 minutes between use of 
OTC products and study medication and latanoprost.  
All subjects will self-dose concomitant latanoprost QD (PM) provided by the Sponsor during the 
treatment period. The latanoprost evening dose will be administered at least 5 minutes before the 
evening dose of study medication.  
With the exception of latanoprost dosing which begins on Day 1, concurrent therapy with any 
form of ocular hypotensive medications (prescription or OTC) is not allowed during the study.  
Disallowed concomitant ocular medications for randomized subjects include: 
• Miotics 
• Epinephrine-related compounds 
• Carbonic anhydrase inhibitors (ocular or systemic) 
• β-adrenoceptor agonists 
• β-adrenoceptor antagonists 
• Muscarinic agonists (e.g., pilocarpine) 
• Rho kinase inhibitors 


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• Prostaglandin analogues other than that which may be contained in the provided 
investigational product 
• Any corticosteroid-containing systemic drug regardless of route of administration 
Systemic therapy with agents that could have an effect on IOP is to be consistent in dose, 
regimen and agent within the 30 days prior to screening and throughout the study. For example, a 
subject can be treated with a systemic β-adrenoceptor antagonist as long as the particular agent 
and its dose and regimen had been consistent for the 30 days prior to screening, and there is no 
reason to believe that alteration would be necessary at some point later during the study. PRN 
use of systemic or inhaled corticosteroid-containing therapies is not allowed. Subjects should be 
cautioned to avoid use of alcohol during the study visit days and use of drugs such as marijuana. 
Use of all medications should be documented on the appropriate Electronic Case Report Form 
(eCRF). Investigators are encouraged to contact the Sponsor for any questions regarding allowed 
medications. 
Judgment of continued study participation by any randomized subject, and inclusion of this 
subject’s subsequent visits in the safety and efficacy analysis, will be made by the Sponsor. 
All medications which the subject has taken within 30 days prior to screening and during the 
study will be recorded in the eCRF. The name of the drug, dose, route of administration, duration 
of treatment, and indication will be recorded for each medication. For combination products 
(e.g., Contac®), the brand name is required. For non-combination products, the generic name is 
desired. Any change in dosing parameters should also be recorded in the eCRF. 
The use of routine ophthalmic diagnostic pharmaceutical agents (e.g., fluorescein and local 
anesthetic) will be allowed and individual documentation is not required. 
8.8 
Restrictions 
8.8.1 
Prior Therapy and Washout 
Prior use of AKB-9778 or study participation in a prior Aerpio Pharmaceuticals Inc., study 
which studied the AKB-9778 investigational product is exclusionary. 
Eligible subjects must be on a stable dose of topical prostaglandin eye drops (for at least 2 weeks 
prior to Screening).  After completion of the Screening Visit, subjects must undergo a minimum 
4-week washout period from IOP lowering treatment prior to attending Qualification Visit #1.  If 
washout is to be extended beyond 6 weeks (42 days) for logistical or other reasons, the Sponsor 
should be contacted.  
8.8.2 
Fluid and Food Intake 
There are no general restrictions on fluid or food intake for subjects participating in this study. 


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8.8.3 
Subject Activity Restrictions 
On study visit days during which diurnal IOP measurements are made, subjects may not engage 
in strenuous activity. Otherwise, there are no restrictions on subject activities during their 
participation in this study. 
8.9 
Treatment Compliance 
Subjects will be instructed on the importance of following their daily dosing regimen. Dosing of 
AM study medication should occur in the morning between 7:00 and 10:00 hours.  Dosing of 
latanoprost and PM study medication should occur in the evening between 19:00 and 22:00 
hours with the latanoprost dose administered at least 5 minutes prior to the dose of PM study 
medication. 
Intermittent interruption of dosing is discouraged, whether initiated by the Investigator or the 
subject. Subjects should contact the Investigator before interrupting treatment, and Investigators 
should contact the Sponsor. 
Subjects will complete a provided dosing diary worksheet to record dosing of study medication 
and latanoprost.  Dosing diaries will be reviewed at each visit. 
8.10 
Product Accountability and Destruction  
Product accountability should be an ongoing process throughout the study.  All bulk study 
medication and latanoprost must be accounted for and any discrepancies explained.   
Proper drug accountability includes, but is not limited to: 
• Continuously monitoring expiration dates if expiry date or retest date is provided to the 
Investigator. 
• Frequently verifying that actual inventory matches documented inventory. 
• Verifying that the master drug log is completed for all study medication and latanoprost 
received at the site and that all required fields are complete, accurate, and legible. 
• Review of temperature log, and that the study medication and latanoprost is stored in 
locked access controlled conditions. 
• Verifying the subject individual drug accountability log is completed for each subject and 
that all required fields (units dispensed, returned, used, compliance) etc., are complete 
accurate and legible. 
• Verifying at each study visit, the subject has completed the dosing diary, and any doses 
missed or not administered are properly documented and explained if necessary.  
Compliance to the dosing regimen should be verified and documented by the site at each 
visit by review of the diary and returned study medication kits. 


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If any dispensing errors or discrepancies are discovered, the Sponsor must be notified 
immediately. 
Prior to site close-out, a representative from the Sponsor will perform clinical study material 
accountability and reconciliation. 
At the end of the study, the Investigator will retain all the original documentation regarding 
clinical study material accountability, return, and/or destruction, and copies will be sent to the 
Sponsor. 
The Investigator or designated study personnel is responsible for keeping accurate records of the 
study medication and latanoprost received from the Sponsor or its designee, all supplies retained 
in inventory at the site, and study medication and latanoprost dispensed to and returned from 
each subject.  This record will be maintained on a Drug Accountability Log that accurately 
reflects the accountability of the study medication and latanoprost at all times. 
During the study, the Investigator will be notified of any expiry dates or retest date extensions of 
study medication or latanoprost.  If an expiry date notification is received during the study, the 
site must complete all instructions outlined in the notification, including segregation of expired 
study material for return to the Sponsor or its designee for destruction. 
At the end of the study, any unused study medication or latanoprost must be returned to the 
Sponsor or its designee for destruction.  If an investigative site has SOPs for destruction of 
clinical trial material on site, the Sponsor may authorize destruction of at the investigative site 
following completion of accountability procedures.  
9.0 
STUDY PROCEDURES  
Please see Appendix 1 for a detailed table of the Schedule of Activities. 
9.1 
Administrative Procedures 
9.1.1 
Informed Consent 
Informed consent must be obtained prior to the subject entering into the study and before any 
protocol-directed procedures are performed (see Section 16.3).  
9.1.2 
Documentation of Screen Failures 
The Investigator or designee must account for all subjects who sign informed consent and will 
maintain a log of subjects screened and indicate who was randomized or screen failed.  If the 
subject is found to be ineligible prior to randomization, the reason(s) for ineligibility must be 
documented.  Screening numbers assigned to subjects who fail screening will not be re-used.   


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9.1.3 
Contraception and Pregnancy Avoidance Measures 
Due to the unknown effects of AKB-9778 Ophthalmic Solution on sperm and the developing 
fetus, all subjects must agree to use adequate contraception throughout the study and for 3 
months after administration of last dose of study medication. 
Adequate contraception is defined as follows: 
Male subjects must agree to use a reliable method of birth control and to not donate sperm during 
the study and for 3 months following the last dose of study medication.   
• Examples of reliable methods of birth control are condoms with spermicide; effective, 
highly effective, or surgical contraceptive method by the female partner; and male 
sterilization such as bilateral orchiectomy or vasectomy. 
Male subjects exclusively with women of non-childbearing potential partners are not required to 
use contraception. 
Female subjects of child-bearing potential must agree to use 1 highly effective method (less than 
1% failure rate) of contraception, or a combination of 2 effective methods of contraception for 
the entirety of the study and for 3 months following the last dose of study medication. 
• Highly effective methods of contraception: Combination oral contraceptives, 
implanted/injectable contraceptives, intrauterine device, bilateral tubal ligation, or 
permanent tubal occlusion. 
• Effective methods of contraception: Male or female condoms with spermicide, 
diaphragms with spermicide, or cervical sponges.  The subject may choose to use a 
double-barrier method of contraception.  Barrier protection methods without concomitant 
use of a spermicide are not a reliable or acceptable method.  Thus, each barrier method 
must include use of a spermicide.  It should be noted that the use of male and female 
condoms as a double-barrier method is not considered acceptable due to the high failure 
rate when these methods are combined.   
Female subjects not of child-bearing potential may participate and include those who are: 
• Infertile due to a congenital anomaly such as mullerianagenesis. 
• Surgical sterility such as hysterectomy, bilateral oophorectomy, or bilateral 
salpingectomy. 
• Post-menopausal: defined as a woman at least 50 years of age with an intact uterus, not 
on hormone therapy, who has had cessation of menses for at least 1 year. 


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9.2 
Study Procedures and Evaluations 
Please see the Schedule of Activities presented in Appendix 1 for designated time points for 
assessments. 
9.2.1 
Clinical Evaluations 
The following section details clinical evaluations which will be conducted during the course of 
the study.   
• Medical history and demographics:  Medical history and demographic information will 
be collected at the Screening visit.  Interim medical history will also be collected at 
Qualifying Visits #1 and #2.  Relevant medical history (with particular emphasis on 
previous medical conditions that may lead to exclusion) and significant ongoing medical 
conditions or diseases should be documented.  
• Adverse Event Assessments:  From the time of informed consent through study 
completion Day 28, the Investigator and study personnel will review all ophthalmic and 
clinical findings and query the subject directly regarding AEs.  Subjects must be followed 
for AEs until the final required protocol visit or until all drug-related toxicities and 
serious adverse events have resolved (or are considered chronic/stable), whichever is 
later.  
• Concomitant Medication Recording:  All medications, both prescription and non-
prescription, and including vitamins, herbals, topicals, inhaled, and intranasal, taken 
within 30 days prior to screening and though Day 28, should be recorded on the 
appropriate eCRF.  All medications and treatments, including vitamin supplements, OTC 
medications, and oral herbal preparations must be recorded in the eCRFs. 
9.2.2 
Ophthalmic Assessments (listed in order of assessment) 
Further information on the conduct of the following procedures can be found in the study 
specific operations manual. Assessments are listed in suggested order of conduct when 
conducted on same visit.  
• Visual Acuity: VA and pinhole visual acuity will be performed as a measure of ocular 
function and will be measured at Screening and frequently throughout the study. 
• Visual Field Testing: Visual field testing must be performed within 3 months prior to 
randomization. Visual fields must be determined as automated threshold perimetry (e.g., 
30-2 or 24-2 Humphrey). Swedish interactive threshold algorithm (SITA) Standard is 
preferred, SITA fast also is allowed. Visual fields must be reliable, defined as those with 
a) fixation losses ≤ 33%, b) false positives ≤33%, and c) false negatives ≤33%. 


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• Biomicroscopy: A slit lamp biomicroscopy examination of the lids, conjunctiva, cornea, 
anterior chamber, iris and lens of both eyes will be conducted at Screening and selected 
subsequent visits. 
• Bulbar Conjunctival Hyperemia Assessment & Grading:  Bulbar conjunctival hyperemia 
will be assessed for both eyes at Screening, Qualification Visits #1 and #2, and frequently 
throughout the study.  All hyperemia assessments coincide with a timed IOP evaluation.  
The hyperemia assessment and grading must be evaluated prior to the use of any ocular 
drops required for the IOP procedure.  The Investigator will evaluate (grade) conjunctival 
hyperemia using the scale presented below. Note: An increase of 2 or more grades on the 
hyperemia scale when compared to the lowest score recorded at any previous timepoint 
for an individual eye should be reported as an adverse event. If a subject complains of 
hyperemia, an AE will be recorded regardless of grade on the hyperemia scale.  
 
 
 
• Intraocular Pressure (IOP): IOP will be assessed by calibrated Goldmann applanation 
tonometry. IOP assessments are conducted as follows: measure twice, with 3rd measure 
if discordant (i.e. previous two readings >2mmHg different). The IOP used at each time 
point is the mean of 2 measurements or the median of 3 measurements. IOP will be 
measured at Screening, Qualification Visit #1 and #2 and frequently throughout the 
study. Note: For purposes of determining eligibility, any non-integer (non-whole 
number) mean IOP should not be rounded (e.g. if the mean of 2 IOP readings is 23.5 
do not round up to 24). 
• Pachymetry: Pachymetry (contact or non-contact method) will be performed at Screening 
and Day 28 and will be used to measure the thickness of the central cornea. 
• Gonioscopy: Gonioscopy will conducted at Screening to confirm the iridocorneal angle is 
open and to what extent. Eligible subjects must have an angle of 3 or 4 (Shaffer grading 
scale; Kolker 1976) for participation in the study. 
• Dilated Ophthalmoscopy: A dilated funduscopic examination including evaluation of the 
retina, vitreous, macula, choroid, optic nerve, and cup/disc ratio will be performed at 
Screening and Day 28. Evaluation of cup-disc ratio will be performed when 
ophthalmoscopy is performed.   
 
Efron 


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9.2.3 
Laboratory Evaluations 
The following laboratory evaluations will be conducted during the course of the study: 
Pregnancy test:  A urine pregnancy test will be performed at Screening, Qualification 
Visit #2/Day -1 and Day 28 for females of childbearing potential.   
The Sponsor will provide urine pregnancy tests to the sites. Expiration dates on the pregnancy 
tests will be reviewed and confirmed by the site prior to use. 
If a female becomes pregnant during the study or within 3 months after administration of last 
dose of study medication, the Investigator should notify the Sponsor immediately after the 
pregnancy is confirmed (Section 11.4) and the subject will stop taking study medication and 
every possible effort will be made to assure there is an exit visit that includes all required 
examinations listed for the Day 28 visit. The Investigator should follow the progress of the 
pregnancy until the fetus is carried to term. 
 
10.0 
SCHEDULE OF ACTIVITIES 
The Schedule of Activities is presented in Appendix 1 and shows the timing of planned study 
procedures to occur at the study site.  Every effort should be made to adhere to the procedure 
schedule and all assessments should be completed at each study visit. 
Subjects will be responsible for self-administration of study medication and latanoprost.  As 
detailed in Section 8.6, subjects will self-dose study medication BID on a morning and evening 
schedule and latanoprost QD on an evening schedule.  Subjects will begin dosing with the AM 
dose of study medication on the morning of Day 1 and conclude dosing after administration of 
the AM dose of study medication on Day 28; there is no PM dose administration on Day 28.  
Subjects discontinuing study medication sooner than the planned 28 day dosing period or 
withdrawing from the study should complete the Day 28 assessments and return all unused study 
medication.  
Detailed descriptions of procedures and activities to be followed during each site visit are 
presented in the following sections.  For specific time points please refer to the Schedule of 
Activities in Appendix 1.   
10.1 
Visit Windows and Study Days 
Clinical and ophthalmic evaluations performed during the Treatment period must be conducted 
within ± 30 minutes of the designated time.  IOP and hyperemia assessments conducted at 8:00, 
10:00, 12:00 and 16:00 hours must be conducted at a minimum of the protocol prescribed 2- or 
4- hour interval (e.g. a minimum of at least 2 hours should occur between the 8:00 and 10:00 
hour assessments and a minimum of at least 4 hours should occur between the 12:00 and 16:00 
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Daily AM dose administration of study medication should occur between 7:00 and 10:00 hours 
and PM dose administration of study medication and latanoprost should occur between 19:00 
and 22:00 hours. If a dose is missed, this dose should be skipped, and the subject should maintain 
the morning and evening dosing schedule. 
At the site visits on Day 14 and 28, the subject will administer AM study medication  at 08.00 (± 
30 min) and will be administered after 8:00 hour ophthalmic assessments are conducted.   
Site visits scheduled for Day 7, 14 and 28 should be conducted within ±3 days relative to the 
Day -1 Visit (i.e., Day 7 visit window is 7 ±3 days from Day -1, Day 14 visit window is 14 ±3 
days from Day -1 and Day 28 visit window is 28 ±3 days from Day -1).   
Study days will be numbered relative to the first day of dosing.  The start of study (Day 1) will 
be defined as the date on which a subject takes the first dose of any study medication, as 
recorded on the CRF. Relative to study start, days will be numbered …..-2, -1, 1, 2… with 
Day -1 being the day prior to the start of study medication. 
10.2 
Visit 1 (Screening Visit) 
This visit may occur at any time of the day. 
The Investigator or designee will maintain a log of subjects screened and indicate who was 
randomized or excluded and the reason for exclusion. 
At Visit 1, the following activities/procedures will be performed: 
• Informed consent  
• Assignment of screening number 
• Review of eligibility criteria 
• Demographics 
• Medical & Ophthalmic History 
• Prior and concomitant medications 
• Urine pregnancy test (for women of childbearing potential) 
• AE monitoring 
• Ophthalmic examination to include  
o Visual Acuity 
o Visual Field Testing 
 If assessment of visual fields requires dilation due to subject small pupils, 
visual field testing should not take place within 48 hours of Visit 2 
(Qualification Visit #1) 
o Biomicroscopy  


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o Bulbar Conjunctival Hyperemia Assessment 
o IOP (before pupil dilation)  
 IOP ≥ 18mmHg and ≤ 27mmHg in one (study eye) or both eyes at this 
visit. 
o Pachymetry 
 Pachymetry within one week of screening is acceptable. 
o Gonioscopy 
 Gonioscopy and visual fields may be assessed up to three months (i.e., 
within 90 days) prior to randomization.  
o Dilated Ophthalmoscopy  
• Begin Washout. All individuals who are qualified for enrollment at this study visit will 
undergo a washout period from IOP lowering treatment as noted in Section 8.8.1 and will be 
asked to return for Visit 2 (Qualification Visit #1).   
10.2.1 
Washout 
As noted in Section 8.8.1, a washout period from IOP lowering treatment is required for all 
subjects. The Investigator is encouraged to have interim visits during the washout period for IOP 
measurements for individuals to whom a washout period may be a risk for further glaucomatous 
progression. 
10.2.2 
Visit 2 (Qualifying Visit #1, For IOP measurement at any hour) 
This visit may occur at any time of the day. After washout of ocular hypotensive medication is 
completed subjects will return to the Investigator’s office for the first IOP qualifying visit.  
This visit should take place no later than 42 days after the screening visit.  
The following activities/procedures will be performed: 
• Review of eligibility criteria 
• Medical & Ophthalmic History 
• Prior and concomitant medications 
• AE monitoring 
• Visual Acuity 
• Bulbar Conjunctival Hyperemia assessment 
• IOP 
IOP measurements (Unmedicated (post-washout)):  


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• 
if tested at or before 10:00 hour: IOP ≥ 24 mmHg in study eye or both eyes 
 OR 
• 
if tested after 10:00 hour: IOP ≥ 22 mmHg in study eye or both eyes 
AND 
• 
 IOP <36 in both eyes at this qualification visit 
This is the first of five qualifying IOPs for randomization.  
Subjects who do NOT meet the IOP requirement may return for up to 2 additional (unscheduled) 
qualification visits within 1 week of failing this qualification visit. Subjects returning at an 
unscheduled visit within 1 week are required to only re-measure IOP in both eyes. Individuals 
who screen fail due to IOP being ≥ 36 mmHg in either eye at this study visit or at an unscheduled 
visit within 1 week of the original visit MAY NOT return for additional qualification visits and 
are to be exited from the study. 
Qualified individuals who have met all criteria at this study visit will be scheduled to return 2-7 
days later for the second qualification visit. 
10.2.3 
Visit 3.0 (Qualifying Visit #2 [Day -1] for IOP measurement at 08:00 hours) 
Two to 7 days after Visit 2, individuals will return to the Investigator’s office in the morning for 
an 08:00 hour IOP measurement.  Subjects will be questioned regarding any changes in their 
health or concomitant medication use. Any change in the individual’s health relative to their 
Visit 1 (screening) or Visit 2 health status and concomitant medication use should be recorded on 
the Medical History page of the eCRF (e.g., the subject has been diagnosed with cancer).   
Inclusion/exclusion criteria will be reviewed again for the qualified individual. 
The following procedures will be performed: 
• Review of eligibility criteria 
• Medical & Ophthalmic History 
• Urine pregnancy test (for women of childbearing potential). Maybe conducted at any 
time prior to randomization.  
• Prior and concomitant medications 
• AE monitoring 
• Visual Acuity 
• Biomicroscopy 
• Bulbar Conjunctival Hyperemia assessment 


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• IOP 
o IOP must be measured within 30 minutes of the nominal time (i.e., 07:30 to 08:30 
hours).  
o For further participation in the study, unmedicated IOP at this time (8:00 hour, 
Day -1) must be ≥ 24 mmHg in study eye or both eyes and < 36 mmHg in both 
eyes. 
This is the second of five qualifying IOPs for randomization. 
Qualified individuals will continue with the measurements of IOP at 10:00 hours, 12:00 hours, 
and 16:00 hours on the day of this study visit. Individuals who do NOT meet the above IOP 
requirement in both eyes may return for up to 2 additional (unscheduled) qualification visits 
within 1 week of failing this qualification visit. Individuals returning at an unscheduled visit 
within 1 week are required to only re-measure IOP in both eyes. Upon return for an unscheduled 
qualification visit, such individuals’ IOP measurements would need to qualify in both eyes at 
each of 08:00, 10:00, 12:00 and 16:00 hours. Individuals who fail due to IOP being ≥ 36 mmHg 
in either eye (exclusion criterion) at any of these time points at this study visit or at an 
unscheduled visit within 1 week of the original visit MAY NOT return for additional 
qualification visits. 
Individuals are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink with no restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.4 
Visit 3.1 (Qualifying Visit #2/Day -1, for IOP measurement at 10:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. Qualified 
individuals will be examined.  Each examination will include: 
• AE Monitoring 
• Bulbar Conjunctival Hyperemia assessment 
• IOP 
o IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours) 
• 
IOP should be conducted at a minimum of the protocol prescribed 2-
hour interval (i.e., ≥ 2-hours) 
o For further participation in the study, unmedicated IOP at this time (10:00 hours, 
Day -1) must be ≥22 mmHg in the study eye or both eyes and < 36 mmHg in 
both eyes.  
This is the third of five qualifying IOPs for randomization. 
Qualified individuals will continue with the qualification visit.  Individuals who do NOT meet 
this requirement in both eyes may return for up to 2 additional unscheduled qualification visits 


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within 1 week of failing this qualification visit.  Individuals returning at an unscheduled visit 
within 1 week are required to only re-measure IOP in both eyes. Upon return, such individuals 
would need to qualify at 08:00, 10:00, 12:00 and 16:00 hours. Individuals who fail due to IOP 
being ≥ 36 mmHg in either eye (exclusion criterion) at any of these time points at this study visit 
or at an unscheduled visit within 1 week of the original visit MAY NOT return for additional 
qualification visits. 
At this and any other in-office visit, any subject complaining of visual function issues will have 
visual function assessed as judged appropriate by the Investigator. 
Individuals are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.5 
Visit 3.2 (Qualifying Visit #2/Day -1, for IOP measurement at 12:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. Qualified 
individuals will be examined.  Each examination will include: 
• AE Monitoring 
• Bulbar Conjunctival Hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 011:30 to 
12:30 hours) 
• 
IOP measurement should be conducted at a minimum of the protocol 
prescribed 2-hour interval (i.e., ≥ 2-hours) 
o For further participation in the study, unmedicated IOP at this time (12:00 hour, 
Day -1) must be ≥22 mmHg in the study eye or both eyes and < 36 mmHg in 
both eyes.  
At this and any other in-office visit, any subject complaining of visual function issues will have 
visual function assessed as judged appropriate by the Investigator. 
This is the fourth of five qualifying IOPs for randomization. 
Qualified individuals will continue with the qualification visit.  Individuals who do NOT meet 
this requirement in both eyes may return for up to 2 additional unscheduled qualification visits 
within 1 week of failing this qualification visit.  Individuals returning at an unscheduled visit 
within 1 week are required to only re-measure IOP in both eyes. Upon return, such individuals 
would need to at 08:00, 10:00, 12:00 and 16:00 hours. Individuals who fail due to IOP being ≥ 
36 mmHg in either eye (exclusion criterion) at any of these time points at this study visit or at an 
unscheduled visit within 1 week of the original visit MAY NOT return for additional 
qualification visits. 


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At this and any other in-office visit, any subject complaining of visual function issues will have 
visual function assessed as judged appropriate by the Investigator. 
Individuals are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.6 
Visit 3.3 (Qualifying Visit #2/Day -1, for IOP measurement at 16:00 hours) 
Inclusion/exclusion criteria will be reviewed again for the qualified individual. 
Qualified individuals will be examined.  Each examination will include: 
• AE Monitoring 
• Bulbar Conjunctival Hyperemia Assessment 
• IOP   
o IOP must be measured within 30 minutes of the nominal time (i.e., 15:30 to 
16:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 4-hour interval (ie, ≥ 4-hours) 
o For further participation in the study, unmedicated IOP at this time (16:00 hour, 
Day -1) must be ≥22 mmHg in the study eye or both eyes and < 36 mmHg in 
both eyes.  
This is the fifth of five qualifying IOPs for randomization. 
Individuals who do NOT meet this requirement in both eyes may return for up to 2 additional 
unscheduled qualification visits within 1 week of failing the first qualification visit. 
Individuals returning at an unscheduled visit within 1 week are required to only re-measure IOP 
in both eyes. Upon return, such individuals would need to qualify at 08:00, 10:00 and 16:00 
hours. Individuals who fail due to IOP being ≥ 36 mmHg in either eye (exclusion criterion) at 
any of these time points at this study visit or at an unscheduled visit within 1 week of the original 
visit MAY NOT return for additional qualification visits. 
If both eyes qualify, the study eye will be the eye with the higher mean diurnal IOP on Visit 3 
(Qualification Visit #2/Day -1). If both eyes have the same mean diurnal IOP on Visit 3, then the 
right eye will be the study eye. In each subject, BOTH eyes will be treated. 
At this point, eligible subjects will be enrolled and assigned to an investigational product through 
an IWRS system. Study medication kits numbers will be assigned through the IWRS system and 
study medication and latanoprost will be dispensed to subjects.   
 


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Subjects will: 
• Receive instructions for dosing study medication and latanoprost, review study 
medication kits and be trained on dosing diary completion.  
• Be instructed to begin self-administration of study medication and latanoprost on the AM 
and PM schedule, starting with AM dosing of study medication on the next day (Day 1). 
• Be instructed to return to the office with their dosing diary and study medication kits and 
latanoprost bottle at Day 7. 
10.2.7 
Visit 4 (Day 7, for IOP measurement at any hour) 
This visit may occur at any hour. Subjects will return to the Investigator’s office with their 
dosing diary. The subject will be questioned about any missed doses and any changes in their 
health or concomitant medication use. 
The following assessments will be conducted: 
• AE Monitoring 
• Conmeds 
• Visual Acuity 
• Bulbar Conjunctival Hyperemia Assessments 
• IOP  
• Dosing diary review will be conducted. Used medication kits will be collected and 
retained by the site.  The latanoprost bottle is retained/re-dispensed. 
Subjects will be: 
• Instructed to return to the office with their dosing diary and study medication kits and 
latanoprost bottle at Day 14. 
• Instructed that they will dose their AM dose of study medication at the study site on Day 
14. 
10.2.8 
Visit 5.0 (Day 14, for IOP measurement at 8:00 hours) 
Subjects will return to the Investigator’s office with study medication kits, latanoprost bottle and 
dosing diary. The subject will be questioned about any missed doses and any changes in their 
health or concomitant medication use. Subjects will dose the Day 14 AM dose of study 
medication following completion of the 8:00 hour ophthalmic assessments. 


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Subjects will be examined. Each examination will include: 
• AE Monitoring 
• Conmeds 
• VA 
• Biomicroscopy 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 07:30 to 8:30 
hours) 
• After ophthalmic assessments are conducted, subjects will be dispensed study medication 
and retain their bottle of latanoprost provided by the sponsor and administer their Day 14 
AM dose of study medication and record this dose in their dosing diary. 
• Dosing diary review will be conducted. Used medication kits will be collected and 
retained by the site.  The latanoprost bottle is retained/re-dispensed. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.9 
Visit 5.1 (Day 14, for IOP measurement at 10:00 hours) 
Subjects will be examined. Each examination will include: 
• AE Monitoring 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 2-hour interval (i.e., ≥ 2-hours) 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 


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10.2.10 
Visit 5.2 (Day 14, for IOP measurement at 12:00 hours) 
Subjects will be examined.  Each examination will include: 
• AE Monitoring 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 11:30 to 
12:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 2-hour interval (i.e., ≥ 2-hours) 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.11 
Visit 5.3 (Day 14, for IOP measurement at 16:00 hours) 
Subjects will be examined. Each examination will include: 
• AE Monitoring 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 15:30 to 
16:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 4-hour interval (i.e., ≥ 4-hours) 
Subjects subsequently will be: 
• Instructed to continue to self-administer their study medication and latanoprost at home 
on the directed schedule and to record dosing in their dosing diary 
• Instructed to return to the office with their dosing diary, study medication kits and 
latanoprost bottle at Day 28  
10.2.12 
Visit 6.0 (Day 28, for IOP measurement at 08:00 hours) 
Subjects will return to the Investigator’s office with study medication kits, latanoprost bottle and 
dosing diary. The subject will be questioned about any missed doses and any changes in their 


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health or concomitant medication use. Subjects will dose the Day 28 AM dose of study 
medication following completion of the 8:00 hour ophthalmic assessment. 
Subjects will be examined.  Each examination will include: 
• Urine Pregnancy Test (female subjects of childbearing potential; as applicable) 
• AE monitoring 
• Conmeds 
• VA 
• Biomicroscopy 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 07:30 to 
08:30 hours) 
• Collect study medication from the subject and review dosing diary at any time Day 28 
visit. All remaining study medication kits and the latanoprost bottle are collected and 
retained by the site.   
• Dose AM study medication from returned study medication kit or if necessary, a new kit 
is dispensed to complete the AM dose. 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.13 
Visit 6.1 (Day 28, for IOP measurement at 10:00 hours) 
Subjects will be examined.  Each examination will include: 
• AE monitoring 
• Bulbar conjunctival hyperemia assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 09:30 to 
10:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 2-hour interval (i.e., ≥ 2-hours) 


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Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.14 
Visit 6.2 (Day 28, for IOP measurement at 12:00 hours) 
Subjects will be examined.  Each examination will include: 
• AE Monitoring 
• Bulbar conjunctival hyperemia assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 11:30 to 
12:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 2-hour interval (i.e., ≥ 2-hours) 
Subjects are allowed to leave the Investigator’s office on the day of this study visit between 
assessments and eat and drink without restrictions. However, individuals are not to consume 
alcohol or engage in strenuous exercise. 
10.2.15 
Visit 6.3 (Day 28, for IOP measurement at 16:00 hours) 
• Subjects will be examined.  Each examination will include: 
• AE monitoring 
• Bulbar conjunctival hyperemia Assessment 
• IOP  
o IOP must be measured within 30 minutes of the nominal time (i.e., 15:30 to 
16:30 hours) 
• 
IOP measurement should be conducted as at a minimum of the protocol 
prescribed 4-hour interval (i.e., ≥ 4-hours) 
• Pachymetry 
o To be conducted after 16:00 IOP assessments are completed  
• A dilated ophthalmoscopy examination (including cup-disc ratio) 
o To be conducted after 16:00 IOP and pachymetry assessments are 
completed. 


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Subjects will be thanked for their participation and released to care of their ophthalmologist. 
10.3 
Unscheduled Visits 
An unscheduled visit may be any visit to the Investigator other than the specific visits requested 
in the protocol as possibly required for the subject’s ophthalmic condition. The Investigator will 
perform all procedures necessary to evaluate the study participant at these visits and record any 
adverse events in the CRF. 
Every possible effort should be made by Investigators to assure that non-completing subjects 
have a final visit that includes all examinations listed for Visit 6.0 (Day 28) plus a dilated 
ophthalmoscopy examination. 
10.4 
Early Termination Visits 
Should a subject withdraw after administration of AKB-9778, or should the Investigator decide 
to withdraw the subject, all efforts will be made to complete and report the protocol-stipulated 
observations up to the time of withdrawal as thoroughly as possible.   
Subjects who discontinue prior to completion of all planned study assessments, should undergo 
the Day 28 assessments at time of discontinuation. 
 
11.0 
ADVERSE EVENTS 
11.1 
Definitions 
11.1.1 
Adverse Events (AEs) 
An AE is any untoward medical occurrence in a patient or trial subject administered a drug or 
biologic (medicinal product) or using a medical device; the event does not necessarily have a 
causal relationship with that treatment or usage. 
AEs include the following: 
• All suspected adverse medication reactions. 
• All reactions from medication overdose, abuse, withdrawal, sensitivity, or toxicity.  
• Apparently unrelated illnesses, including the worsening of a preexisting illness (see 
paragraph below on Preexisting Conditions). 
• Injury or accidents.  Note that if a medical condition is known to have caused the injury 
or accident (e.g., a fall secondary to dizziness), the medical condition (dizziness) and the 
accident (fall) should be reported as two separate adverse events.  The outcome of the 
accident (e.g., hip fracture secondary to the fall) should be recorded under Comments. 


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• Abnormalities in physiological testing or physical examination findings that require 
clinical intervention or further investigation (beyond ordering a repeat [confirmatory] 
test). 
• An increase of 2 or more grades on the hyperemia scale when compared to the lowest 
score recorded at any previous timepoint for an individual eye should be reported as an 
adverse event. If a subject complains of hyperemia, an AE will be recorded regardless of 
grade on the hyperemia scale (Section 9.2.2). 
Procedures – Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as adverse events.  However, the medical condition for which the 
procedure was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the adverse event reporting period should be reported as the 
adverse event and the resulting appendectomy noted under Comments. 
Preexisting Conditions – In this trial, a preexisting condition (i.e., a disorder present before the 
adverse event reporting period started and noted on the pretreatment medical history/physical 
examination form) should not be reported as an adverse event unless the condition worsens, or 
episodes increase in frequency during the adverse event reporting period. 
11.1.2 
Serious Adverse Events (SAEs) 
Each adverse event is to be classified by the Investigator as SERIOUS or NONSERIOUS.  An 
adverse event that meets one or more of the following criteria/outcomes is classified as serious: 
• Death 
• Life-threatening (see paragraph below on Life-threatening) 
• In-patient hospitalization or prolongation of existing hospitalization (see paragraph below 
on Hospitalization) 
• Persistent or significant disability/incapacity (see paragraph below on Disability)  
• Congenital anomaly/birth defect 
Important adverse events that may not result in death, be life-threatening, or require 
hospitalization may be considered Serious Adverse Events (SAEs) when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject or may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
The term serious also includes any other event that the Investigator or Sponsor judges to be 
serious or which is defined as serious by the regulatory agency in the country in which the event 
occurred.  If there is any doubt whether the information constitutes an AE or SAE, the 
information is to be treated as an SAE. 


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Life-threatening – Any AE that places the subject at immediate risk of death from the event as 
it occurred.  A life-threatening event does not include an event that might have caused death had 
it occurred in a more severe form but that did not create an immediate risk of death as it actually 
occurred.  For example, drug-induced hepatitis that resolved without evidence of hepatic failure 
would not be considered life threatening, even though drug-induced hepatitis of a more severe 
nature can be fatal. 
Hospitalization – Hospitalization is defined as an overnight admission with observation of a 
minimum of 24 hours.  A hospitalization planned before the start of the study for a preexisting 
condition that has not worsened does not constitute an SAE (e.g., elective hospitalization for a 
total knee replacement due to a preexisting condition of osteoarthritis of the knee that has not 
worsened during the course of the study). 
Disability – Defined as a substantial disruption in a person’s ability to conduct normal life 
functions. 
11.1.3 
Severity 
If required on the adverse event CRF, the Investigator will use the adjectives MILD, 
MODERATE, or SEVERE to describe the maximum intensity of the adverse event.  For 
purposes of consistency, these intensity grades are defined as follows: 
MILD: 
Does not interfere with subject's usual function 
MODERATE: 
Interferes to some extent with subject's usual function 
SEVERE: 
Interferes significantly with subject's usual function 
Note the distinction between the gravity and the intensity of an adverse event.  Severe is a 
measure of intensity; thus, a severe reaction is not necessarily a serious reaction.  For example, a 
headache may be severe in intensity, but would not be classified as serious unless it met one of 
the criteria for serious events listed above. 
11.2 
Eliciting Adverse Event Information 
The Investigator is to report all directly observed AEs and all AEs spontaneously reported by the 
study subject.  In addition, each study subject will be questioned about AEs at each visit 
following the initiation of treatment. 
11.3 
Reporting 
Each AE is to be classified by the Investigator as SERIOUS or NONSERIOUS.  This 
classification of the gravity of the event determines the reporting procedures to be followed.  If 
an SAE occurs, expedited reporting will follow local and international regulations, as 
appropriate. 


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All AEs that occur in study subjects during the adverse event reporting period specified in the 
protocol must be reported, WHETHER OR NOT THE EVENT IS CONSIDERED 
MEDICATION RELATED. 
11.3.1 
Reporting Period 
The AE reporting period for this study begins from the time of informed consent and ends at the 
final protocol required visit. 
IN ADDITION, any known untoward event that occurs subsequent to the AE reporting period 
that the Investigator assesses as possibly or probably related to the study medication and meets 
criteria for serious should also be reported as an SAE. 
11.3.2 
Reporting AEs 
NONSERIOUS AEs are to be reported on the adverse event case report forms. 
11.3.3 
Reporting SAEs 
Serious adverse events should be reported on both the clinical trial adverse event CRF and 
the Serious Adverse Event Report Form. 
Note:  Where the same data are collected, the forms must be completed in a consistent manner.  
For example, the same AE term should be used on both forms. 
Any SAE, regardless of causal relationship, must be reported to the clinical safety contact at the 
Sponsor within 24 hours after the Investigator becomes aware of the SAE by completing and 
sending an SAE report form.  Compliance with this time requirement is essential so that the 
Sponsor may comply with its regulatory obligations. 
The initial SAE report should be completed as fully as possible but should contain, at a 
minimum: 
• A short description of the event and the reason why the event is categorized as serious 
• Subject identification number 
• Investigator’s name 
• Name of the suspected medicinal product (not applicable for double-masked studies) 
• Causality assessment 
• Onset date 
Follow-Up information relating to an SAE must be reported to the clinical safety contact at the 
Sponsor within 24 hours of receipt by the Investigator by sending a completed SAE report form 


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with new information.  The subject should be observed and monitored carefully until the 
condition resolves or stabilizes. 
Any emergency event deemed related to study medication must be reported to the trial monitor 
or to the Sponsor’s Medical Monitor immediately. 
All deaths are to be thoroughly investigated and reported as SAEs.  Autopsy reports are to be 
obtained, if possible. 
The Sponsor and/or its designee are responsible for reporting SAEs to all applicable regulatory 
agencies and the central ethics committees within the required timeline. 
The Investigator is responsible for submitting required safety information to their local IRB. This 
information includes but is not limited to any safety alert letter received from the Sponsor and 
any SAEs occurring at their site. 
11.3.4 
Relationship to Study Medication 
The causal relationship of the AE to study medication will be assessed by both the Investigator 
and the Sponsor.  The following definitions will be used in assessment. 
Probably Related:  The AE follows a reasonable temporal sequence from the time of drug 
administration.  It follows a known response pattern to the study medication.  The AE cannot be 
reasonably explained by other factors such as the subject’s clinical state, therapeutic 
interventions, or concomitant drugs. 
Possibly Related:  The AE follows a reasonable temporal sequence from the time of drug 
administration but could have been produced by other factors such as the subject’s clinical state, 
other therapeutic interventions, or concomitant drugs. 
Unrelated:  The AE does not follow a reasonable temporal sequence from administration of the 
product or the AE is clearly related to other factors such as the subject’s clinical state, other 
therapeutic interventions, or concomitant drugs administered to the subject. 
11.3.5 
Follow-Up of Unresolved Events 
All AEs should be followed until they are resolved or the PI assesses them as chronic or stable or 
the subject’s participation in the trial ends (i.e., until a final report is completed for that subject). 
In addition, all serious adverse events and those nonserious events assessed by the Investigator as 
possibly or probably related to the study medication should continue to be followed even after 
the subject's participation in the trial is over.  Such events should be followed until they resolve 
or until the Investigator assesses them as “chronic” or “stable.”  Resolution of such events is to 
be documented on the appropriate CRF. 


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11.4 
Exposure In Utero  
If any study subject becomes or is found to be pregnant while receiving a study medication or 
within 30 days of discontinuing the study medication, the Investigator submits this information 
on a Pregnancy Report Form which must be submitted within 24 hours of awareness of the 
pregnancy.  The information submitted should include the anticipated date of birth or pregnancy 
termination.  
If the pregnancy is discovered during the study treatment period, the study medication should be 
discontinued. 
The PI will follow the subject until completion of the pregnancy and will notify Aerpio 
Pharmaceuticals of the outcome within 5 days or as specified below.  
If the outcome of the pregnancy meets the criteria for immediate classification as a serious 
adverse event (i.e., spontaneous abortion, stillbirth, neonatal death, or congenital anomaly 
[including that in an aborted fetus]), the Investigator should follow the procedures for reporting a 
serious adverse event. 
Additional information about pregnancy outcomes that are classified as serious adverse events 
follows: 
• Note that “spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within one month of birth should be reported, without 
regard to causality, as serious adverse events.  In addition, any infant death after one 
month that the Investigator assesses as possibly or probably related to the in utero 
exposure to the study medication should also be reported. 
• In the case of a live birth, the “normality” of the newborn can be assessed at time of birth. 
• The “normality” of an aborted fetus can be assessed by gross visual inspection unless 
there are pre-abortion laboratory findings suggestive of a congenital anomaly. 
12.0 
STATISTICAL METHODS 
12.1 
Primary Hypotheses 
• H01: The difference between study eyes treated with AKB-9778 BID + Latanoprost and 
study eyes treated with Latanoprost monotherapy in Day 28 mean diurnal IOP (IOP 
averaged over the 08:00, 10:00, 12:00, and 16:00 hour time points) is ≥ 0 mmHg. 
• H11: The difference between study eyes treated with AKB-9778 BID + Latanoprost and 
study eyes treated with Latanoprost monotherapy in Day 28 mean diurnal IOP is < 0 
mmHg 


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• H02: The difference between study eyes treated with AKB-9778 QD + Latanoprost and 
study eyes treated with Latanoprost monotherapy in Day 28 mean diurnal IOP is ≥ 0 
mmHg. 
• H12: The difference between study eyes treated with AKB-9778 QD + Latanoprost and 
study eyes treated with Latanoprost monotherapy in Day 28 mean diurnal IOP is < 0 
mmHg. 
The study will be considered a success if either H01 or H02 is rejected. 
12.2 
Multiplicity Adjustment 
No multiplicity adjustment for the two sets of primary hypotheses will be made in this Phase 2 
protocol, yielding an overall two-sided Type I Error of 0.10. 
12.3 
Sample Size Considerations 
Efficacy: 
Sixty-five (65) subjects per arm completing 28 days of treatment yields 80% power to conclude 
statistical superiority of AKB-9778 (QD or BID) + Latanoprost to Latanoprost monotherapy 
assuming a two-sided alpha = 0.05, a true difference in mean diurnal change from baseline IOP 
of 1.5 mmHg, a common standard deviation of 3.5 mmHg at each time point, and a correlation of 
0.60 among time points within a subject’s study eye (leading to an SD of the mean diurnal IOP 
of 3.0 mmHg)  
12.4 
Analysis Populations 
Randomized Population: The randomized population will include all subjects who were 
randomized to treatment. Baseline variables and demographic characteristics will be summarized 
for this population. 
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects who 
have received at least one dose of study medication. This population will be the primary 
population for efficacy analyses and will be used to summarize all efficacy variables and will 
summarize subjects as randomized. 
Per-protocol population (PP): The PP population is a subset of the ITT population, which will 
include those subjects (and their visits) who do not have major protocol violations likely to 
seriously affect the primary outcome of the study as judged by a masked evaluation prior to the 
unmasking of the study treatment.  This population will be the secondary population for efficacy 
analyses and will be used to summarize a subset of efficacy variables.  If the PP and ITT 
populations are exactly the same, then additional efficacy analyses on the PP population will not 
be performed.  The PP population will summarize subjects as treated. 


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Safety Population: The safety population will include all randomized subjects who have received 
at least one dose of study medication. This population will be used to summarize safety variables 
and will summarize subjects as treated. 
12.5 
Statistical Methods to be Employed 
12.5.1 
General Considerations 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum). All 
categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and percentages. 
Hypothesis testing, unless otherwise indicated, will be performed at a 2-sided 0.05 significance 
level.  When applicable, two-sided 95% confidence intervals will be reported. All p-values will 
be displayed to four decimal places, with p-values less than 0.0001 presented as '< 0.0001' and p-
values greater than 0.9999 presented as ‘> 0.9999’. Differences between AKB-9778 + 
Latanoprost and Latanoprost monotherapy will be calculated as AKB-9778 + Latanoprost minus 
Latanoprost monotherapy. 
All study data will be listed by treatment, subject and time point (as applicable). 
For diurnally-adjusted IOP, baseline will refer to the time-relevant measure at Visit 3.0 through 
3.3 (e.g., IOP at 08:00 hours at Visit 3.0 will be the baseline for 08:00 hours at Visits 5.0 and 6.0, 
IOP at 10:00 hours at Visit 3.1 will be the baseline for 10:00 hours at Visits 5.1 and 6.1, etc.). 
For all other variables, baseline is defined as the last measurement prior to the first dose of study 
medication. 
The unit of analysis for efficacy will be the study eye. The study eye will be the eye with the 
higher mean diurnal IOP on Visit 3. If both eyes have the same mean diurnal IOP on Visit 3, 
then the right eye will be the study eye. 
Statistical methods will be more fully described in a separate document (i.e., the Statistical 
Analysis Plan). 
12.5.2 
Interim Analyses 
An interim analysis for futility is planned to be performed when 50% of randomized subjects 
have completed 28 days of therapy. For this analysis the diurnal mean reduction of IOP in each 
AKB-9778 treatment group will be compared to that of the Latanoprost monotherapy treatment 
group. Futility will be declared if the conditional probability of achieving a 1.5 mmHg reduction 
in IOP compared to Latanoprost monotherapy in each AKB-9778 treatment group is < 30%.  
Conditional probability of achieving a 1.5 mmHg reduction in IOP compared to Latanoprost 
monotherapy will be based on the observed data and projected data for the remaining subjects. 
Projections will be based on the initial assumptions of a true effect of AKB-9778 + Latanoprost 
over Latanoprost monotherapy of -1.5 mmHg with a SD of 3.0 mmHg. 


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12.5.3 
Analysis of Baseline Data 
Demographic and baseline characteristics such as age, gender, or disease status (e.g., IOP, cup-
disc ratio) will be summarized and listed. Medical history, history of ocular surgery and 
procedures, OAG/OHT history and washout period will also be summarized and listed. 
12.5.4 
Subject Disposition 
Subject enrollment, discontinuation of Investigational Product, and withdrawal from the study 
will be summarized and listed. 
12.5.5 
Analysis of Efficacy 
All efficacy analyses will be conducted in the study eye and both eyes (average of study eye and 
eligible fellow eye) 
The primary efficacy outcome will be comparison of AKB-9778 + Latanoprost (QD or BID) 
relative to Latanoprost monotherapy for: 
• Mean change from baseline in diurnal IOP on Day 28 
Secondary efficacy outcomes will include comparison of AKB-9778 + Latanoprost (QD or BID) 
relative to Latanoprost monotherapy for: 
• Mean change from baseline in diurnal IOP on Day 14 (study eye) 
• Mean change from baseline in diurnal IOP on Days 14 and 28 (both eyes) 
• Mean diurnal IOP on Days 14 and 28 (both eyes) 
• Mean observed IOP at each time point on Days 14 and 28 
• Mean change from diurnally adjusted baseline IOP at each time point on Days 14 and 28 
• Mean percent change from diurnally adjusted baseline IOP at each time point on Days 14 
and 28 
• Mean percent change from baseline in diurnal IOP on Days 14 and 28 
• Percentages of subjects achieving pre-specified mean, mean change, and percent mean 
change in diurnal IOP levels 
Additional secondary efficacy analyses may be conducted as described in the study Statistical 
Analysis Plan.  Note that each subject will have one eye designated as the study eye.  Only the 
study eyes will be evaluated for the primary efficacy measure or for selected secondary efficacy 
measures; however, both eyes will be treated. Fellow eyes will be evaluated separately for the 
primary analysis of the primary efficacy measure. In addition, analyses using the average IOP 


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between the Study and eligible Fellow eyes will be performed. If the Fellow eye of a given 
subject is ineligible, then the both eyes analysis will utilize only the Study eye for that subject 
Primary Estimand 
The primary comparisons in this trial will be between two doses of AKB-9778 (QD and BID) + 
Latanoprost vs Latanoprost monotherapy at the Day 28 Visit in the ITT population with 
intercurrent events handled as described in the following estimand.   
• Population: subjects with Open-Angle Glaucoma or Ocular Hypertension defined through 
enrolment criteria 
• Endpoint: 
- 
Mean diurnal (averaged over 08:00, 10:00, 12:00, and 16:00 hour time points) 
change from baseline IOP (mm Hg) at the Day 28 Visit in the study eye 
• Intercurrent event: 
- 
Discontinuation of study medication and non-optimal compliance will be ignored 
[treatment policy strategy]. 
- 
Withdrawal due to lack of efficacy or adverse event: missing data will be imputed 
employing Multiple Imputation (MI) assuming missing not at random using: 
▪     Control-based Markov Chain Monte Carlo (MCMC) methodology 
[hypothetical strategy]. 
- 
Missing data without withdrawal or withdrawal due to reasons other than lack of 
efficacy or adverse event: missing data will be imputed employing Multiple 
Imputation (MI) assuming missing at random using randomized treatment-based 
Markov Chain Monte Carlo (MCMC) methodology [hypothetical strategy]. 
• Population-level summary: 
- 
The difference in the mean diurnal change from baseline IOP at the Day 28 Visit, 
between study eyes treated with each dose of AKB-9778 (QD and BID) + 
Latanoprost and study eyes treated with Latanoprost monotherapy. 
Sensitivity analyses will be performed on observed data only and where worst time consistent 
observation within a subject is carried forward for withdrawal due to lack of efficacy or adverse 
event and last time consistent observation within a subject is carried forward for other missing 
data. 
The primary analysis of the primary outcome will employ a linear model with Day 28 mean 
diurnal change from baseline IOP as the response, baseline mean diurnal IOP (mean diurnal IOP 
on Day -1) as a covariate, and treatment as a main effect factor, using the intent to treat 
population with multiple imputation techniques (e.g., Monte Carlo Markov Chain) used to 
impute missing data. The least squares mean differences (test – control) between AKB-9778 + 
Latanoprost and Latanoprost monotherapy will be presented as well as 2-sided p-values and 95% 
confidence intervals. Inference will be made on the p-value < 0.05.  


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Analyses will be performed primarily on the ITT population using multiple imputation 
techniques to impute missing data and secondarily using: observed data only, last observation 
carried forward (LOCF) where LOCF will be performed using time-relevant measures; and 
baseline observation carried forward (BOCF) using time-relevant measures to determine the 
robustness of results. Additionally, the above analyses will be repeated on the PP population to 
determine robustness of results.  Additional imputation techniques may be designated in the 
formal Statistical Analysis Plan. 
Secondary analyses of the primary endpoint will be completed using individual two-sample t- 
tests and 95% t-distribution confidence intervals at each time point (08:00, 10:00, and 16:00 at 
the Day 14, and Day 28 Visits) using the ITT population. Similar analyses will be completed on 
the secondary endpoints: mean IOP measure at each time point and visit and mean diurnal IOP 
and change from baseline diurnal IOP measures. Models adjusting for baseline will only be 
performed on the mean IOP response variable as inference is identical between this response and 
the change from baseline IOP response variable in such a model. 
Additionally, for the mean IOP values at each time point, mixed model repeated measures will 
be run with baseline as the covariate; treatment, visit, time point, treatment by visit, treatment by 
time point, visit by time point, and treatment by visit by time point as the fixed effect factors; and 
subject as the random effect, repeated measure. An unstructured covariance structure will be 
used to model the within subject, between visit and time point variances. This allows for 
different variances and covariances within and between time points and visits. The treatment by 
visit, treatment by time point, visit by time point, and treatment by visit by time point 
interactions allow for a different rate of change in IOP in the different treatment arms among 
visits and time points. This model will be run including the Day 14, and Day 28 visits. 
Percent change from diurnally adjusted baseline IOP at each time point will be analyzed using 
two-sample t-tests, between AKB-9778 and each comparator, at each time point and visit, 
including two-sample t-tests and 95% t-distribution confidence intervals on the difference (AKB-
9778 – comparator). 
Mean diurnal IOP values will be constructed by averaging the 4 diurnal IOP measurements on 
each of the Day 14, and Day 28 visits. Mean diurnal baseline IOP will be constructed as the 
average of the four Day -1 IOP measurements. Mean change from mean baseline diurnal IOP 
will be created by taking the average of the four time points on each of Day 14, and Day 28 visits 
and subtracting the single mean baseline diurnal IOP measurement. 
Sub-group analyses based upon pre-study characteristics such as site, demographics, or pre- 
study ocular hypotensive medications may be completed to further investigate the efficacy 
measures. 


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12.5.6 
Analysis of Safety 
12.5.6.1 
Ocular and Systemic Safety Assessments 
Slit lamp biomicroscopy, hyperemia and dilated ophthalmoscopy measures will be summarized 
at each measured time point using discrete summary statistics. 
Visual acuity data will be summarized at each time point using both continuous summaries 
(logMAR), including change from baseline, and discrete summaries, including change from 
baseline. 
12.5.6.2 
Adverse Events 
Verbatim descriptions of treatment-emergent adverse events (TEAEs) will be mapped to Medical 
Dictionary for Regulatory Activities (MedDRA) thesaurus terms and be presented in a data 
listing.  Treatment emergent AEs, those that occur after the first dose of study medication will be 
summarized by treatment group using frequency and percent for each system organ class (SOC) 
and preferred term (PT) within each SOC. Summaries will be presented separately for ocular and 
non-ocular TEAEs. These summaries will also be presented for relation to Investigational 
Product and by severity. Fisher’s exact test will be used to test the difference in proportions of 
subjects with each TEAE between treatment groups (SOC and PT). 
12.6 
Procedure for Accounting for Missing, Unused, or Spurious Data 
Analyses will be performed primarily on missing data imputed using multiple imputation 
techniques as defined in the primary estimand. Sensitivity analyses will be performed on 
observed data only and where worst time consistent observation within a subject is carried 
forward for withdrawal due to lack of efficacy or adverse event and last time consistent 
observation within a subject is carried forward for other missing data. Any missing, unused, or 
spurious data will be noted in the final statistical report. 
12.7 
Procedure for Reporting Deviations from the Statistical Plan 
Any deviations from the Statistical Analysis Plan will be described and a justification given in 
the final statistical report. 
12.8 
Data Listings 
Data listings will be prepared for all data in the database. 
 


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13.0 
DATA HANDLING AND RECORD KEEPING 
13.1 
Case Report Forms (CRFs) 
CRFs are required and should be completed for each included subject.  The completed original 
CRFs are the sole property of the Sponsor and should not be made available in any form to third 
parties, except for authorized representatives of the Sponsor or appropriate regulatory authorities, 
without written permission from the Sponsor.  CRFs for this study will be electronic (eCRFs). 
The PI has ultimate responsibility for the accuracy, authenticity, and timely collection and 
reporting of all clinical, safety, and laboratory data entered on the CRFs and any other data 
collection forms.  The CRFs must be signed by the Investigator (for electronic CRFs, they can be 
signed electronically) or by an authorized staff member to attest that the data contained on the 
CRFs is true.  Any corrections to entries made in the CRFs and source documents must be dated, 
initialed and explained (if necessary) and should not obscure the original entry.  
In most cases, the source documents are contained in the subject’s chart at the hospital or the 
physician's office.  In these cases, data collected on the CRFs must match the data in those 
charts.  
In some cases, the CRFs, or part of the CRFs, may also serve as source documents.  In these 
cases, a document should be available at both the Investigator’s site and at the Sponsor or its 
designee that clearly identify those data that will be recorded in the CRFs, and for which the 
CRF will stand as the source document. 
13.2 
Record Retention 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
agrees to keep records, including the identity of all participating subjects (sufficient information 
to link records, e.g., CRFs and hospital records), all original signed Informed Consent Forms, 
copies of all CRFs, SAE forms, source documents, detailed records of drug disposition, and 
adequate documentation of relevant correspondence (e.g., letters, meeting minutes, telephone 
calls reports).  The records should be retained by the Investigator according to the International 
Conference on Harmonisation (ICH), local regulations, or as specified in the Clinical Study 
Agreement, whichever time period is longer. 
If the Investigator becomes unable for any reason to continue to retain study records for the 
required period (e.g., retirement, relocation), the Sponsor should be prospectively notified.  The 
study records must be transferred to a designee acceptable to the Sponsor, such as another 
Investigator, another institution, or to the Sponsor.  The Investigator must obtain Sponsor’s 
written permission before disposing of any records, even if retention requirements have been 
met. 
 


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14.0 
QUALITY CONTROL (QC) AND QUALITY ASSURANCE (QA) 
14.1 
Study Site Monitoring Visits 
During study conduct, the Sponsor or its agent will conduct periodic monitoring visits to ensure 
that the protocol and Good Clinical Practice (GCP) are being followed.  The monitors will 
review source documents to confirm that the data recorded on CRFs is accurate.  The 
Investigator/institution will allow Sponsor monitors or designees and appropriate regulatory 
authorities direct access to source documents to perform this verification. 
The study site may also be subject to Quality Assurance audits performed by the Sponsor or 
companies working with or on behalf of the Sponsor, and/or review by the independent review 
board (IRB), and/or to inspection by appropriate regulatory authorities 
It is important that the PI and their relevant personnel are available during the monitoring visits 
and possible audits or inspections and that sufficient time is devoted to the process. 
14.2 
Protocol Deviations 
The PI should not deviate from the protocol, except where necessary to eliminate an immediate 
hazard to study subjects.  Should other unexpected circumstances arise that will require deviation 
from protocol-specified procedures, the Investigator should consult with the Sponsor or designee 
(and IRB, as required) to determine the appropriate course of action. 
The site should document all protocol deviations in the subject’s source documents.  In the event 
of a significant deviation, the site should notify the Sponsor or its designee (and IRB, as 
required).  Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessments. 
15.0 
TRIAL DISCONTINUATION/INVESTIGATIVE SITE TERMINATION 
The Sponsor reserves the right to discontinue the trial prior to inclusion of the intended number 
of subjects but intends only to exercise this right for valid scientific or administrative reasons.  
After such a decision, the Investigator must contact all participating subjects within a time period 
specified by the Sponsor to inform them of the decision to discontinue the trial. 
15.1 
Criteria for Premature Termination or Suspension of the Study 
The following criteria may result in either temporary suspension or early termination of the 
study: 
• New information regarding the safety or efficacy of the study medication that indicates a 
change in the known risk/benefit profile for the compound, such that the risk/benefit is no 
longer acceptable for subjects participating in the study. 


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• Significant violation of GCP that compromises the ability to achieve the primary study 
objectives or compromises subject safety. 
The Sponsor reserves the right to discontinue the trial for other valid administrative reasons. 
15.2 
Criteria for Premature Termination or Suspension of Investigational Site 
A study site may be terminated prematurely or suspended if the site (including the PI) is found to 
be in significant violation of GCP, protocol, contractual agreement, or is unable to ensure 
adequate performance of the study. 
15.3 
Procedures for Premature Termination or Suspension of the Study or 
Investigational Site(s) 
In the event that the Sponsor elects to terminate or suspend the study or the participation of an 
Investigational site, a study-specific procedure for early termination or suspension will be 
provided by the Sponsor; the procedure will be followed by applicable Investigational sites 
during the course of termination or study suspension. 
 
16.0 
ETHICS 
16.1 
Ethical Conduct of the Study 
The study will be conducted in accordance with the Declaration of Helsinki on Ethical Principles 
for Medical Research Involving Human Subjects, adopted by the General Assembly of the World 
Medical Association (1996). 
In addition, the study will be conducted in accordance with the protocol, the ICH guideline on 
GCP, and applicable local regulatory requirements and laws. 
16.2 
Institutional Review Board (IRB)  
It is the responsibility of the Investigator to have prospective approval of the study protocol, 
protocol amendments, informed consent forms, and other relevant documents, (e.g., recruitment 
advertisements, if applicable) from the IRB.  All correspondence with the IRB should be retained 
in the Investigator File.  Copies of IRB approvals should be forwarded to the Sponsor. 
The only circumstance in which an amendment may be initiated prior to IRB approval is where 
the change is necessary to eliminate apparent immediate hazards to the subjects.  In that event, 
the Investigator must notify the IRB and the Sponsor in writing immediately after the 
implementation. 


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16.3 
Subject Information and Consent 
It is the responsibility of the Investigator to give each subject (or the subject’s acceptable 
representative), prior to inclusion in the trial, full and adequate verbal and written information 
regarding the objective and procedures of the trial and the possible risks involved.  The subjects 
must be informed about their right to withdraw from the trial at any time.   
Furthermore, it is the responsibility of the Investigator, or a person designated by the 
Investigator, to obtain signed informed consent from each subject or the subject’s legally 
acceptable representative prior to inclusion in the trial.  The Investigator will retain the original 
of each subject's signed consent form. 
The informed consent form must be in compliance with International Conference on 
Harmonisation (ICH) GCP, local regulatory requirements, and legal requirements.  The informed 
consent form used in this study, and any changes made during the course of the study, must be 
prospectively approved by both the IRB and the Sponsor before use. 
16.4 
Reporting of Safety Issues and Serious Breaches of the Protocol or ICH GCP 
In the event of any prohibition or restriction imposed (i.e., clinical hold) by an applicable 
Competent Authority, or if the Investigator is aware of any new information which might 
influence the evaluation of the benefits and risks of the investigational product, the Sponsor 
should be informed immediately.  
In addition, the Investigator will inform the Sponsor immediately of any urgent safety measures 
taken by the Investigator to protect the study subjects against any immediate hazard, and of any 
serious breaches of this protocol or of ICH GCP that comes to the attention of the Investigator. 
16.5 
Subject Confidentiality 
All parties will ensure protection of subject personal data and will not include subject names on 
any Sponsor forms, reports, publications, or in any other disclosures, except where required by 
laws.  In case of data transfer, the Sponsor will maintain high standards of confidentiality and 
protection of subject personal data. 
The Sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy.  Throughout this study, a subject’s source data will only be linked to 
the Sponsor’s clinical study database or documentation via a unique identification number.  As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or 
date of birth, and subject initials may be used to verify the subject and accuracy of the subject’s 
unique identification number. 
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the 
Sponsor requires the Investigator to permit its monitor or designee’s monitor, representatives 
from any regulatory authority (e.g., Food and Drug Administration [FDA]), the Sponsor’s 
designated auditors, and the appropriate IRB to review the subject’s original medical records 
(source data or documents), including, but not limited to, laboratory test result reports, 


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electrocardiogram (ECG) reports, admission and discharge summaries for hospital admissions 
occurring during a subject’s study participation, and autopsy reports.  Access to a subject’s 
original medical records requires the specific authorization of the subject as part of the informed 
consent process. 
Copies of any subject source documents that are provided to the Sponsor must have certain 
personally identifiable information removed (i.e., subject name, address, and other identifier 
fields not collected on the subject’s CRF). 
 
17.0 
PUBLICATION OF STUDY RESULTS 
No publication or disclosure of study results will be permitted, except under the terms and 
conditions of a separate, written agreement between Sponsor and the Investigator and/or the 
Investigator’s institution.  The Sponsor must have the opportunity to review and approve all 
proposed abstracts, manuscripts, or presentations regarding this study prior to submission for 
publication/presentation.  Any information identified by the Sponsor as confidential must be 
deleted prior to submission. 
For all publications relating to the study, the institution will comply with recognized ethical 
standards concerning publications and authorship, including:  Section II - “Ethical 
Considerations in the Conduct and Reporting of Research” of the Uniform Requirements for 
Manuscripts Submitted to Biomedical Journals, http://www.icmje.org/index.html#authorship, 
established by the International Committee of Medical Journal Editors. 
 


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18.0 
REFERENCES 
Aptel F, Aryal-Charles N, Giraud JM, El Chehab H, Delbarre M, Chiquet C, et al. Progression of 
visual field in patients with primary open-angle glaucoma - ProgF study 1. Acta 
Ophthalmol. 2015 Dec;93(8):e615-20.  
Aspelund A, Tammela T, Antila S, Nurmi H, Leppanen VM, Zarkada G, et al. The Schlemm's 
canal is a VEGF-C/VEGFR-3-responsive lymphatic-like vessel. J Clin Invest. 2014 
Sep;124(9):3975-86.  
Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and 
homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009 
Mar;10(3):165-77. 
Bailey JK, Gharahkhani P, Tompson SW, Souma T, Siggs OM, Young TL, et al. Association of 
angpt1 with primary open angle glaucoma [abstract]. ARVO. 2017;3822. 
Bernier-Latmani, J, and Petrova, TV. All TIEd up: mechanisms of Schlemm's canal 
maintenance. J Clin Invest. 2017; 127, 3594-3597. 
Braunger BM, Fuchshofer R, Tamm ER. The aqueous humor outflow pathways in glaucoma: A 
unifying concept of disease mechanisms and causative treatment. Eur J Pharm Biopharm. 
2015 Sep;95(Pt B):173-81.  
Frye M, Dierkes M, Kuppers V, Vockel M, Tomm J, Zeuschner D, et al. Interfering with VE-
PTP stabilizes endothelial junctions in vivo via Tie-2 in the absence of VE-cadherin. J 
Exp Med. 2015 Dec 14;212(13):2267-87.  
Choquet H, Thai KK, Yin J, Hoffmann TJ, Kvale MN, Banda Y, et al. A large multi-ethnic 
genome-wide association study identifies novel genetic loci for intraocular pressure. Nat 
Commun. 2017 Dec 13;8(1):2108.  
Gordon MO, Beiser JA, Brandt JD, Heuer DK, Higginbotham EJ, Johnson CA, et al. The Ocular 
Hypertension Treatment Study: baseline factors that predict the onset of primary open-
angle glaucoma. Arch Ophthalmol. 2002 Jun;120(6):714-20. 
Grant WM. Clinical tonography. Trans Am Acad Ophthalmol Otolaryngol. 1951 Nov-
Dec;55:774-81. 
Grant, W.M. Experimental aqueous perfusion in enucleated human eyes. Arch Ophthalmol. 1963 
69, 783-801. 
Hamanaka T, Bill A, Ichinohasama R, Ishida T. Aspects of the development of Schlemm's canal. 
Exp Eye Res. 1992 Sep;55(3):479-88. 


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Heijl A, Leske MC, Bengtsson B, Hyman L, Hussein M. Reduction of intraocular pressure and 
glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 
2002 Oct;120(10):1268-79. 
Kabra M, Zhang W, Rathi S, Mandal AK, Senthil S, Pyatla G, et al. Angiopoietin receptor TEK 
interacts with CYP1B1 in primary congenital glaucoma. Hum Genet. 2017 
Aug;136(8):941-9.  
Kass MA, Heuer DK, Higginbotham EJ, Johnson CA, Keltner JL, Miller JP, et al. The Ocular 
Hypertension Treatment Study: a randomized trial determines that topical ocular 
hypotensive medication delays or prevents the onset of primary open-angle glaucoma. 
Arch Ophthalmol. 2002 Jun;120(6):701-713.  
Kim J, Park DY, Bae H, Kim D, Lee CK, et al. Impaired angiopoietin/Tie2 signaling 
compromises Schlemm's canal integrity and induces glaucoma. J Clin Invest. 2017 
Oct;127(10):3877-96.  
Kolker AE, Hetherington J Jr, eds. Becker and Shaffer’s diagnosis and therapy of the glaucomas, 
5th ed.  St Louis: CV Mosby, 1976. 
Kizhatil K, Ryan M, Marchant JK, Henrich S, John SW. Schlemm's canal is a unique vessel with 
a combination of blood vascular and lymphatic phenotypes that forms by a novel 
developmental process. PLoS Biol. 2014 Jun 22;12(7):e1001912.  
Leske MC, Heijl A, Hyman L, Bengtsson B, Dong L, Yang Z, et al. Predictors of long-term 
progression in the early manifest glaucoma trial. Ophthalmology. 2007 Nov;114(11):1965-
72.  
Morisada T, Oike Y, Yamada Y, Urano T, Akao M, Kubota Y, et al. Angiopoietin-1 promotes 
LYVE-1-positive lymphatic vessel formation. Blood. 2005 Jun 15;105(2):4649-56.  
Park DY, Lee J, Park I, Choi D, Lee S, Song S, et al. Lymphatic regulator PROX1 determines 
Schlemm's canal integrity and identity. J Clin Invest. 2014 Sep;124(9):3960-74. 
Peters KG, Kontos CD, Lin PC, Wong AL, Rao P, Huang L, et al. Functional significance of 
Tie2 signaling in the adult vasculature. Recent Prog Horm Res. 2004;59:51-71. 
Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway. Nat 
Rev Drug Discov. 2017 Sep;16(9):635-61. 
Shen J, Frye M, Lee BL, Reinardy JL, McClung JM, Ding K, et al. Targeting VE-PTP activates 
TIE2 and stabilizes the ocular vasculature. J Clin Invest. 2014 Oct;124(10):4564-76.  
Souma T, Tompson SW, Thomson BR, Siggs OM, Kizhatil K, Yamaguchi S, et al. Angiopoietin 
receptor TEK mutations underlie primary congenital glaucoma with variable expressivity. J 
Clin Invest. 2016 Jul;126(7):2575-87.  


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Stamer WD, Acott TS. Current understanding of conventional outflow dysfunction in glaucoma. 
Curr Opin Ophthalmol. 2012 Mar;23(2):135-43.  
Stamer WD. The cell and molecular biology of glaucoma: mechanisms in the conventional 
outflow pathway. Invest Ophthalmol Vis Sci. 2012 May 04;53(5):2470-2. 
Tammela T, Saaristo A, Lohela M, Morisada T, Tornberg J, Norrmén C, et al. Angiopoietin-1 
promotes lymphatic sprouting and hyperplasia. Blood. 2005 Jun 15;105(12):4642-8.  
Tham YC, Li X, Wong TY, Quigley HA, Aung T, Cheng CY. Global prevalence of glaucoma 
and projections of glaucoma burden through 2040: a systematic review and meta-analysis. 
Ophthalmology. 2014 Nov;121(11):2081-90. 
Thomson BR, Heinen S, Jeansson M, Ghosh AK, Fatima A, Sung HK, et al. A lymphatic defect 
causes ocular hypertension and glaucoma in mice. J Clin Invest. 2014 Oct;124(10):4320-4.  
Truong TN, Li H, Hong YK, Chen L. Novel characterization and live imaging of Schlemm's 
canal expressing Prox-1. PLoS One. 2014 May 14;9(5):e98245. 
Vajaranant TS, Wu S, Torres M, Varma R. A 40-year forecast of the demographic shift in 
primary open-angle glaucoma in the United States. Invest Ophthalmol Vis Sci. 2012 May 
4;53(5):2464-6.  
Vajaranant TS, Wu S, Torres M, Varma R. The changing face of primary open-angle glaucoma 
in the United States: demographic and geographic changes from 2011 to 2050. Am J 
Ophthalmol. 2012b Aug;154(2):303-14.   
Wong AL, Haroon ZA, Werner S, Dewhirst MW, Greenberg CS, Peters KG. Tie2 expression 
and phosphorylation in angiogenic and quiescent adult tissues. Circ Res. 1997 
Oct;81(4):567-74. 
 
 


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 APPENDIX 1 
SCHEDULE OF VISITS AND PROCEDURES  
Day 
Screen 
Qual. 
#1 [J] 
Qual. #2 
Day -1 (Baseline) 
Day 1[H] 
Day 7 
(±3) [J] 
Day 14 (±3) 
Day 28 (±3) 
Visit 
1 
2 
3.0 
3.1 
3.2 
3.3 
 
4.0 
5.0 
5.1 
5.2 
5.3 
6.0 
6.1 
6.2 
6.3 
Hour 
 
Any 
08:00 
10:00 
12:00 
16:00 
8:00  
& 
20:00 
Any 
08:00 
10:00 
12:00 
16:00 
08:00 
10:00 
12:00 
16:00 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Washout [A] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Med/Ophthalmic Hist 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant Medications 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Urine Pregnancy Test[B] 
X 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
AEs 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
VA  
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Visual Field[D] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Biomicroscopy 
X 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
Bulbar Conjunctival 
Hyperemia Assessment 
[F] 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
IOP  
X 
X 
X[K] 
X[K] 
X[K] 
X[K] 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pachymetry 
[C] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X[L] 
Gonioscopy[E] 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmoscopy 
(dilated) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X[L] 
Study Med Dispensing[G] 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
Study Med Return, Diary 
Review[H] 
 
 
 
 
 
 
 
X 
X 
 
 
 
X 
 
 
 
Dosing[I] 
 
 
 
 
 
 
X-------------------------------------------------------------------------------------X 
 
 
 
Study Completed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 


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Abbreviations: Qual, Qualification; Med/Ophthalmic Hist, Medical/Ophthalmic History; AE, adverse event; VA, visual acuity; IOP, intraocular 
pressure 
[A] Subjects must undergo a minimum 4-week washout period. 
[B] Urine pregnancy test for women of childbearing potential is required. May be taken anytime during Qual Visit # 2. 
[C] Screening: Pachymetry within one week of Screening is acceptable; If conducted at Screening must not be conducted before IOP. 
[D] Entry visual field evaluation up to 3 months prior to randomization is acceptable. Visual field collection must meet the requirement for 
automated threshold visual field assessment (e.g., 30-2 or 24-2 Humphrey) and reliability. 
[E] Gonioscopy evaluation up to 3 months prior to randomization is acceptable. 
[F] All hyperemia assessments coincide with a timed IOP evaluation.  The hyperemia assessment and grading must be evaluated prior to the use 
of any ocular drops required for the IOP procedure. 
[G] Study Medication is dispensed on Day-1 after randomization and at anytime during the Day 14 Visit.  
[H] Collect used study medication kit(s) and review dosing diary on Days 7, 14 and 28. Collection of used kit(s) and dosing diary may occur 
anytime during the visit. Subjects who fail to return their used study medication at Day 7 or 14 may return it at a subsequent visit.   
[I] Subjects will begin dosing at home with the AM dose of study medication on the morning of Day 1 and conclude dosing after administration 
of the AM dose of study medication on Day 28; there is no PM dose administration on Day 28. At visits conducted on Days 14 and 28, 
subjects will self-administer the AM dose of study medication at the site after the 8:00 hour ophthalmic assessments have been completed. 
[J] Subject visit can occur at anytime.  
[K] Individuals returning at an unscheduled visit within 1 week are required to only remeasure IOP in both eyes (Section 10.2.3 to Section 10.2.6). 
[L] Pachymetry and Ophthalmoscopy (dilated) at Visit 6.0 at 16:00 hours after 16:00 IOP assessments are completed. Pachymetry is conducted before dilated 
ophthalmoscopy.  
 
 
 


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 APPENDIX 2 
MARKETED PRODUCT: XALATAN® (LATANOPROST 
OPHTHALMIC SOLUTION) 0.005% 
 
The following is taken from the most recent package insert (4/2017) as of the date of this 
protocol for latanoprost ophthalmic solution 0.005% as marketed by Pfizer. 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use LATANOPROST safely and 
effectively. See full prescribing information for LATANOPROST. 
LATANOPROST (latanoprost ophthalmic solution) 0.005% Initial U.S. Approval: 1996 
------------------INDICATIONS AND USAGE------------------- 
Latanoprost is a prostaglandin F2α analogue indicated for the reduction of elevated intraocular 
pressure in patients with open-angle glaucoma or ocular hypertension. (1) 
--------------DOSAGE AND ADMINISTRATION---------------- 
One drop in the affected eye(s) once daily in the evening. (2) 
------------ DOSAGE FORMS AND STRENGTHS-------------- 
Ophthalmic solution containing 50 mcg/mL latanoprost (0.005%). (3) 
--------------------CONTRAINDICATIONS---------------------- 
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this 
product. (4) 
-------------WARNINGS AND PRECAUTIONS---------------- 
• Pigmentation: pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can occur. Iris 
pigmentation likely to be permanent. (5.1) 
• Eyelash Changes: gradual change to eyelashes including increased length, thickness and 
number of lashes. Usually reversible. (5.2) 
--------------------ADVERSE REACTIONS---------------------- 
Most common adverse reactions (≥4%) from clinical trials are blurred vision, burning and 
stinging, conjunctival hyperemia, foreign body sensation, itching, increased pigmentation of the 
iris, punctate epithelial keratopathy, and upper respiratory tract 
infection/nasopharyngitis/ingluenza. (6). 
To report SUSPECTED ADVERSE REACTIONS, contact Pfizer at 1-800-438-1985 or or 
FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 
--------------------DRUG INTERACTIONS---------------------- 
In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are 
mixed with XALATAN.  If such drugs are used, they should be administered at least 5 minutes 
apart. (7) 
Revised: 04/2017 


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FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
 
XALATAN is indicated for the reduction of elevated intraocular pressure in patients with open-
angle glaucoma or ocular hypertension. 
 
2 
DOSAGE AND ADMINISTRATION 
 
The recommended dosage is one drop in the affected eye(s) once daily in the evening. If one 
dose is missed, treatment should continue with the next dose as normal. 
 
The dosage of XALATAN should not exceed once daily; the combined use of two or more 
prostaglandins, or prostaglandin analogs including XALATAN is not recommended. It has been 
shown that administration of these prostaglandin drug products more than once daily may 
decrease the intraocular pressure (IOP) lowering effect or cause paradoxical elevations in IOP. 
 
Reduction of the IOP starts approximately 3 to 4 hours after administration and the maximum 
effect is reached after 8 to 12 hours. 
 
XALATAN may be used concomitantly with other topical ophthalmic drug products to lower 
IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at 
least five (5) minutes apart. Contact lenses should be removed prior to the administration of 
XALATAN, and may be reinserted 15 minutes after administration 
 
3 
DOSAGE FORMS AND STRENGTHS 
 
Sterile ophthalmic solution containing 50 mcg/mL latanoprost. 
 
4 
CONTRAINDICATIONS 
 
Known hypersensitivity to latanoprost, benzalkonium chloride, or any other ingredients in this 
product. 
 
5 
WARNINGS AND PRECAUTIONS 
 
5.1 
Pigmentation 
 
XALATAN has been reported to cause changes to pigmented tissues. The most frequently 
reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid), and 
eyelashes. Pigmentation is expected to increase as long as latanoprost is administered. 
 
The pigmentation change is due to increased melanin content in the melanocytes rather than to 
an increase in the number of melanocytes. After discontinuation of latanoprost, pigmentation of 
the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash 
changes have been reported to be reversible in some patients. Patients who receive treatment 


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should be informed of the possibility of increased pigmentation. Beyond 5 years the effects of 
increased pigmentation are not known [see Clinical Studies (14.2)]. 
 
Iris color change may not be noticeable for several months to years. Typically, the brown 
pigmentation around the pupil spreads concentrically towards the periphery of the iris and the 
entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear 
to be affected by treatment. While treatment with XALATAN can be continued in patients who 
develop noticeably increased iris pigmentation, these patients should be examined regularly [see 
Patient Counseling Information (17)]. 
 
5.2 
Eyelash Changes 
 
XALATAN may gradually change eyelashes and vellus hair in the treated eye; these changes 
include increased length, thickness, pigmentation, the number of lashes or hairs, and misdirected 
growth of eyelashes. Eyelash changes are usually reversible upon discontinuation of treatment 
[see Patient Counseling Information (17)]. 
 
5.3 
Intraocular Inflammation 
 
XALATAN should be used with caution in patients with a history of intraocular inflammation 
(iritis/uveitis) and should generally not be used in patients with active intraocular inflammation 
because inflammation may be exacerbated. 
 
5.4 
Macular Edema 
 
Macular edema, including cystoid macular edema, has been reported during treatment with 
XALATAN. XALATAN should be used with caution in aphakic patients, in pseudophakic 
patients with a torn posterior lens capsule, or in patients with known risk factors for macular 
edema. 
 
5.5 
Herpetic Keratitis 
 
Reactivation of Herpes Simplex keratitis has been reported during treatment with XALATAN. 
XALATAN should be used with caution in patients with a history of herpetic keratitis. 
XALATAN should be avoided in cases of active herpes simplex keratitis because inflammation 
may be exacerbated. 
 
5.6 
Bacterial Keratitis 
 
There have been reports of bacterial keratitis associated with the use of multiple-dose containers 
of topical ophthalmic products. These containers had been inadvertently contaminated by 
patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular 
epithelial surface [see Patient Counseling Information (17)]. 
 
5.7 
Use with Contact Lenses 
 


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Contact lenses should be removed prior to the administration of XALATAN, and may be 
reinserted 15 minutes after administration. 
 
6 
ADVERSE REACTIONS 
 
The following adverse reactions were reported in postmarketing experience and are discussed in 
greater detail in other sections of the label: 
 
• 
Iris pigmentation changes [see Warnings and Precautions (5.1)] 
• 
Eyelid skin darkening [see Warnings and Precautions (5.1)] 
• 
Eyelash changes (increased length, thickness, pigmentation, and number of lashes) [see 
Warnings and Precautions (5.2)]  
• 
Intraocular inflammation (iritis/uveitis) [see Warnings and Precautions (5.3)] 
• 
Macular edema, including cystoid macular edema [see Warnings and Precautions (5.4)] 
 
6.1 Clinical Trials Experience 
 
Because clinical trials are conducted under widely varying conditions, the adverse reaction rates 
observed in the clinical studies of a drug cannot be directly compared to rates in the clinical trials 
of another drug and may not reflect the rates observed in clinical practice. 
 
XALATAN was studied in three multicenter, randomized, controlled clinical trials. Patients 
received 50 mcg/mL XALATAN once daily or 5 mg/mL active-comparator (timolol) twice 
daily. The patient population studied had a mean age of 65±10 years. Seven percent of patients 
withdrew before the 6-month endpoint. 
 
Table 1: Ocular Adverse Reactions and Ocular Signs/Symptoms Reported by 5-15% of 
Patients Receiving Latanoprost 
Symptom/Finding 
Adverse Reactions (incidence (%)) 
Latanoprost (n=460) Timolol (n=369) 
Foreign body sensation 
13 
8 
Punctate keratitis 
10 
9 
Stinging 
9 
12 
Conjunctival hyperemia 
8 
3 
Blurred vision 
8 
8 
Itching 
8 
8 
Burning 
7 
8 
Increased pigmentation of the Iris 
7 
0 
 
Less than 1% of the patients treated with XALATAN required discontinuation of therapy 
because of intolerance to conjunctival hyperemia. 
 


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Table 2: Adverse Reactions That Were Reported in 1-5% of Patients Receiving 
Latanoprost 
Adverse Reactions (incidence (%)) 
Latanoprost (n=460) Timolol (n=369) 
Ocular Events/Signs and Symptoms 
Excessive tearing 
4 
6 
Eyelid discomfort/pain 
4 
2 
Dry eye 
3 
3 
Eye pain 
3 
3 
Eyelid margin crusting 
3 
3 
Erythema of the eyelid 
3 
2 
Photophobia 
2 
1 
Eyelid edema 
1 
3 
Systemic Events 
Upper respiratory tract 
infection/nasopharyngitis/influenza 
3 
3 
Myalgia/arthralgia/back pain 
1 
0.5 
Rash/allergic skin reaction 
1 
0.3 
The ocular event/signs and symptoms of blepharitis have been identified as “commonly 
observed” through analysis of clinical trial data. 
 
6.2 
Postmarketing Experience 
 
The following reactions have been identified during postmarketing use of XALATAN in clinical 
practice. Because they are reported voluntarily from a population of unknown size, it is not 
always possible to reliably estimate their frequency or establish a causal relationship to drug 
exposure. The reactions, which have been chosen for inclusion due to either their seriousness, 
frequency of reporting, possible causal connection to XALATAN, or a combination of these 
factors, include: 
 
Nervous System disorders: Dizziness; headache; toxic epidermal necrolysis 
 
Eye Disorders: Eyelash and vellus hair changes of the eyelid (increased length, thickness, 
pigmentation, and number of eyelashes); keratitis; corneal edema and erosions; intraocular 
inflammation (iritis/uveitis); macular edema, including cystoid macular edema; trichiasis; 
periorbital and lid changes resulting in deepening of the eyelid sulcus; iris cyst; eyelid skin 
darkening; localised skin reaction on the eyelids; conjunctivitis; pseudopemphigoid of the ocular 
conjunctiva 
 
Respiratory, Thoracic and Mediastinal Disorders: Asthma and exacerbation of asthma; dyspnea 
Skin and Subcutaneous Tissue Disorders: Pruritus 
Infections and Infestations:   Herpes; keratitis 


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Cardiac Disorders: Angina; palpitations; angina unstable 
General Disorders and Administration Site Conditions: Chest pain 
 
7 
DRUG INTERACTIONS 
 
In vitro studies have shown that precipitation occurs when eye drops containing thimerosal are 
mixed with XALATAN. If such drugs are used, they should be administered at least five (5) 
minutes apart. 
 
The combined use of two or more prostaglandins, or prostaglandin analogs including 
XALATAN is not recommended. It has been shown that administration of these prostaglandin 
drug products more than once daily may decrease the IOP lowering effect or cause paradoxical 
elevations in IOP. 
 
8 
USE IN SPECIFIC POPULATIONS 
 
8.1 
Pregnancy 
Teratogenic Effects: Pregnancy Category C. 
 
Reproduction studies have been performed in rats and rabbits. In rabbits, an incidence of 4 of 16 
dams had no viable fetuses at a dose that was approximately 80 times the maximum human dose, 
and the highest nonembryocidal dose in rabbits was approximately 15 times the maximum 
human dose. 
 
There are no adequate and well-controlled studies in pregnant women. XALATAN should be 
used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 
 
8.3 
Nursing Mothers 
 
It is not known whether this drug or its metabolites are excreted in human milk. Because many 
drugs are excreted in human milk, caution should be exercised when XALATAN is administered 
to a nursing woman. 
 
8.4 
Pediatric Use 
 
Safety and effectiveness in pediatric patients have not been established. 
 
8.5 
Geriatric Use 
 
No overall differences in safety or effectiveness have been observed between elderly and 
younger patients. 
 
10 OVERDOSAGE 
 


Protocol No. AKB-9778-CI-OS-2001 
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Intravenous infusion of up to 3 mcg/kg in healthy volunteers produced mean plasma 
concentrations 200 times higher than during clinical treatment and no adverse reactions were 
observed. Intravenous dosages of 
5.5 to 10 mcg/kg caused abdominal pain, dizziness, fatigue, hot flushes, nausea, and sweating. 
 
If overdosage with XALATAN occurs, treatment should be symptomatic. 
 
11 DESCRIPTION 
 
Latanoprost is a prostaglandin F2α analogue. Its chemical name is isopropyl-(Z)-
7[(1R,2R,3R,5S)3,5- dihydroxy-2-[(3R)-3-hydroxy-5-phenylpentyl]cyclopentyl]-5-heptenoate. 
Its molecular formula is C26H40O5 and its chemical structure is: 
 
 
Latanoprost is a colorless to slightly yellow oil that is very soluble in acetonitrile and freely 
soluble in acetone, ethanol, ethyl acetate, isopropanol, methanol, and octanol. It is practically 
insoluble in water. 
 
XALATAN® (latanoprost ophthalmic solution) 0.005% is supplied as a sterile, isotonic, 
buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of 
approximately 267 mOsmol/kg. Each mL of XALATAN contains 50 mcg of latanoprost. 
Benzalkonium chloride, 0.02% is added as a preservative. The inactive ingredients are: sodium 
chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, 
and water for injection. One drop contains approximately 1.5 mcg of latanoprost. 
 
12 CLINICAL PHARMACOLOGY 
 
12.1 
Mechanism of Action 
 
Latanoprost is a prostanoid selective FP receptor agonist that is believed to reduce the intraocular 
pressure (IOP) by increasing the outflow of aqueous humor. Studies in animals and man suggest 
that the main 
mechanism of action is increased uveoscleral outflow. Elevated IOP represents a major risk 
factor for glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic 
nerve damage and visual field loss. 
 
12.2 
Pharmacodynamics 
 
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Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
  
Aerpio — Company Confidential 
Page 87 of 89 
 
Reduction of the IOP in man starts about 3-4 hours after administration and maximum effect is 
reached after 8-12 hours. IOP reduction is present for at least 24 hours. 
 
12.3 
Pharmacokinetics 
 
Absorption 
 
Latanoprost is absorbed through the cornea where the isopropyl ester prodrug is hydrolyzed to 
the acid form to become biologically active. 
 
Distribution 
 
The distribution volume in humans is 0.16 ± 0.02 L/kg. The acid of latanoprost can be measured 
in aqueous humor during the first 4 hours, and in plasma only during the first hour after local 
administration. Studies in man indicate that the peak concentration in the aqueous humor is 
reached about two hours after topical administration. 
 
Metabolism 
 
Latanoprost, an isopropyl ester prodrug, is hydrolyzed by esterases in the cornea to the 
biologically active acid. The active acid of latanoprost reaching the systemic circulation is 
primarily metabolized by the liver to the 1,2-dinor and 1,2,3,4-tetranor metabolites via fatty acid 
β-oxidation. 
 
Excretion 
 
The elimination of the acid of latanoprost from human plasma is rapid (t1/2 = 17 min) after both 
intravenous and topical administration. Systemic clearance is approximately 7 mL/min/kg. 
Following hepatic β- oxidation, the metabolites are mainly eliminated via the kidneys. 
Approximately 88% and 98% of the administered dose are recovered in the urine after topical 
and intravenous dosing, respectively. 
 
13 NONCLINICAL TOXICOLOGY 
 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
 
Latanoprost was not carcinogenic in either mice or rats when administered by oral gavage at 
doses of up to 170 mcg/kg/day (approximately 2800 times the recommended maximum human 
dose) for up to 20 and 24 months, respectively. 
 
Latanoprost was not mutagenic in bacteria, in mouse lymphoma, or in mouse micronucleus tests. 
Chromosome aberrations were observed in vitro with human lymphocytes. Additional in vitro 
and in vivo studies on unscheduled DNA synthesis in rats were negative. 
 
Latanoprost has not been found to have any effect on male or female fertility in animal studies. 
 


Protocol No. AKB-9778-CI-OS-2001 
Amendment #2 Integrated 
 
May 17, 2020 
  
Aerpio — Company Confidential 
Page 88 of 89 
 
14 CLINICAL STUDIES 
 
14.1 
Elevated Baseline IOP 
 
Patients with mean baseline IOP of 24 – 25 mmHg who were treated for 6 months in multi-
center, randomized, controlled trials demonstrated 6 – 8 mmHg reductions in IOP. This IOP 
reduction with XALATAN 0.005% dosed once daily was equivalent to the effect of timolol 0.5% 
dosed twice daily. 
 
14.2 
Progression of Increased Iris Pigmentation 
 
A 3-year open-label, prospective safety study with a 2-year extension phase was conducted to 
evaluate the progression of increased iris pigmentation with continuous use of XALATAN once-
daily as adjunctive therapy in 519 patients with open-angle glaucoma. The analysis was based on 
observed-cases population of the 380 patients who continued in the extension phase. 
 
Results showed that the onset of noticeable increased iris pigmentation occurred within the first 
year of treatment for the majority of the patients who developed noticeable increased iris 
pigmentation. Patients continued to show signs of increasing iris pigmentation throughout the 
five years of the study. Observation of increased iris pigmentation did not affect the incidence, 
nature, or severity of adverse events (other than increased iris pigmentation) recorded in the 
study. IOP reduction was similar regardless of the development of increased iris pigmentation 
during the study. 
 
16 HOW SUPPLIED/STORAGE AND HANDLING 
 
XALATAN is a clear, isotonic, buffered, preserved colorless solution of latanoprost 0.005% (50 
mcg/mL). It is supplied as a 2.5 mL solution in a 5 mL clear low density polyethylene bottle with 
a clear polyethylene dropper tip, a turquoise high density polyethylene screw cap, and a tamper-
evident clear low density polyethylene overcap. 
 
2.5 mL fill, 0.005% (50 mcg/mL): Package of 1 bottle: NDC 0013-8303-04 
 
Storage: Protect from light. Store unopened bottle(s) under refrigeration at 2° to 8°C (36° to 
46°F). During shipment to the patient, the bottle may be maintained at temperatures up to 40°C 
(104°F) for a period not exceeding 8 days. Once a bottle is opened for use, it may be stored at 
room temperature up to 25°C (77°F) for 6 weeks. 
17. PATIENT COUNSELING INFORMATION 
 
Potential for Pigmentation 
Advise patients about the potential for increased brown pigmentation of the iris, which may be 
permanent. Inform patients about the possibility of eyelid skin darkening, which may be 
reversible after discontinuation of XALATAN [see Warnings and Precautions (5.1)]. 
 
Potential for Eyelash Changes 
 


Protocol No. AKB-9778-CI-OS-2001 
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May 17, 2020 
  
Aerpio — Company Confidential 
Page 89 of 89 
 
Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during 
treatment with XALATAN. These changes may result in a disparity between eyes in length, 
thickness, pigmentation, number of eyelashes or vellus hairs, and/or direction of eyelash growth. 
Eyelash changes are usually reversible upon discontinuation of treatment. 
 
Handling the Container 
 
Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or 
surrounding structures because this could cause the tip to become contaminated by common 
bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of 
vision may result from using contaminated solutions [see Warnings and Precautions (5.6)]. 
 
When to Seek Physician Advice 
 
Advise patients that if they develop an intercurrent ocular condition (e.g., trauma or infection) or 
have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid 
reactions, they should immediately seek their physician’s advice concerning the continued use of 
the multiple-dose container. 
 
Use with Contact Lenses 
 
Advise patients that XALATAN contains benzalkonium chloride, which may be absorbed by 
contact lenses. Contact lenses should be removed prior to administration of the solution. Lenses 
may be reinserted 15 minutes following administration of XALATAN. 
 
Use with Other Ophthalmic Drugs 
 
If more than one topical ophthalmic drug is being used, the drugs should be administered at least 
five (5) minutes apart. 
 
Pfizer Manufacturing Belgium NV Puurs, Belgium 
LAB-0135-13.0 


Study # AKB-9778-CI-OS-2001 – Final Clinical Study Report 
Final, Version 1.0, 18-Feb-2021 
 
Page 16-4 
• This section is updated to state: Analyses will be performed primarily on 
missing data imputed using multiple imputation techniques as defined in 
the primary estimand. Sensitivity analyses will be performed on 
observed data only and where worst time consistent observation within a 
subject is carried forward for withdrawal due to lack of efficacy or 
adverse event and last time consistent observation within a subject is 
carried forward for other missing data 
Amendment #2 
version 2.0 
17-May-2020 
• Clarified that at the Day 7 Visit, subjects were to bring their dosing diary, 
study medication kits and latanoprost to the site 
• Moved the requirement to perform biomicroscopy from the Day 7 Visit to 
the Day 14 Visit 8:00 hours 
• Moved the requirement to perform pachymetry and dilated ophthalmoscopy 
from 12:00 hours to 16:00 hours